Inhalation of beryllium (Be) has been associated with 2 pulmonary syndromes, which are an acute chemical pneumonitis and a granulomatous lung disease known as chronic beryllium disease (CBD), or berylliosis.
In acute beryllium disease, the metal acts as a direct chemical irritant, causing a nonspecific inflammatory reaction (acute chemical pneumonitis). Due to improved industrial hygiene measures, acute beryllium disease virtually has disappeared and is not discussed in this article.
CBD continues to occur in industries where beryllium is manufactured and processed and workers are exposed to beryllium fumes or dust. It is clinically similar to other granulomatous diseases such as sarcoidosis.
To make the diagnosis of CBD, the following criteria need to be satisfied: (1) evidence of sensitization to beryllium by positive findings on blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT) (see Workup) and (2) the presence of compatible lung pathology (usually nonnecrotizing granulomas on lung biopsy).
Patients with a positive finding on blood BeLPT but no lung pathology are considered sensitized to beryllium, but they do not have CBD.
In patients with unclear or uncertain history of exposure to beryllium, a positive finding on BeLPT can be used as evidence of prior exposure.
The key to the pathogenesis of chronic beryllium disease (CBD) is a delayed-type hypersensitivity reaction in which beryllium most likely functions as a hapten and acts as a class II restricted antigen, stimulating local proliferation and accumulation in the lung of beryllium-specific T cells.
Beryllium exposure occurs primarily by inhalation of beryllium fumes or dust and contact through broken skin.
Most beryllium is excreted in the urine, and the pulmonary half-life ranges from several weeks to 6 months. Relatively insoluble chemical forms of beryllium may be retained for years.
Following inhalation of beryllium, large numbers of CD4+ lymphocytes accumulate in the lungs. These helper T cells demonstrate a marked proliferative response on exposure to beryllium.[1]
A study by Van Dyke et al found that a genetic factor, a glutamic acid at position 69 (E69), and exposure to beryllium contribute to the odds of developing chronic beryllium disease and beryllium sensitization.[2]
Beryllium not only has antigen-specific effects but also acts in nonspecific inflammatory ways to promote the cellular events leading to granuloma formation. It may induce changes in lung permeability and production of proinflammatory cytokines and growth factors that lead to granuloma formation and maintenance.
As the disease progresses, the granulomas become organized and eventually form small, fibrous nodules; progressive impairment of pulmonary function occurs.
A small percentage of exposed persons (1-10%) develop beryllium hypersensitivity and a portion of those go on to develop chronic disease.
Attack rates can be as high as 16% in selected worker populations with higher exposures. Usually the attack rate is highest in areas of highest exposure.
The disease also has been reported in populations with very low exposure, such as secretaries, who are not involved in the manufacturing process.
Mortality/Morbidity
A wide spectrum of morbidity exists with CBD. Some patients may be completely asymptomatic while others may progress to disabling lung dysfunction and death. The factors that determine progression of the disease are not clear.
The lung is the primary organ involved in CBD, and, as the disease progresses, granulomas become organized and eventually form small fibrous nodules that lead to progressive impairment of pulmonary function.
Inhaled beryllium is solubilized in the lungs and distributed primarily to bone, liver, and kidneys. However, other organs can be involved, including extrapulmonary lymph nodes, skin, salivary glands, myocardium, and skeletal muscle.
Race
Although strong evidence of genetic susceptibility exists, no racial preference has been shown.
Sex
Males and females are affected equally.
Age
CBD is reported in all age groups, from children (due to secondary exposure) to elderly people. Because this is mostly an occupationally acquired disease, the most commonly affected age group is adults.
The most significant exposure to beryllium occurs in the occupational setting. Obtaining a good occupational history is critical to effective diagnosis.[3]
Occupations with the highest potential for exposure to beryllium are those involved with primary production, metal machining, and reclaiming scrap alloys. Other high-exposure occupations are in the nuclear power, aerospace, and electronics industries. Some of the modern day uses of beryllium include the following:
Nuclear reactors and weapons
Inertial guidance systems
X-ray tube windows
Turbine rotor blades
Spark plugs
Laser tubes
Electrical components
Rocket engine liners
Ceramic applications
Springs, gears, aircraft brakes, aircraft engines, landing gear, and bearings
Oil and gas industries
Injection and blow mold tooling
Welding electrodes
Electrical contacts
Computer electronics
Automotive electronics
The number of industries that use beryllium is continuously expanding and the above list should not be viewed as exclusive. Beryllium has been used in a wide variety of products, including some bicycles and golf clubs.
