10 Beryllium-Related Diseases
David A. Lynch
D.A. Lynch, MD
Professor of Radiology and Medicine, Department of Radiol- ogy, Box A030, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, Denver, CO 80262, USA
CONTENTS
10.1 Health Effects of Beryllium Disease 249 10.2 Clinical Presentation/Pathology 250 10.3 Imaging Appearances 250
10.4 Comparison of Chronic Beryllium Disease and Sarcoidosis 254
10.5 Beryllium and Lung Cancer 254 10.6 Summary 256
References 256
response to inhaled beryllium, and (2) its incidence and severity is not always related to the intensity and duration of exposure; in fact, it may occur with relatively trivial exposure.
Inhalation of beryllium in the form of dust, fumes, or vapors can lead to a beryllium-mediated T-cell immune response in exposed workers (Maier 2002a). Such sensitization is detected by abnormal lymphocyte proliferation in response to beryllium.
The beryllium lymphocyte proliferation test may be performed on lymphocytes obtained from periph- eral blood or from broncho-alveolar lavage fluid, with the latter being more sensitive. Sensitization is found in between 2% and 19% of exposed workers.
Up to 30% of sensitized workers progress to biopsy- proven chronic beryllium disease (Newman et al.
2005). Beryllium sensitization may occur after as little as 9 weeks of exposure, while CBD may develop after only 3 months (Newman et al. 2001). However, because the latency may be as long as 40 years, past employment history must be rigorously evaluated in individuals presenting with findings suggestive of this condition. Although the exposure response relationship for beryllium sensitization and CBD is nonlinear, higher exposures may be associated with higher rates of sensitization and CBD (Maier 2002b).
Beryllium sensitization is usually detected during workplace screenings or medical surveillance pro- grams. A diagnosis of beryllium sensitivity requires two abnormal beryllium lymphocyte proliferation test results. If sensitization is detected, a thorough clinical, physiological and radiological evaluation is required, and transbronchial lung biopsy is usu- ally performed. If granulomatous inflammation is found on biopsy, the worker receives the diagnosis of CBD. Beryllium sensitization is diagnosed if the patient has no symptoms or radiological, physi- ological, or pathological abnormalities attribut- able to CBD (Maier 2002a). Once sensitization is diagnosed, serial follow-up is usually performed to watch for the development of CBD (Newman, Mroz et al. 2005).
10.1
Health Effects of Beryllium Disease
There are two distinct types of lung injury related to beryllium exposure: an acute chemical pneumo- nitis (acute berylliosis) and a chronic granuloma- tous disease similar to sarcoidosis [chronic beryl- lium disease (CBD)]. With modern manufacturing safeguards, acute berylliosis has become rare, but chronic beryllium disease remains an important cause of disability in exposed workers. CBD is com- monly classified as a pneumoconiosis, because it represents a reaction of the lungs to inhalation of an inorganic dust particle. However, it differs from the classic pneumoconioses in the following ways:
(1) it represents a granulomatous hypersensitivity
Table 10.1. Health effects of beryllium exposure
Condition Imaging manifestations Acute berylliosis Chemical pneumonitis Beryllium sensitization None
Chronic beryllium disease Adenopathy, nodules, ground glass abnormality
Lung cancer Lung nodules or masses
Exposure to beryllium occurs in a variety of high- technology industries (including aerospace, ceram- ics, dentistry and dental supplies, nuclear weapons and reactors, recycling, telecommunications, and several others) where workers may be at risk for dis- ease from either direct or indirect exposure to the metal. Beryllium machinists may be at highest risk for sensitization and CBD (Newman, Mroz et al.
2005). However, CBD has also been found in com- munities surrounding beryllium-manufacturing facilities and in office workers with relatively trivial exposure in these plants (Maier 2002a).
10.2
Clinical Presentation/Pathology
Acute berylliosis (Hooper 1981), which usually results from a single intense exposure, is now rare with appropriate workplace protection. It manifests as an acute tracheobronchitis and pulmonary edema.
Before the advent of widespread workplace screening using the beryllium lymphocyte prolif- eration test results, individuals with CBD presented with chronic respiratory symptoms of cough and progressive shortness of breath, often associated with systemic symptoms of fatigue, night sweats, arthralgias, myalgias, and weight loss (Maier 2002a). These cases were often quite advanced, with crackles on lung examination, clubbing, cyanosis, and evidence of pulmonary hypertension and cor pulmonale. Although some patients still present with more advanced disease, workplace screening with the lymphocyte proliferation test has allowed earlier detection of CBD, often before the onset of symptoms. The clinical significance of CBD diag- nosed in this way remains unclear, as it is unclear how many patients with biopsy-proven CBD prog- ress to clinically significant disease (Cullen 2005).
