Berylliosis

Etiology

Exposure to beryllium is the underlying causative factor. Heavy beryllium-using industries include metal machine shops, electronics, defense industries, and beryllium extraction companies. Other industries include ceramics, automotive, aerospace, jewelry making, dental/alloy appliance, and computer. It appears that some people may have a genetic predisposition towards developing severe CBD.[5] Beryllium exposure typically occurs via inhalation of beryllium fumes or dust, but it can also be absorbed through skin contact. The organic forms of beryllium are rapidly excreted, but the insoluble inorganic particles can remain in the body for many years.

Epidemiology

CBD is a hypersensitivity granulomatous disease that occurs in 2 to 5% of beryllium-exposed workers.[6] Stopping exposure to beryllium has not been shown to stop the progression to CBD. Unless an individual lives very close to an industrial site, the general population is unlikely to develop acute beryllium disease (CBD) because ambient air beryllium levels are typically very low (<0.03 ng/m3).[5]

Pathophysiology

Exposure to beryllium can lead to a cell-mediated immune response in which T-cells become sensitized to beryllium. Each subsequent exposure triggers an immune response in which macrophages and CD4+ helper T-lymphocytes accumulate in the lungs. As this response progresses, macrophages, CD4+ T-lymphocytes, and plasma cells aggregate to form noncaseating granulomas that can progress to cause fibrosis of the lung.

Studies have revealed a genetic component to beryllium sensitivity. Specifically, beryllium-exposed workers with a mutation at the HLA-DPB1 Glu69 position have an increased prevalence of beryllium sensitization and CBD. The HLA-DPB1 gene is important for the function of MHC class II molecules on antigen-presenting cells. Beryllium and beryllium compounds are category 1 carcinogens and carcinogenic to both animals and humans.[7]

Histopathology

The key feature on histopathology is the nonnecrotizing granulomas in the lung, which mimic those seen in sarcoidosis.

History and Physical

The clinical manifestations of CBD are nonspecific.[8] The latency period between beryllium exposure and the onset of symptoms varies from three months to 30 years.[9] Common symptoms include fever, night sweats, weight loss, dry cough, and fatigue. Continued exposure causes noncaseating inflammatory granulomas. They also see granulomas in other chronic diseases, such as tuberculosis and sarcoidosis. CBD leads to restrictive lung disease (a decrease in diffusion capacity). Rarely, granulomas occur in other organs, such as the liver. The physical exam may reveal lymphadenopathy, crackles, rash, and hepatosplenomegaly.

Evaluation

A definitive diagnosis of berylliosis is based on the history, positive blood or bronchoalveolar lavage (BAL) beryllium lymphocyte proliferation test (BeLPT), and granulomatous inflammation on lung biopsy.[1] Establishing beryllium sensitivity is the first step, determined by the beryllium lymphocyte proliferation test (BeLPT). The test is performed by acquiring either peripheral blood or bronchial alveolar lavage fluid and culturing lymphocytes with beryllium sulfate.

Cells are then counted, and those with an elevated cell count are considered abnormal. Those exposed persons with two abnormal BeLPTs with peripheral blood or one abnormal and one borderline result are beryllium sensitized. Also, those with a single abnormal BeLPT using bronchial alveolar lavage fluid are considered sensitized. For patients with positive BeLPT, bronchoscopy with bronchoalveolar lavage (BAL) is performed to obtain cell counts.[1] Lastly, a tissue biopsy is obtained via bronchoscopy to meet the final criterion for the diagnosis of CBD.[10]

Chest radiography findings of berylliosis are non-specific. Early in the disease, radiographic findings are usually normal. In later stages, interstitial fibrosis, pleural irregularities, hilar lymphadenopathy, and ground-glass opacities have been reported. Findings on CT are not specific for berylliosis. Findings commonly seen on CT scans in people with berylliosis include parenchymal nodules in the early stages. One study found that ground-glass opacities were more commonly seen on CT scans in berylliosis than in sarcoidosis. In later stages, hilar lymphadenopathy, interstitial pulmonary fibrosis, and pleural thickening are found.

Other tests include:

• Arterial blood gas
• Pulmonary function tests
• Spirometry
• DLCO levels

Treatment / Management

The goals of treatment for berylliosis are to reduce symptoms and slow disease progression, as no cure is available. Although there is no evidence that stopping exposure to beryllium slows disease progression, it is still considered an accepted treatment approach. People with early stages, without lung function abnormalities or clinical symptoms, are periodically monitored with physical exams, pulmonary function tests, and radiography. All patients require influenza and pneumococcal vaccinations, as well as smoking cessation counseling. After the onset of clinical symptoms or significant abnormalities on pulmonary function testing, oxygen and oral corticosteroids are initiated, along with other supportive therapy as required.[1] 

The drugs of choice to treat chronic beryllium disease are corticosteroids. It usually requires a high starting dose, and the treatment duration is often for several months before symptom resolution is seen. Once symptoms subside, tapering of the steroids is necessary to prevent adverse effects. Patients who fail to respond to steroids are started on immunosuppressive agents such as methotrexate and azathioprine. Oral methotrexate at a weekly dose of 7.5 mg is given with folic acid 1 mg. Complete blood counts and liver function tests should be repeated 8 to 12 weeks at a time. Once a diagnosis of CBD is made, the patient needs lifelong follow-up with serial arterial blood gases, chest x-ray, and pulmonary function tests.[11] (B2)

Differential Diagnosis

Differential diagnosis includes sarcoidosis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, asthma, and other granulomatous lung diseases such as histoplasmosis, tuberculosis, and silicosis. It is estimated that 6% of all patients diagnosed with sarcoidosis may have CBD.[12]

Prognosis

Patients with beryllium sensitization in the absence of CBD do not require treatment but should undergo periodic evaluation. Among these patients, the risk of progression to CBD is increased compared with non-sensitized workers. Overall mortality rates are 5% to 38%.[13] CBD has a variable clinical course. A higher percentage of lymphocytes in bronchoalveolar lavage fluid correlates with greater illness severity.[14] Disability is common in people with preexisting lung disease and smokers. The granulomas lead to nodule formation, which can impair lung function.