You are in: eMedicine Specialties >
Pulmonology > Occupational Lung Diseases
Berylliosis
Article Last Updated: Nov 19, 2008
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Raed A Dweik, MD, FACP, FCCP, FRCPC, Associate Professor of Medicine; The Cleveland Clinic, Lerner College of Medicine; Director, Pulmonary Vascular Program, Respiratory Institute, The Cleveland Clinic Foundation
Raed A Dweik is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Federation for Medical Research, American Medical Association, American Thoracic Society, Royal College of Physicians and Surgeons of Canada, and Society of Critical Care Medicine
Editors: 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; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Gregg T Anders, DO, Medical Director, Great Plains Regional Medical Command , Brook Army Medical Center; Clinical Associate Professor, Department of Internal Medicine, Division of Pulmonary Disease, University of Texas Health Science Center at San Antonio; Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine; Zab Mosenifar, MD, Director, Division of Pulmonary and Critical Care Medicine, Director, Women's Guild Pulmonary Disease Institute, Executive Vice Chair, Department of Medicine, Cedars Sinai Medical Center; Professor of Medicine, David Geffen School of Medicine at UCLA
Author and Editor Disclosure
Synonyms and related keywords:
berylliosis, beryllium, Be, chronic beryllium disease, CBD, acute beryllium disease, acute chemical pneumonitis
Background
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.
Pathophysiology
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 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.
Frequency
United States
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.
History
- The most significant exposure to beryllium occurs in the occupational setting. Obtaining a good occupational history is critical to effective diagnosis.
- 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:
- Cough
- Chest pain
- Arthralgia
- Fatigue
- Weight loss
Physical
- Making the diagnosis of CBD before any physical signs can be detected now is common.
- Physical signs include the following:
- Inspiratory crackles on pulmonary auscultation
- Lymphadenopathy
- Skin rash (dermatitis)2
- Hepatosplenomegaly
Causes
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.3
- 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%).
Hypersensitivity Pneumonitis
Pulmonary Fibrosis, Idiopathic
Sarcoidosis
Tuberculosis
Other Problems to be Considered
Mycobacterial infections (other than tuberculosis)
Granulomatous disease caused by other metals such as aluminum or titanium
Lab Studies
- Blood BeLPT currently is the test of choice to identify beryllium workers who develop beryllium sensitization or chronic beryllium disease (CBD).4, 5, 6 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
1400 Jackson Street
Denver, CO 80206
(303) 388-4461 - Specialty Laboratories, Inc.
OncQuest
2211 Michigan Avenue
Santa Monica, CA 90404-3900
(310) 828-6543 or (800) 421-4449
Imaging Studies
- 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.7
- Typical findings on HRCT scan are ground glass opacification (see Media File 1), parenchymal nodules, or septal lines.
- Findings on HRCT scan are negative in 25% of patients with documented CBD.
Other Tests
- Pulmonary function tests include the following:
- Spirometry
- Lung volumes
- 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.
Procedures
- 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.
Histologic Findings
The hallmark of CBD is the presence of nonnecrotizing granulomas on lung biopsy (see Media File 2). These granulomas are histopathologically indistinguishable from sarcoid granulomas.
Medical Care
- 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.8
- 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.
Surgical Care
In end-stage cases, lung transplantation may be considered.
Consultations
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.
Drug Category: Corticosteroids
Have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Orasone, Sterapred) |
|---|
| Description | 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. |
|---|
| Adult Dose | Initiation phase: 20-40 mg PO qd or qod for 4-6 wk
Tapering phase: Reduce dose gradually over 2-6 mo to lowest dose that keeps disease under control as determined by patient symptoms and pulmonary function testing (eg, spirometry, lung volumes, DLCO, ABGs, exercise capacity)
Maintenance phase: Lowest effective dose used for maintenance; further tapering or complete discontinuation of corticosteroids generally is not recommended |
|---|
| Pediatric Dose | Not established |
|---|
| Contraindications | Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease |
|---|
| Interactions | Coadministration with estrogens may decrease prednisone clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
|---|
| Pregnancy | B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
|
|---|
| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use |
|---|
Drug Category: Cytotoxic agents
Inhibit cell growth and proliferation, which decreases immune system activity.