Physiological evaluations of individuals with CBD detected using workplace screening reveals a variety of physiological patterns, including normal, obstructive, restrictive, or mixed spirometric pat- terns. Diffusion capacity for carbon monoxide may be normal or reduced (Maier 2002a). An important clinical difference between CBD and sarcoidosis is that extrathoracic involvement is rare in CBD.
The histological appearance of chronic beryllium disease is indistinguishable from that of sarcoid- osis, with non-caseating granulomas accompanied by mononuclear cell infiltrates and variable inter- stitial fibrosis (Maier 2002a).The granulomas are
primarily found along the bronchovascular bundle, in the bronchial submucosa, in the pulmonary inter- stitium, and occasionally in regional lymph nodes.
However, absence of granulomas on transbronchial or thoracoscopic lung biopsy does not exclude a diagnosis of CBD (Maier 2002a). Diagnostic crite- ria for chronic beryllium disease include: (1) a his- tory of beryllium exposure; (2) demonstration of a beryllium-specific cell-mediated immune response;
and (3) granulomas and/or mononuclear cell infil- trates on biopsy in the absence of infection.
With early diagnosis, no treatment may be needed.
With symptomatic, progressive, or impairing chronic beryllium disease, oral corticosteroids are used. Other immunosuppressive agents and lung transplantation should be considered if there is no response to cor- ticosteroids. Removal of sensitized individuals and those with CBD from further beryllium exposure is generally recommended, but it is unclear whether this influences the clinical course of the disease.
10.3
Imaging Appearances
The radiographic and computed tomography (CT) appearances of chronic beryllium disease are simi- lar to those of sarcoidosis, though mediastinal and hilar lymphadenopathy is less common. In a study of 28 patients with CBD, only 15 (54%) had abnor- mal chest radiographs (Newman et al. 1994). Most of these patients had diffuse symmetric parenchymal abnormality, with relatively mild profusion [Category 1 according to the International Labour Organization (ILO) classification system]. Of these patients, 11 had predominantly round nodules (p, q, or r according to the ILO classification system), while the remaining 4 had small irregular opacities. Typically, the abnor- malities predominate in the upper lobes (Fig. 10.1).
Hilar or mediastinal adenopathy was seen in 6 cases (21%), always in the presence of parenchymal opaci- ties (Newman, Buschman et al. 1994). Adenopathy without parenchymal abnormality appears to be rare.
In advanced disease, there is progressive volume loss
and hilar distortion. Conglomerate masses were seen
on chest radiographs in 2 (7%) of the 28 cases in the
series described above, while 3 (11%) had enlargement
of central pulmonary arteries suggesting pulmonary
hypertension. Because patients with beryllium expo-
sure may also have had exposure to asbestos, changes
of asbestos-related pleural disease or even asbestosis
may be found.
On thin-section CT, enlarged lymph nodes are detected in the pulmonary hila in 32% of patients with CBD and in the mediastinum in 25% (Fig. 10.2) (Newman, Buschman et al. 1994). As with the chest radiograph, adenopathy was found on CT only in the presence of parenchymal abnormalities. The adenop- athy may show an amorphous or eggshell pattern of calcification similar to that seen in sarcoidosis and distinct from the more punctuate dense calcification seen in patients with previous tuberculosis or histo-
Fig. 10.1. Chest radiograph in a patient with advanced chronic beryllium disease shows abnormality predominating in the upper lobes, consisting of coarse well-defi ned nodules, which appear to coalesce in areas. Some of the nodules appear calci- fi ed. There is moderate upper lobe volume loss with superior hilar retraction and some anatomic distortion. Hilar enlarge- ment is likely due to a combination of adenopathy and pulmo- nary arterial enlargement due to pulmonary hypertension
Fig. 10.2. Computed tomography image obtained just above the aortic arch in a patient with chronic beryllium disease shows multiple moderately enlarged pretracheal and paratra- cheal nodes (arrows)
Fig. 10.3. Computed tomography through the subcarinal region in a patient with chronic beryllium disease shows right hilar enlargement due to adenopathy. A mildly enlarged left subcarinal node (arrow) shows an amorphous pattern of calcifi cation
Fig. 10.4. Computed tomography through the subcarinal region in a patient with chronic beryllium disease shows slightly hyperdense, mildly enlarged mediastinal nodes (arrows)
plasmosis (Fig. 10.3). Even if not overtly calcified, the nodes may be slightly hyperdense (Fig. 10.4).
