Epidemiology

The first well-documented cases of asbestosis were reported in the early 1900s among asbestos textile workers. Through the 1920s and 1930s, reports emerged of asbestosis, pleural thickening, pleural calcification, and right ventricular failure in asbestos-exposed workers. Radiographic studies that began in the 1930s documented an asbestosis prevalence of 25% to 55% in these workers, especially among those with greater cumulative exposure. Early evidence from these studies suggested that exposure to higher concentrations of asbestos over longer periods of time resulted in increased risk for development of pulmonary fibrosis.

Asbestos use increased extensively in the early 1940s, and this mineral substance was used widely in the United States for the next 30 years. Asbestos use began to diminish when the Occupational Safety and Health Administration (OSHA) regulated workplace asbestos exposure in 1972. It is estimated that between 1940 and 1979, more than 27 million people had potential exposure in the United States alone. Data from a study of sheet metal workers examined between 1986 and 2004, reported by Welch and colleagues, found that asbestosis is continuing to occur even 50 years after first exposure. The study also found that the strongest predictor of nonmalignant asbestos-related disease in the workers was the cutoff year in which employment commenced: Prevalence was lowest among those who began working in the sheet metal industry after 1970 and highest among those who began work before 1949. With thousands of commercial applications and the mineral’s resistance to degradation, asbestos remains ubiquitous. Efforts have been made to limit ongoing exposure through abatement programs of asbestos removal from buildings and/or on-site encapsulation. Nevertheless, asbestos-related disability and mortality will continue well into the next decade.

Although the use of asbestos has been curtailed in many developed nations, in less-developed countries this inexpensive but hazardous material continues to be used widely. Many developed countries are now fast replacing the developed ones in the production and use of asbestos. Currently, Russia is the leading producer of asbestos worldwide, followed by China, Brazil, Kazakhstan, and Canada. More than 85% of the world production of asbestos is used to manufacture products in Asia and Eastern Europe. Although asbestos usage in developing countries is increasing, information about asbestos-related disease remains largely obscure. Epidemiologic questions have not been systematically researched.

In keeping with the long latency required before asbestosis becomes clinically apparent, all past and current asbestos workers must be considered to be at risk for development of this fibrosing lung disorder.

Etiology and Risk Factors

The minerals referred to herein as “asbestos” are a family of naturally occurring, flexible, fibrous hydrous silicates found in soil worldwide. Mined asbestos fibers are categorized as either long and curly (serpentine) or straight and rodlike (amphibole). The serpentine fiber, chrysotile, accounts for most of the commercially used asbestos, favored for its properties of heat resistance, flexibility, and ease of spinning for textiles. Five categories of amphiboles are recognized: crocidolite, amosite, anthophyllite, tremolite, and actinolite. These more rigid fibers are less commonly used but are still pathogenic. All major commercial forms have been associated with development of nonmalignant respiratory disorders and of lung cancer and mesothelioma, as discussed in Chapters 47, 65, and 70.

Asbestosis is the result of either direct or “bystander” exposure to asbestos-containing materials. Major sources of exposure are summarized in Table 52-2. During the first half of the 20th century, high-level exposures to asbestos dust occurred in the manufacturing of asbestos textiles and construction materials and in the construction and ship-building trades. Potential exposures still occur in the construction trades and in the process of asbestos abatement. Although the use of asbestos has been curtailed in many developed nations since the 1970s, in less developed countries this inexpensive but hazardous material continues to be used widely. High cumulative, occupational exposures in these settings are still commonplace.

Table 52-2 Major Asbestos Uses and Sources of Exposure

Environmental exposure to asbestiform fibers also is well described as the cause of nonmalignant and malignant asbestos-related lung disease in countries including Turkey, Greece, Japan, and China and the territory of New Caledonia. Exposure in these settings usually occurs when villagers in rural areas disturb natural soil deposits while working in fields or when applying whitewash prepared from these outcrops to their dwellings. In the United States, asbestos-related lung disease caused by nonoccupational exposures is a recently recognized problem, mostly in current and former residents of Libby, Montana. Amphibole asbestos–contaminated vermiculite was mined, milled, and processed near this small town for many years. Personal and commercial use of the contaminated mineral was widespread among residents. During a health screening in 2000 to 2001, nearly 18% of 6668 participants were noted to have pleural thickening on chest radiographs. Less than 1% had findings compatible with asbestosis.

A clear dose-response relationship between asbestos exposure and asbestosis has been recognized, although controversy remains concerning risks at low-level exposure. Risk for asbestosis varies widely among industries, with more disease seen in textile and construction workers than with those in mining. Development of the disease is associated with factors such as respirability of the fiber type, the cumulative dose of exposure, the capacity of the lung to clear the fibers, and the biopersistence of the asbestos. In general, the relative risk for development of asbestosis for asbestos workers increases in proportion to the asbestos exposure levels in the workplace. More severe disease has been associated with higher retention of asbestos fiber in the lungs. Typical asbestos fibers found in the lungs are 20 to 50 µm long and initially are deposited at the bifurcations of conducting airways. Thin fibers, of diameters less than 3 µm, translocate readily into the alveolar space, interstitium, and pleural space. Thicker fibers tend to be incompletely phagocytosed by alveolar macrophages and are retained in the lung, where they can trigger the inflammatory events that lead to fibrosis, as discussed next.