| Drug Name | Methotrexate (Folex PFS, Rheumatrex) |
|---|
| Description | 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. |
|---|
| Adult Dose | 5-10 mg PO qwk |
|---|
| Pediatric Dose | Not established |
|---|
| Contraindications | Documented hypersensitivity; alcoholism; hepatic insufficiency; documented immunodeficiency syndromes; preexisting blood dyscrasias (eg, bone marrow hypoplasia, leukopenia, thrombocytopenia, significant anemia); renal insufficiency |
|---|
| Interactions | Oral aminoglycosides may decrease absorption and blood levels of concurrent oral MTX; charcoal lowers MTX levels; coadministration with etretinate may increase hepatotoxicity of MTX; folic acid or its derivatives contained in some vitamins may decrease response to MTX; coadministration with NSAIDs may be fatal; indomethacin and phenylbutazone can increase MTX plasma levels; may decrease phenytoin serum levels; probenecid, salicylates, procarbazine, and sulfonamides, including TMP-SMZ, may increase effects and toxicity of MTX; may increase plasma levels of thiopurines |
|---|
| Pregnancy | X - Contraindicated; benefit does not outweigh risk
|
|---|
| Precautions | Monitor CBC counts monthly and liver and renal function q1-3mo during therapy (monitor more frequently during initial dosing, dose adjustments, or during risk of elevated MTX levels, eg, dehydration); MTX has toxic effects on hematologic, renal, GI, pulmonary, and neurologic systems; discontinue if significant drop in blood counts occurs; aspirin, NSAIDs, or low-dose steroids may be administered concomitantly with MTX (possibility of increased toxicity with NSAIDs, including salicylates, has not been tested) |
|---|
Further Outpatient Care
- 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.
Deterrence/Prevention
- 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.
Complications
Monitor for complications of corticosteroid therapy in patients receiving such therapy.
Prognosis
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.
Patient Education
Medical/Legal Pitfalls
- All patients with sarcoidosis should have a detailed occupational history obtained to rule out potential exposure to beryllium and the possibility of CBD.
- If occupational exposure to beryllium is suspected, a blood BeLPT should be performed.
- Due to the expanding use and applications of beryllium and its alloys, exposure can occur in places other than the traditional areas of beryllium manufacturing.
- The Medscape Medical Malpractice and Legal Issues Resource Center may be helpful.
| Media file 1:
A high-resolution CT scan of the chest showing the typical ground glass appearance in a patient with chronic beryllium disease, or berylliosis. |
 |  View Full Size Image | |
Media type: CT
|
| Media file 2:
A histopathology slide (hematosin and eosin stain) showing the typical well-formed granuloma of chronic beryllium disease, or berylliosis. |
 | View Full Size Image | |
Media type: Photo
|
- Saltini C, Winestock K, Kirby M, Pinkston P, Crystal RG. Maintenance of alveolitis in patients with chronic beryllium disease by beryllium-specific helper T cells. N Engl J Med. Apr 27 1989;320(17):1103-9. [Medline].
- Berlin JM, Taylor JS, Sigel JE, Bergfeld WF, Dweik RA. Beryllium dermatitis. J Am Acad Dermatol. Nov 2003;49(5):939-41. [Medline].
- Richeldi L, Sorrentino R, Saltini C. HLA-DPB1 glutamate 69: a genetic marker of beryllium disease. Science. Oct 8 1993;262(5131):242-4. [Medline].
- Barna BP, Culver DA, Yen-Lieberman B, Dweik RA, Thomassen MJ. Clinical application of beryllium lymphocyte proliferation testing. Clin Diagn Lab Immunol. Nov 2003;10(6):990-4. [Medline].
- Newman LS. Significance of the blood beryllium lymphocyte proliferation test. Environ Health Perspect. Oct 1996;104 Suppl 5:953-6. [Medline].
