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 ceramic, 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 tends to occur via inhalation of beryllium fumes or dust, but it can also be absorbed following skin exposure. 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 or CBD because ambient air levels of beryllium are normally very low (< 0.03 ng/m3)[5].

Pathophysiology

Exposure to beryllium can lead to a cell-mediated immune response where T-cells become sensitized to beryllium. Each subsequent exposure leads to an immune response involving macrophages and CD4+ helper T-lymphocytes accumulating in the lungs. As this response proceeds, macrophages, CD+4 T-lymphocytes, and plasma cells aggregate to form noncaseating granulomas that evolve to cause fibrosis of the lung. Studies have revealed there is a genetic component to beryllium sensitivity. Specifically, those beryllium-exposed workers with a mutation at the HLA-DPB1 Glu69 position have increased the prevalence of beryllium sensitization and CBD. The HLA-DPB1 gene is important for MCH class II molecule function 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, and this is determined by the beryllium lymphocyte proliferation test (BeLPT). The test is performed by acquiring either peripheral blood or fluid from a bronchial alveolar lavage and culturing lymphocytes with beryllium sulfate. Cells are then counted, and they consider those with an elevated number of cells abnormal. Those exposed persons with two abnormal BeLPTs with peripheral blood or one abnormal and one borderline result are beryllium sensitized. Also, those with one abnormal BeLPT with fluid from a bronchial alveolar lavage is 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 from bronchoscopy to fulfill the last criterion for CBD diagnosis. [10]

Chest radiography findings of berylliosis are non-specific. Early in the disease, radiography 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 that are common in CT scans of people with berylliosis include parenchymal nodules in early stages. One study found that ground-glass opacities were more commonly seen on CT scan 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 when treating berylliosis are to reduce symptoms and slow the progression of the disease as no cure is available. Although there is no evidence that stopping exposure to beryllium decreases the progression of the disease, they still consider it to be an accepted approach to treatment. 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 vaccination and smoking cessation counseling. After the appearance of clinical symptoms or significant abnormalities appears in pulmonary function testing, oxygen and oral corticosteroids are started as well as 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 they see symptom resolution. Once symptoms subside, tapering of the steroids is necessary to prevent the adverse effects. Patients who fail to respond to steroids are started on immunosuppressive agents such as methotrexate and azathioprine. Oral methotrexate at a 7.5mg weekly dose 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 life-long 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, silicosis. It is estimated that 6 percent 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 the bronchoalveolar lavage correlates with greater severity of illness[14]. Disability is common in people with preexisting lung disease and smokers. The granulomas lead to nodule formation, which can impair lung function.