Histopathology and grading

Asbestosis is defined histopathologically as bilateral, diffuse interstitial fibrosis of the lungs caused by the inhalation of asbestos fibers (Figure 52-1). Gray streaks of fibrosis can be seen in the parenchyma along interlobar and interlobular septa. Later, the pleural surface becomes more nodular in appearance, and the parenchyma loses volume and elasticity and forms more fibrotic scars and honeycombing. The gross pathologic changes are most obvious in the lower lung zones bilaterally, with the worst disease nearest to the pleura.

Figure 52-1 Histopathologic features of asbestosis. Disease severity is classified according to a modified grading scheme from the College of American Pathologists, as described in the text. A, In this grade 1 lesion, fibrosis is limited to the peribronchiolar tissue and the walls of the respiratory bronchioles. B, Enlargement of a grade 1 lesion illustrates presence of asbestos bodies. C, In this grade 3 lesion, fibrosis extends into the interstitial space between the respiratory units and into the alveolar ducts. (A to C, Hematoxylin and eosin stain.)

(Courtesy Dr. Val Vallythan, National Institute for Occupational Safety and Health, Morgantown, West Virginia.)

The College of American Pathologists and Pulmonary Pathology Society has modified a 12-point grading scheme that has been shown to be consistently reproducible. The modified grading scheme, based on histologic criteria presented in the 2010 update on the original diagnostic criteria, consists of the following categories of disease severity:

Although histologic evidence of pulmonary fibrosis may occasionally be obtained in the course of clinical evaluation, routine lung biopsy and lavage are not recommended, and microscopic evidence is rarely required to diagnose asbestosis.

Occasionally, the determination of asbestos fibers in lung tissue, bronchoalveolar lavage, or sputum may be used to document past exposure, although these measurements are neither usually relied on nor required for the clinical diagnosis of asbestosis. Under light microscopy or by use of transmission electron microscopy, uncoated fibers or fibers coated with proteinaceous material may be detected. These coated fibers—so-called asbestos bodies or ferruginous bodies—are nonspecific, because they can be found in occupationally unexposed people, in occupationally exposed people who have no asbestos-related lung disease, and in workers who have asbestosis. Generally, the most exposed and most severely affected people have higher asbestos fiber counts, but a significant interlaboratory variability is found in these measures.

Pathogenesis

Some of the major events thought to be involved in the pathogenesis of asbestosis are summarized in Figure 52-2. Within minutes after asbestos fibers have been inhaled, a local tissue response is initiated at the bifurcations of terminal bronchioles and alveolar ducts. The first changes occur in epithelial cells and then in alveolar macrophages as they attempt to engulf and are pierced by the fibers. In addition to cell death, which leads to the release of macrophage contents, asbestos-activated macrophages release reactive oxygen species that directly damage the tissue through peroxidation and direct cytotoxicity. Asbestos also can induce toxicity by mechanisms independent of its ability to promote formation of reactive oxygen species.

Figure 52-2 Proposed pathogenesis of asbestosis. Asbestos fibers deposit at branch points in the distal airways and alveolar ducts, which prompts an inflammatory cascade characterized by cellular activation, recruitment, and injury. The result is fibroblast proliferation and extracellular matrix deposition in the interstitial space.

Increasing numbers of alveolar macrophages accumulate within 48 hours of first exposure. With chronic inhalation, a localized fibrosing alveolitis in the peribronchiolar region develops, followed by diffuse fibrotic scarring. Increasing the dose of asbestos increases the cellular response. A cascade of events ensues in which the macrophages and neutrophils release various cytokines (such as interleukin-8 and interferon-γ), chemokines, oxidants, and growth factors (such as fibronectin, platelet-derived growth factor, insulin-like growth factor, transforming growth factor-β, tumor necrosis factor-α, and fibroblast growth factor). These attract and alter the function of other inflammatory cells and resident cells, thereby promoting inflammation and fibrosis. The response of fibroblasts to these signals is to proliferate and produce the constituents of extracellular matrix (e.g., collagen, proteoglycans) in the pulmonary interstitium. Resident cells themselves are both targets and perpetrators of the fibrotic response. The pathogenesis of the chronic fibrotic response is complex and remains to be fully elucidated. It is clear, however, that this chronic response is progressive and that, apart from macrophage, neutrophil, and epithelial cells, a number of other cell types, such as lymphocytes and mast cells, contribute to the cycle of lung remodeling and fibrosis. Multiple, functionally overlapping, redundant inflammatory events occur in the lung simultaneously during the period of fibrogenesis. The consequence is an irreversible alteration in the structure and function of the lung.