Individuals using end products that contain beryllium, however, are not currently considered at risk for sensitization or disease. Only if the beryllium component is handled in a way that generates beryllium dust or particles (eg, sanding) would there be a risk.
With the use of the BeLPT, establishing the diagnosis of CBD before any symptoms develop now is common.
Dyspnea, usually of insidious onset, is the most common symptom. Other symptoms include the following:
Chronic beryllium disease (CBD), or berylliosis, is an occupationally acquired lung disease caused by exposure to beryllium, primarily by inhalation and contact through broken skin.
Genetic predisposition seems to have a major role in the development of CBD. A variant of the major histocompatibility complex HLA-DPb1(Glu 69) was found in 97% of patients with CBD and only in 30% of controls. In this genetic variant, glutamine is expressed instead of lysine at position 69 of the beta region of class II of the major histocompatibility complex.[5] This genotype is a marker for susceptibility to CBD, but it is not useful as a screening test due to its high prevalence in the general population (>30%).
Blood BeLPT currently is the test of choice to identify beryllium workers who develop beryllium sensitization or chronic beryllium disease (CBD).[6, 7, 8, 9, 10] Blood BeLPT has an integral role in reaching a diagnosis of CBD. The test involves exposing peripheral blood mononuclear cells in vitro to beryllium salts at varying concentrations for variable time intervals. Cell proliferation in the presence of beryllium indicates a positive test result. BeLPT is only performed in selected specialized laboratories, including the following:
Center for Epidemiologic Research
Oak Ridge Institute for Science and Education
Former Beryllium Worker Medical Surveillance Program
ORISE/CER, P.O. Box 117
Oak Ridge, TN 27831-0117
(865) 576-3115
(865) 241-6152
FAX (865) 241-2923
Cleveland Clinic Foundation
9500 Euclid Avenue
Cleveland, OH 44195-0001
(216) 444-2200
(216) 444-8844
(800) CCF-CARE (223-2273) ext 48844 or 55763
Hospital of the University of Pennsylvania
Pulmonary Immunology Laboratory
815 East Gates Building, 4300 Spruce Street
Philadelphia, PA 19104-4283
National Jewish Center for Immunology and Respiratory Medicine
Cellular Immunology Tests
Pulmonary Division and Occupational/Environmental Medicine Division
Findings on chest radiograph are normal in about half of the patients with documented chronic beryllium disease (CBD). Abnormal findings include hilar adenopathy and/or increased interstitial markings.
High-resolution CT (HRCT) scan of the chest is more sensitive than the chest radiograph.[11] Typical findings on HRCT scan are ground glass opacification (see the image below), parenchymal nodules, or septal lines. Findings on HRCT scan are negative in 25% of patients with documented CBD.
View Image
A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or berylliosis.
Diffusing capacity of lung for carbon monoxide (DLCO)
Arterial blood gases
Cardiopulmonary exercise
With disease progression, spirometry may show evidence of obstruction, restriction, or both. In an early study in 40 patients with advanced CBD, an obstructive pattern was observed in 39% of patients, a restrictive pattern in 20%, and a low DLCO in 36%.
The DLCO declines over the course of the disease.
The most sensitive test is abnormalities in gas exchange during exercise.
Laser microprobe mass spectrographic (LAMMS) analysis can be used to detect beryllium in histologic sections from lung biopsy specimens. This test is not necessary for the diagnosis and is not widely available.
Flexible fiberoptic bronchoscopy with BAL and transbronchial biopsies (TBBX) usually is the first invasive step necessary to confirm a suspected diagnosis of CBD. Patients with CBD usually have BAL lymphocytosis (>20% lymphocytes). The BeLPT test also can be performed on BAL cells. Transbronchial biopsies are sent for histology. A minimum of 6 high-quality biopsies should be obtained to optimize the yield. If TBBX results are negative but the suspicion for CBD remains high (eg, a positive result on BeLPT and/or a high percentage of lymphocytes in the BAL specimens), consider repeat bronchoscopy.
Open lung biopsy may need to be performed if repeat bronchoscopy findings still are negative.
The hallmark of CBD is the presence of nonnecrotizing granulomas on lung biopsy (see the image below). These granulomas are histopathologically indistinguishable from sarcoid granulomas.
View Image
A histopathology slide (hematosin and eosin stain) showing the typical well-formed granuloma of chronic beryllium disease, or berylliosis.
