Berylliosis

Inhalation of beryllium (Be) has been associated with two 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. ^[1] Signs and symptoms of CBD can include shortness of breath, an unexplained cough, fatigue, weight loss, fever, and night sweats. Some workers may develop severe symptoms very quickly, while others may not experience signs and symptoms until months or years after their exposure to beryllium. CBD can continue to progress even after exposure has been removed. Beryllium sensitization (BeS) is affected by both exposure and genetic characteristics and only individuals with BeS are at risk for developing CBD. Cross-sectional studies of workers in various U.S. industries have found that the prevalence of BeS ranged from 0.9 to 14.6%, and the prevalence of CBD ranged from 0.0 to 7.8%. ^[2]

Due to the use of the beryllium lymphocyte proliferation test (BeLPT) 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. Patients with a positive finding on blood BeLPT but no lung pathology are considered sensitized to beryllium, but they do not have CBD. 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).

The current indications for therapy include the presence of symptoms, abnormal pulmonary function test results, or a decline in pulmonary function over time. ^[2] In the absence of any of these criteria, no therapy is recommended. Close monitoring of symptoms and follow-up pulmonary function testing is recommended.

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. ^[3]

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. ^[4]

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. 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.

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. Although BeS is required for the development of CBD, not all individuals with BeS progress to CBD. Both genetic factors and higher exposure contribute to risk of CBD, but only genetic factors appear to be associated with BeS. ^[5] .

In 1993, 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. ^[6] All Glu69 alleles do not confer equal risk, as those with greater negative surface charge (ie, greater binding affinity) are related to increased risk of CBD. ^[5]

As of 2016, 630 known DNA sequence variants of HLA-DPB1 have been identified, of which 204 are Glu69 alleles (coded as E69). Presence of one copy of the most common E69 allele, HLA-DPB1*02:01, confers an odds ratio of 2 for CBD compared with workers having no E69 alleles; but having any two E69 alleles or having one of the E69 alleles with a −9 (most electronegative) charge on the surface of the molecule is associated with much higher odds ratios, up to 30.8 for CBD, compared with workers with no E69 allele. The subset of HLA-DPB1*E69 alleles with −9 surface charge includes *93:01, *37:01, *29:01, *17:01, *16:01, *10:01, *09:01, *08:01, and *06:01. ^[7]

The genotype associated with the highest CBD prevalence (72.7%) contains the most common E69 allele (−7-charged) paired with an E69 −9-charged allele, HLA-DPB1*02:01:02/DPB1*17:01. The genotype associated with the second highest CBD prevalence (53.3%) is HLA-DPB1*04:01/DPB1*10:01—a non-E69 −3-charged allele paired with an E69 −9-charged allele. The genotype HLA-DPB1*02:01:02/HLA-DPB1*02:01:02 (homozygous for the most common E69 allele) has a 33.3% CBD prevalence. ^[7]

Longitudinal studies of defined cohorts showed that 1.0 to 16.2% of exposed workers developed BeS over time, and 0.0 to 11.0% developed CBD. Usually the attack rate is highest in areas of highest exposure. Longitudinal studies of workers hired after a comprehensive preventive program showed lower levels of BeS. ^[2]

Although strong evidence of genetic susceptibility exists, no racial preference has been shown and males and females are affected equally. 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.

Due to the persistence of beryllium in the lung years after exposure cessation, the natural history of CBD is characterized by a gradual decline in lung function, with one-third of untreated patients historically progressing to end-stage respiratory insufficiency. ^[5]

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 Act. More information is available on the US Department of Labor Web site, Division of Energy Employees Occupational Illness Compensation.

For patient education resources, see the Lungs Center and Bronchoscopy.