Genetics

Asbestos exposure is the principal risk factor for the development of nonmalignant asbestos-related disorders. The genetic contribution to this risk is uncertain. A small number of cross-sectional, candidate gene studies have examined the possible contribution of genetic determinants of susceptibility to asbestosis. The glutathione S-transferases (GSTs) and N-acetyltransferases (NATs) are enzymes that aid in the detoxification of hazardous agents. Several small studies examined GST-null (deletion) polymorphisms and NAT2 slow acetylator genotype in workers with and without asbestosis. Results from these studies, although somewhat inconsistent suggest that people who have a constitutional, homozygous deletion in the GSTM1 gene that codes for GST class mu, as well as those who are NAT2 slow acetylators, may be at higher risk for asbestosis if exposed to sufficiently high levels of asbestos. On the basis of the premise that asbestos causes DNA damage and alters DNA repair, Zhao and colleagues demonstrated an association between polymorphisms of the DNA repair gene XRCC1 and the in vitro extent of asbestos-induced DNA damage in Chinese asbestosis cases versus that in nonasbestosis cases. In Spain, patients with asbestosis were more likely than exposed control subjects to be heterozygous for the α₁-antitrypsin polymorphism Pi*Z.

Radiologic Findings

Radiographically, asbestosis typically manifests in the lower lobes with irregular “reticular” markings toward the lung periphery and costophrenic angles (Figure 52-3). Linear opacities that resemble extensions of vascular markings may assume a netlike appearance. In early or less severe disease, the middle and upper lung zones may appear relatively spared. With progression, the linear and irregular opacities thicken and spread to the midlung zones, but rarely to the apex. The International Labour Organization (ILO) International Classification of Radiographs of Pneumoconioses characterizes each type of irregular opacity on the basis of increasing size and thickness as either s, t, or u, and on a scale of profusion (number) of opacities from normal profusion (0/−, 0/0, 0/1) to severe (3/2, 3/3, 3/+) (see Chapter 51, Table 51-2, for classification details). When irregular opacities are seen on the chest radiograph in conjunction with pleural thickening, the radiograph can be considered virtually pathognomonic for asbestosis. However, the chest radiograph lacks sensitivity, because 15% to 18% of symptomatic, biopsy-proven asbestosis cases are associated with a normal appearance on chest radiographs. Focal masses are uncommon except for those caused by rounded atelectasis.

Figure 52-3 Chest radiograph illustrating parenchymal abnormalities in asbestosis. Descriptive designations are from the International Labour Organization (ILO) classification for the radiographic appearance of pneumoconioses (see Chapter 51, Table 51-2). In this case, fine linear opacities of profusion category 1/0 can be seen in the middle and lower lung zones. Calcified pleural plaques are seen along the diaphragm bilaterally.

Computed Tomography

Conventional CT and high-resolution CT (HRCT) are more sensitive and specific than radiography for the diagnosis of pleural disease related to asbestos. HRCT, with use of 1- to 3-mm slices, is superior in sensitivity to plain chest radiography for detection of the fine reticular opacities in this disease. Of asbestos-exposed workers who have normal-appearing chest radiographs, 10% to 30% have HRCT scans suggestive of underlying interstitial disease. Thus, the HRCT scan can prove useful when the clinical index of suspicion for asbestosis is high but the chest radiograph appears normal. The most common HRCT findings in asbestosis are short, peripheral septal lines; subpleural curvilinear lines; ground glass attenuation; peripheral cystic lesions (honeycombing); parenchymal bands adjacent to areas of pleural thickening; and bronchiolar thickening (Figure 52-4). The density of interstitial abnormalities found on HRCT has been shown to correlate with the symptoms and with physiologic and inflammatory indicators of asbestosis, although in general, findings on both the chest radiograph and the HRCT scan demonstrate only a limited correlation with disease severity measured by assessment of lung physiology.

Figure 52-4 Asbestosis. This high-resolution computed tomography (CT) scan of the thorax was obtained in an asbestos-exposed worker with asbestosis and mild pleural thickening. Patchy subpleural accentuation of interstitial markings (thick arrows) with honeycombing (thin arrows) and traction bronchiectasis (white arrow) are classic for the CT appearance in advanced asbestosis.

Pulmonary Physiology Assessment

The earliest pathophysiologic changes include small airway dysfunction (e.g., decreased forced expiratory flow). As the disease progresses, restriction, evidenced by diminished total lung capacity and forced vital capacity, is observed, as is worsening gas exchange as measured by diffusing capacity and by arterial blood gas partial pressures determined under conditions of exercise and rest. These different parameters do not necessarily show the same degree of abnormality. Measures of gas exchange generally are more sensitive than measures of lung volumes in this disorder. Isolated, severe, obstructive airway disease usually is not attributable to asbestosis alone, although airflow obstruction may be present with or without restriction and occurs even in asbestos-exposed workers who were nonsmokers.