Nodules are seen in about 60% of cases, often clus-
tered together around the bronchi, interlobular septa,
or in the subpleural region (Fig. 10.5) (Newman,
Buschman et al. 1994). Subpleural clusters of nod-
ules may form pseudo-plaques, and pleural irregu-
larity is found in about 25%. As in sarcoidosis, even
small subpleural nodules may be readily visible along
the major fissures (Fig. 10.5). Although the nodules
are usually well defined and 2–5 mm in size, fine
micronodules, quite similar to those found in hyper-
sensitivity pneumonitis, may also be seen (Fig. 10.6).
Ground glass opacity (Fig. 10.7), bronchial wall thickening (Fig. 10.8), and thickening of interlobular septa (Fig. 10.9) are common CT features, found in 32%, 46%, and 50% of cases, respectively (Newman, Buschman et al. 1994). The ground glass abnormal- ity is commonly predominantly peribronchovascu- lar (Fig. 10.6, Fig. 10.8). Bronchial wall thickening, although commonly related to cigarette smoking, appears to be more common in subjects with CBD than in control subjects. Reticular opacity (Fig. 10.10) and architectural distortion (Fig. 10.11) may occur.
The prevalence of honeycombing has ranged from
7% in a series including cases detected using medical screening (Newman, Buschman et al. 1994) to 38%
in a series of 8 patients who presented with clinically established disease (Harris et al. 1993). In advanced disease, subpleural cysts and conglomerate masses (Fig. 10.11) may be found. Bronchial stenoses may rarely occur (Iles 1981). As with sarcoidosis, the nod- ules, masses, and adenopathy may show large areas of increased lung attenuation, presumed to represent calcification (Gevenois et al. 1994).
On follow-up evaluation of subjects with CBD, the CT findings of nodules, ground glass abnormal-
Fig. 10.5. Thin-section computed tomography through thelower lobes shows nodules less than 5 mm in diameter, some of which are peribronchovascular (arrows), but most of which are subpleural (arrowheads)
Fig. 10.6. Thin-section CT through the left upper lobe in a patient with chronic beryllium disease shows quite widespread, subtle, fi ne micronodules (arrows). There is a peribronchovas- cular patch of ground glass abnormality more posteriorly
Fig. 10.7. a Thin-section CT through the lower lungs in a patient with chronic beryllium disease shows a large patch of ground glass abnormality in the lingula. b Follow-up 15 months later, following removal from exposure and corticosteroid treatment shows signifi cant improvement
a b
Fig. 10.8. Thin-section computed tomography through the mid-lungs in a patient with chronic beryllium disease shows marked airway wall thickening and mild, predominantly peri- bronchovascular, ground glass abnormality
Fig. 10.9. Thin-section computed tomography through the lower lungs in a patient with chronic beryllium disease shows fi ne anterior septal thickening (arrows, arrowheads)
Fig. 10.10. a Thin-section computed tomography through the lung bases in a patient with chronic beryllium disease shows asymmetric reticular and ground glass abnormality. b Thin-section computed tomography at a slightly lower level 13 months later shows progression of reticular abnormality, particularly on the left
Fig. 10.11. Thin-section computed tomography through the upper lungs in a patient with advanced chronic beryllium dis- ease shows multiple predominantly subpleural nodules, with a conglomerate mass on the right, associated with marked dis- tortion and dilation of segmental bronchi. Anterior displace- ment of the right major fi ssure indicates signifi cant upper lobe volume loss. An azygos lobe is present
a b
ity, and septal thickening are commonly reversible (Fig. 10.12). As in sarcoidosis (Brauner et al. 1992;
Murdoch and Muller 1992), architectural distortion, cysts, and honeycombing are usually irreversible.
In the study by Newman et al. cited above, the sensi- tivity of the chest radiograph for biopsy-proven chronic beryllium disease was approximately 45%, compared with approximately 89% for thin-section CT (Newman, Buschman et al. 1994). However, 4 study patients who were cigarette smokers had bronchial wall thicken- ing as the sole abnormality on thin-section CT. If this non-specific abnormality was excluded, the sensitivity of thin-section CT for detection of beryllium disease was 75%. In reviewing the 13 patients in this series who presented through medical screening and had normal chest radiographs, CT showed at least one abnormality in 10 (77%) and was entirely normal in the remaining 3.
