Beryllium Toxicity

Etiology

Beryllium is a naturally occurring element typically distributed in soil and volcanic dust.[1] Beryllium is released into the environment through natural processes such as weathering or volcanic activity and artificially through processes such as mining and combustion. It was first identified as a health hazard in the 1930s, and its acute and chronic toxic manifestations were discovered first in workers at a fluorescent lamp manufacturing plant.[2] 

Beryllium exposure has since been linked to workers in nuclear, defense, electronics, biomedical, and semiconductor industries, with the number of exposed US workers ranging from 21,200 to 800,000 between the 1970s and 1980s.[3] Clusters of berylliosis have also been linked to concrete dust exposure and beryllium manufacturing plants.[4][5]

Beryllium is typically used in industry as either a pure metal, beryllium oxide, or alloy. Beryllium oxide, in particular, is known for having a high heat capacity and is used primarily in select electronic equipment.[6] Beryllium alloys can be divided into two categories: high beryllium content (up to 30% beryllium) and low beryllium content (2 to 3% beryllium). Beryllium alloys are involved in the manufacture of cars, computers, sports equipment, and dental bridges. 

Acute beryllium pneumonitis occurs after high-intensity exposure and results from respiratory tract inflammation. Depending on the solubility of the beryllium compound, both upper and lower respiratory inflammation can be seen, and this is not specific to beryllium. Due to increased workplace safety initiatives, acute beryllium toxicity has become rare after the 1980s. 

A patient must become sensitized to beryllium to develop chronic beryllium disease via a cell-mediated type IV hypersensitivity mechanism. Patients with a specific HLA-DPB1-Glu polymorphism are more susceptible to beryllium sensitization. Beryllium-specific CD4+ T cells, in turn, recognize beryllium and induce proliferation. The release of various inflammatory cytokines results in granuloma formation and is histologically indistinguishable from sarcoidosis.

Epidemiology

Occupational exposure to beryllium and other metals is a health risk to workers worldwide. Increased regulations such as limiting the permissible exposure limit (PEL) of beryllium in US workers, enforced by governing bodies such as the Occupational Safety and Health Administration (OSHA), have made acute beryllium pneumonitis rare. But, despite this increase in safety, the mortality from tracheal, bronchial, and lung cancer resulting from general, occupational carcinogen exposure has increased globally from 1990 to 2019.[7] The International Agency for Research on Cancer has classified beryllium as a Class I human carcinogen.[8]

One study found that the standardized mortality ratio for berylliosis in workers involved in nuclear weapons research was significantly elevated.[9] Because beryllium sensitivity and chronic beryllium disease only occur in individuals exposed to beryllium, men are more predisposed to developing these conditions secondary to work practices. Family members of those working with beryllium are also at risk of exposure, and vehicles owned and used by machinists in this industry were contaminated with beryllium.[10] 

While beryllium toxicity is more commonly due to occupational exposure, the general public also has exposure risk. Beryllium can be present in small amounts in contaminated soil, air, food, or water. Individuals who live near waste disposal sites, in particular, may be at increased risk for beryllium exposure through the soil.[11] Although beryllium can be released into waterways through weathering, volcanic activity, or artificial processes, it is typically bound to sediment in this setting and is generally immobile.

Pathophysiology

Acute

Acute beryllium exposure, typically via inhalation, can cause a diffuse inflammatory response involving the upper and lower airway. Acute beryllium disease is similar to other cases of chemical pneumonitis, and symptoms depend on the compound's solubility.[12] This inflammation commonly results in bronchiolitis, pulmonary edema, and pneumonitis. Skin contact with beryllium can also cause dermatologic inflammation resulting in irritation, ulceration, and subcutaneous granulomas.

Chronic

Chronic beryllium disease (CBD), or berylliosis, is a granulomatous lung disease that results from beryllium exposure and sensitization and is due to an antigen-specific, cell-mediated immune response.[13][14][15] Research suggests the degree of immune response may be genetic and is associated with HLA DPB-1 E69 genotypes.[16][17] 

It is clinically indistinguishable from sarcoidosis and causes noncaseating granulomas in lung tissue and thoracic lymph nodes.[17] Chronic beryllium disease can remain stable for many years but rarely progresses into pulmonary fibrosis and is associated with an increased risk of lung cancer.