Prevention is a key component in the management of chronic beryllium disease (CBD). The current Occupational Safety and Health Administration (OSHA) standards for workplace air require an 8-hour, time-weighted average maximum permissible level of 2 mcg/m3 along with a peak level of 25 mcg/m3. The beryllium concentration in the air around factories is not to exceed 0.01 mcg/m3. Some studies suggest that the current standard of 2 mcg/m3 is not protective.[12] Although no proof exists that cessation of exposure to beryllium improves the disease course or slows the progression, advising all patients with CBD to avoid any further exposure to beryllium is prudent.
Due to the use of BeLPT testing to screen workers exposed to beryllium, many cases now are diagnosed very early in the course of the disease, before radiographic or physiologic changes are observed and before symptoms or physical signs develop.
The natural history of the disease is not clear in patients who have granulomas on TBBX but who are asymptomatic and have no physiologic or radiographic abnormalities.
The current indications for therapy include the presence of symptoms, abnormal pulmonary function test results, or a decline in pulmonary function over time. In the absence of any of these criteria, no therapy is recommended. Close monitoring of symptoms and follow-up pulmonary function testing is recommended.
No controlled studies for CBD therapy are available. Based on the pathogenesis of the disease (immune-mediated) and due to the similarities with sarcoidosis, CBD is treated with corticosteroids. When corticosteroid therapy fails or in patients who develop significant adverse effects, methotrexate (MTX) may be considered.
A team approach involving industrial hygiene, occupational health, and pulmonary specialists is necessary for prevention, screening, early diagnosis, and appropriate treatment of CBD.
Corticosteroids are the treatment of choice for chronic beryllium disease (CBD). No consensus on the dose or duration of corticosteroid therapy exists. A starting dose of 20-40 mg of oral prednisone daily or every other day usually is used. After an initial 4-6 weeks of therapy, prednisone is tapered, depending on the clinical response.
MTX may be considered in patients who do not respond to corticosteroids or in patients who develop significant adverse effects on corticosteroid therapy.
Clinical Context:
Immunosuppressant for treatment of autoimmune disorders. May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. A 3-phase approach is suggested.
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
Clinical Context:
Unknown mechanism of action in treatment of inflammatory reactions. May affect immune function. Ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust dose gradually to attain satisfactory response.
Chronic beryllium disease (CBD, berylliosis) patients should be monitored by a pulmonologist. The frequency of follow-up depends on the extent of the disease and the need for therapy.
Prevention is a key component in the management of CBD.
The current OSHA standards for workplace air require an 8-hour, time-weighted average maximum permissible level of 2 mcg/m3, along with a peak level of 25 mcg/m3. The beryllium concentration in the air around factories is not to exceed 0.01 mcg/m3. Some recent studies suggest that the current standard of 2 mcg/m3 is not protective.
Although no proof exists that cessation of exposure to beryllium improves the disease course or slows the progression, advising all patients with CBD to avoid any further exposure to beryllium is prudent.
The natural history of CBD remains unclear. While many patients are asymptomatic at the time of diagnosis and may remain so, some patients experience progressive decline in their lung function that may progress to respiratory failure requiring oxygen supplementation and, in certain advanced cases, lung transplantation.
Certain individuals with beryllium sensitization or chronic beryllium disease may be eligible for government benefits and compensation under the Energy Employees Occupational Illness Compensation Program. More information is available on the US Department of Labor Web site, Division of Energy Employees Occupational Illness Compensation.
For excellent patient education resources, see eMedicineHealth's patient education article Bronchoscopy.
Raed A Dweik, MD, MBA, FACP, FRCPC, FCCP, FCCM, FAHA, Professor of Medicine, Cleveland Clinic Lerner College of Medicine;
Chairman, Respiratory Institute, Cleveland Clinic
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Zab Mosenifar, MD, FACP, FCCP, Geri and Richard Brawerman Chair in Pulmonary and Critical Care Medicine, Professor and Executive Vice Chairman, Department of Medicine, Medical Director, Women's Guild Lung Institute, Cedars Sinai Medical Center, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
Gregg T Anders, DO Medical Director, Great Plains Regional Medical Command , Brooke Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio
Disclosure: Nothing to disclose.
Oleh Wasyl Hnatiuk, MD Program Director, National Capital Consortium, Pulmonary and Critical Care, Walter Reed Army Medical Center; Associate Professor, Department of Medicine, Uniformed Services University of Health Sciences
Oleh Wasyl Hnatiuk, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and American Thoracic Society
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