- Rossman MD, Kern JA, Elias JA, Cullen MR, Epstein PE, Preuss OP, et al. Proliferative response of bronchoalveolar lymphocytes to beryllium. A test for chronic beryllium disease. Ann Intern Med. May 1988;108(5):687-93. [Medline].
- Newman LS, Buschman DL, Newell JD Jr, Lynch DA. Beryllium disease: assessment with CT. Radiology. Mar 1994;190(3):835-40. [Medline].
- Kreiss K, Mroz MM, Newman LS, Martyny J, Zhen B. Machining risk of beryllium disease and sensitization with median exposures below 2 micrograms/m3. Am J Ind Med. Jul 1996;30(1):16-25. [Medline].
- Amicosante M, Berretta F, Franchi A, Rogliani P, Dotti C, Losi M, et al. HLA-DP-unrestricted TNF-alpha release in beryllium-stimulated peripheral blood mononuclear cells. Eur Respir J. Nov 2002;20(5):1174-8. [Medline].
- Culver DA, Dweik RA. Chronic beryllium disease. Clin Pulm Med. 2003;10:72-9.
- Kreiss K, Miller F, Newman LS, Ojo-Amaize EA, Rossman MD, Saltini C. Chronic beryllium disease--from the workplace to cellular immunology, molecular immunogenetics, and back. Clin Immunol Immunopathol. May 1994;71(2):123-9. [Medline].
- Kreiss K, Mroz MM, Zhen B, Wiedemann H, Barna B. Risks of beryllium disease related to work processes at a metal, alloy, and oxide production plant. Occup Environ Med. Aug 1997;54(8):605-12. [Medline].
- Kreiss K, Newman LS, Mroz MM, Campbell PA. Screening blood test identifies subclinical beryllium disease. J Occup Med. Jul 1989;31(7):603-8. [Medline].
- Kriebel D, Brain JD, Sprince NL, Kazemi H. The pulmonary toxicity of beryllium. Am Rev Respir Dis. Feb 1988;137(2):464-73. [Medline].
- Meyer KC. Beryllium and lung disease. Chest. Sep 1994;106(3):942-6. [Medline].
- MOSBY'S GENRx-The Complete Reference For Generic And Brand Drugs. 9th ed. St. Louis, Mo: Mosby-Year Book; 1999.
- Müller-Quernheim J, Gaede KI, Fireman E, Zissel G. Diagnoses of chronic beryllium disease within cohorts of sarcoidosis patients. Eur Respir J. Jun 2006;27(6):1190-5. [Medline].
- Newman LS. Immunology, genetics, and epidemiology of beryllium disease. Chest. Mar 1996;109(3 Suppl):40S-43S. [Medline].
- Newman LS, Kreiss K, King TE Jr, Seay S, Campbell PA. Pathologic and immunologic alterations in early stages of beryllium disease. Re-examination of disease definition and natural history. Am Rev Respir Dis. Jun 1989;139(6):1479-86. [Medline].
- Newman LS, Lloyd J, Daniloff E. The natural history of beryllium sensitization and chronic beryllium disease. Environ Health Perspect. Oct 1996;104 Suppl 5:937-43. [Medline].
- Newman LS, Mroz MM, Balkissoon R, Maier LA. Beryllium sensitization progresses to chronic beryllium disease: a longitudinal study of disease risk. Am J Respir Crit Care Med. Jan 1 2005;171(1):54-60. [Medline].
- Pappas GP, Newman LS. Early pulmonary physiologic abnormalities in beryllium disease. Am Rev Respir Dis. Sep 1993;148(3):661-6. [Medline].
- Saber W, Dweik RA. A 65-year-old factory worker with dyspnea on exertion and a normal chest x-ray. Cleve Clin J Med. Nov 2000;67(11):791-2, 794, 797-8, 800. [Medline].
- Stokes RF, Rossman MD. Blood cell proliferation response to beryllium: analysis by receiver-operating characteristics. J Occup Med. Jan 1991;33(1):23-8. [Medline].
Berylliosis excerpt Article Last Updated: Nov 19, 2008
|