Histopathology

In chronic beryllium disease, epithelioid noncaseating granulomatous inflammation will be present on lung biopsy. These pathognomonic lesions are indistinguishable from those of sarcoidosis.[18] In one case study, bronchoalveolar lavage performed on two beryllium production facility workers revealed lymphocytic alveolitis.[12]

Toxicokinetics

Acute beryllium disease presents similar to other cases of chemical pneumonitis, and symptoms depend on the compound's solubility.[12] Sensitization and chronic disease occur in genetically susceptible people and commonly occur via inhalational exposure. Acute beryllium toxicity is a risk for chronic beryllium disease, and 17% of patients with acute toxicity will develop CBD.[19] 

Sensitization (not acute toxicity) precedes the development of CBD, and of those sensitized, 31% progressed to chronic beryllium disease.[20] Chronic beryllium disease is a granulomatous lung disease that results from beryllium exposure and sensitization and is due to an antigen-specific, cell-mediated immune response.[13][14][15] 

Inhalation of beryllium salts disrupts the capillary-alveolar membrane and causes epithelial cell membrane disruption, presenting an opportunity for antigen and antigen-presenting-cell (APC) interaction.[21] Helper-T cells seem to be the primary lymphocyte population involved in the early immune response to beryllium salts, followed by sustained cytokine production, particularly TNF-α and IL-6.[22] 

Research has shown that macrophages attracted to the site of inflammation can phagocytose beryllium, which will lead to lymphocyte proliferation.[23] Approximately 80% of patients diagnosed with beryllium sensitivity or chronic beryllium disease possess an HLA-DPB1 glu69 polymorphism, suggesting that the density of these molecules on an antigen-presenting cell may affect disease development and progression.[24][25] 

Because of this genetic predisposition, there is no classical dose-response relationship between the level of beryllium exposure and the severity of symptoms or disease progression.

History and Physical

Acute beryllium sensitivity and Berylliosis should be suspected in any patient presenting with respiratory complaints alongside known or suspected beryllium exposure. Acute beryllium toxicity will typically occur after exposure levels of 25 to 100 μg/m. It will typically manifest with inflammation of the upper and lower respiratory tract, similar to other cases of chemical pneumonitis.[26] 

People with acute beryllium toxicity may present with cough, shortness of breath, fatigue, chest pain, hemoptysis, palpitations, decreased appetite, or fever. Beryllium sensitivity can develop after initial exposure, and those who are sensitized can be asymptomatic.

Skin manifestations of beryllium exposure include dermatitis, beryllium ulcers, and dermal granulomas. Chronic, non-healing ulcers may result from beryllium implantation into an abrasion or laceration in the skin, with excision required for treatment.[27][28] Small granulomatous nodules often are found on the hands, arms, and chest. 

The most common complaints of patients presenting with chronic beryllium disease are dyspnea with exertion, dry cough, unintended weight loss, night sweats, and fatigue.[29] For both acute and chronic beryllium toxicity, initial treatment involves immediate removal from the source of exposure. Beryllium sensitization can be confirmed with a positive beryllium lymphocyte proliferation test (BeLPT), which is further discussed in the evaluation portion of this article.[30]

Evaluation

Acute findings of beryllium toxicity on chest X-ray may initially be normal, followed by diffuse alveolar infiltrates 1 to 3 weeks after initial exposure.[31] Patients with beryllium sensitivity have normal lung physiology and typically only have an abnormal BeLPT. Early pulmonary function testing may only have isolated abnormalities of the diffusing capacity. Patients will develop restrictive, obstructive, and/or gas exchange abnormalities as the disease progresses.[18] Patients with advanced chronic disease will usually have a restrictive pattern with fibrosis. 