Findings detectable on CT but not on chest radiograph in these cases included ground glass abnormality, septal thickening, and nodules. The prognostic significance of normal or abnormal CT in screen-detected patients with CBD has not been evaluated.
A study by Daniloff et al. evaluated the interob- server variation of assessment of thin-section CT find- ings and the relationship between these findings and physiological impairment (Daniloff et al. 1997). Mod- erate intra-observer and inter-observer agreement was found for assessment of extent of ground glass abnor- mality, septal thickening, nodules, and percentage of abnormal lung. Interobserver variation was higher for bronchial wall thickening. All of the thin-section CT measures showed significant inverse correlations with the percent predicted forced expiratory volume in 1 s (FEV
1), while the percentage of abnormal lung corre- lated inversely with percent predicted values of forced vital capacity and total lung capacity. All measures of CT abnormality correlated significantly with indices of impaired gas exchange on exercise. However, the strength of the correlations was not strong (Spearman rho values between 0.3 and 0.7). These findings are consistent with previous studies evaluating the corre- lation between CT findings of sarcoidosis and physi- ological impairment (Brauner et al. 1989; Muller et al. 1989; Remy-Jardin et al. 1994).
10.4
Comparison of
Chronic Beryllium Disease and Sarcoidosis
Although the clinical, histological, and imaging manifestations of chronic beryllium disease are
indistinguishable from those of sarcoidosis, it should be noted that extrathoracic manifestations are very uncommon in berylliosis. Also, hilar and mediasti- nal adenopathy without parenchymal radiographic abnormality is a common radiographic presentation of sarcoidosis but has not been described in beryl- liosis. Despite these differences, the most important message for the radiologist is that berylliosis must always be considered in the differential diagnosis of sarcoidosis. Listing berylliosis as part of the differ- ential diagnosis of sarcoidosis may lead the clinician to obtain a more detailed occupational history.
10.5
Beryllium and Lung Cancer
Animal studies have demonstrated that beryllium can induce cancer in a number of species (Finch et al. 1996, Newman 1994). On histological evaluation, these animal tumors were mainly adenocarcinomas or bronchioloalveolar carcinoma (Finch, Hoover et al. 1996) (Gottschall 2002). Several large epide- miological studies have reported an increased risk for lung cancer in beryllium-exposed workers, with increased standardized mortality ratios (SMR) of 1.37 to 1.97 in beryllium production workers and as high as 3.14 for individuals who have had acute beryllium disease (Infante et al. 1980; Wagoner et al. 1980) (Mancuso and el-Attar 1969; Mancuso 1970; Mancuso 1980). A study of cases from the US Beryllium Case Registry supported an increased risk for lung cancer in those with chronic beryllium disease (SMR: 1.57) and those with acute beryllium disease (SMR: 2.32) (Steenland and Ward 1991).
In workers at beryllium-processing plants, the SMR for lung cancer was increased at 1.26, even after allowing for the effects of smoking (Ward et al.
1992). Most, if not all, of these studies dealt with heavily exposed workers, and it seems that the risk of cancer increases with increasing levels of expo- sure (Sanderson et al. 2001). Data regarding the carcinogenic risks of lighter exposure levels remain unclear. However, the quality of the evidence from the animal and human studies cited above was suffi- cient to allow the International Agency for Research on Cancer (IARC) to list beryllium as a known car- cinogen in humans (Gottschall 2002).
Lung cancer should be suspected on chest radio-
graphs or CT of patients with CBD if there is a domi-
nant nodule or mass and if adenopathy is markedly
asymmetric (Fig. 10.13).
Fig. 10.13. a Chest radiograph in a patient with chronic beryl- lium disease shows a focal left lower lung nodule (arrow), with left hilar enlargement (arrowhead). b Computed tomography (CT) through the lower lungs confi rms an irregular lingular nodule, proven to represent lung cancer. c CT through the mediastinum confi rms enlarged left hilar and mediastinal nodes (arrows)
Fig. 10.12. a Prone high resolution computed tomography (CT) through the lower lungs in a patient with chronic beryllium disease shows moderate interlobular septal thickening and ground glass abnormality. b Follow-up CT 15 months later shows decrease in ground glass abnormality and septal thickening
a b
a
b
c
10.6 Summary
Beryllium exposure occurs in a wide variety of occupations. It may cause acute berylliosis (cur- rently very rare), beryllium sensitization, chronic beryllium disease, or lung cancer. Imaging mani- festations of chronic beryllium disease are generally similar to those of sarcoidosis, with nodules, ground glass abnormality, septal thickening, conglomerate masses, and mediastinal or hilar lymphadenopathy.
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