The chest x-ray findings of chronic beryllium disease are nonspecific and similar to those of sarcoidosis. Ill-defined nodular or irregular opacities and hilar adenopathy can be seen. The abnormalities often may only be present in the upper lobes. With more advanced disease, fibrosis and the development of blebs and emphysema in adjacent areas can be seen. Radiographic abnormalities will sometimes improve with the removal of the offending agent and initiation of corticosteroids but will typically never fully resolve.[29]

Chronic beryllium disease has a latency period and is usually identified 10 to 20 years after initial exposure but can develop up to 40 years after initial exposure.[32] Chronic beryllium disease presents very similarly to pulmonary sarcoidosis and should be suspected in individuals presenting with known sarcoidosis or poor pulmonary function with previous exposure to beryllium. Diagnosis of chronic beryllium disease can be suggested via in-vitro lymphocyte proliferation testing that results in a cell-mediated immune response to beryllium, known as the beryllium lymphocyte proliferation test (BeLPT) or in-vivo patch-testing.[18] 

In addition to the BeLPT, tissue confirmation via biopsy should be performed. As a result of the development of these tests, many workers are now screened for beryllium sensitivity and chronic beryllium disease before developing symptoms, leading to early intervention and treatment. 

Sarcoidosis vs. Berylliosis

While pulmonary manifestations of these two diseases are nearly identical clinically, chronic beryllium disease typically lacks the extrapulmonary findings common in sarcoidosis. Cystic bone lesions, ocular involvement, neurosarcoidosis, cardiac disease, parotitis, and salivary gland involvement are all significant findings in sarcoidosis but not chronic beryllium disease.[18] Acute conjunctivitis may result from ocular exposure to beryllium salts but is not a finding in chronic beryllium disease.[33]

Treatment / Management

Management of acute beryllium exposure and sensitivity primarily involves removal from the source of exposure and symptomatic treatment alongside stabilization of any abnormal vital signs. Inhaled corticosteroids and short-acting bronchodilators can be used for symptomatic relief. Corticosteroids are the primary treatment of chronic beryllium disease, and many patients will see symptomatic improvement with steroid administration. Primary treatment is typically prednisone 40mg daily or every other day, with the response to therapy assessed every 3 to 6 months both clinically and radiographically. The prednisone dose can be reduced based on improvement in symptoms, CT findings of inflammation/fibrosis, and PFT results.[34] 

Despite early identification and treatment, progressive decline in pulmonary function and fibrosis is possible even in individuals who receive continued immunosuppressive therapy.[29] Over time and as the disease progresses, relapses and worsening pulmonary function are common and may require a transition to lifelong immunosuppressant treatment.[35] (B3)

Due to the significant potential for side effects associated with long-term steroid use, the use of steroid-sparing therapies (e.g., methotrexate, azathioprine, or infliximab) may be considered in patients experiencing notable side effects.[34]

Differential Diagnosis

Acute and chronic beryllium toxicity presents very similarly to other respiratory diseases, including but not limited to the following:

• Pulmonary edema
• Chronic obstructive pulmonary disease
• Asthma 
• Pulmonary embolism
• Pneumonia
• Chemical pneumonitis
• Pulmonary sarcoidosis
• Idiopathic pulmonary fibrosis
• Chronic obstructive pulmonary disease
• Heavy metal diseases

Prognosis

Prognosis is highly variable and is dependent on the duration of exposure, exposure levels, and genetic susceptibility. Many patients who develop beryllium sensitivity will not go on to develop chronic beryllium disease and may only require short-term treatment and monitoring. The course of illness may be self-limiting and mild but can also rapidly progress, involving death in approximately 10% of cases.[31] Research on cases in the 1940s and 1950s suggested mortality may be as high as 30%, but with advancements in monitoring and treatment, the mortality rate today is not certain.[29]

Complications

Acute complications of beryllium sensitivity include pulmonary edema and cor pulmonale.[36][37] Patients with chronic beryllium disease can develop granulomatous hepatitis and chronic interstitial nephritis due to the persistent inflammatory response produced by the body. Patients who require chronic steroid use are also at risk of developing complications from their treatment, such as hyperglycemia, osteoporosis, weight gain, and increased risk of infection.