For Your Doctor

This sheet contains technical information for your doctor.

Introduction

The National Institute for Occupational Safety and Health (NIOSH) conducted two retrospective cohort mortality studies, a workplace study of employees exposed to beryllium compounds and a registry study of patients who had beryllium disease.

Your patient was a subject of the workplace study. He was employed by a beryllium manufacturer in the past and may continue to be exposed to beryllium. Your patient can provide you with information about his exposure history.

We are providing this fact sheet about beryllium disease to physicians because beryllium disease is rare and may be hard to diagnose. We also include a summary of the study results that may relate to your patient's health.

Purpose of the Studies

Previous studies that showed a link between beryllium and lung cancer had been criticizedfor methodologic difficulties. Thus, our studies were designed to re-examine the relationship between beryllium exposure and lung cancer.

Findings of the Two Studies

The workplace study found a modest excess of lung cancer in workers exposed to beryllium after taking smoking habits into consideration. It also found an expected increase in beryllium disease.

The registry study showed that those who had had acute beryllium disease, a form of the disease associated with very high exposures to beryllium, had the highest increase in lung cancer. We believe that the most likely cause of the increase in lung cancer was exposure to beryllium.

Other diseases found in excess in the workplace study were emphysema, heart diseases, including ischemic heart disease and cor pulmonale (a known sequela of beryllium disease), chronic kidney diseases, and oral cancer. The increase in emphysema may have resulted from the misdiagnosis of beryllium disease. We do not know the cause of the increases in heart diseases (other than cor pulmonale), kidney diseases, or oral cancer. The increase in oral cancer was seen only atone plant, where some of the subjects worked. Cor pulmonale and emphysema were also elevated only in one plant.

Beryllium Disease

Beryllium disease occurs in two forms: acute and chronic. The acute form has a short latency period, usually occurs during exposure, is brief in duration, and presents clinically as a type of chemical pneumonitis.

Since the adoption of the Atomic Energy Commission beryllium standard (which later became the Occupational Safety and Health Administration standard) that has reduced exposure, acute beryllium disease is very rare and should not occur unless there is an industrial accident.

However, some patients who have had the acute form later develop the chronic form. This fact sheet focuses on chronic beryllium disease (CBD) which may occur many years after exposure to beryllium has stopped, whether or not the patient has had prior acute beryllium disease.

Chronic beryllium disease occurs from inhalation of beryllium. It is characterized mainly by pulmonary noncaseating granulomas.

Even individuals with short exposures to beryllium (less than 1 year) may eventually develop CBD. Most studies report an average time between first exposure and onset of symptoms of 10 to 15 years, although some cases do not develop disease for several decades following first exposure.

Diagnostic Criteria for Chronic Beryllium Disease

In 1952, the Beryllium Case Registry, currently inactive, was established as a means of following the effects of beryllium and beryllium disease. This registry consists of persons suspected of having several different forms of beryllium disease, including both acute and chronic beryllium disease.

As a result of observations on many of these cases, the following criteria were developed to identify those cases with chronic beryllium disease:

1. documentation of beryllium exposure,

2. presence of beryllium in body tissues or fluids,

3. evidence of lower respiratory tract disease and a clinical course consistent with chronic beryllium disease,

4. radiographic evidence of pulmonary interstitialfibronodular changes,

5. restrictive or obstructive spirometry or reduced carbon monoxide diffusing capacity, and

6. noncaseating granuloma in lung or lymph node biopsy or pulmonary mononuclear cell infiltrates.

To be included as a registry case, the subject needed to satisfy at least four of the six criteria including at least one of the first two.

While the above criteria may be used for a presumptive diagnosis of CBD, to make a definitive diagnosis of CBD, most clinical experts now require evidence of beryllium hypersensitivity along with histopathology on lung biopsy consistent with beryllium disease, as well as a history of exposure to beryllium.

Beryllium disease may be confused with sarcoidosis or other interstitial lung diseases. Individuals who have had exposure to beryllium should receive a thorough assessment of respiratory symptoms, a chest examination, pulmonary function tests, and chest x ray. Some cases may present with a paucity of symptoms and subtle clinical abnormalities.

Pulmonary Function Tests

Patients with CBD usually have a reduced diffusing capacity, often, but not always, with a restrictive pattern onspirometry. Patients with CBD sometimes develop an obstructive impairment due to peribronchial granuloma formation.

Radiologic Studies

The typical radiographic findings in CBD are diffuse infiltrates often accompanied by bilateral hilar lymphadenopathy. The radiographic infiltrates are granular, nodular, linear, or mixed. Coarse interstitial densities indicative of fibrosis, and in rare cases, hyperlucent areas indicative of emphysema, may be seen.

Beryllium Sensitivity Tests

The beryllium-specific lymphocyte proliferation test (LPT) often referred to as the beryllium-specific lymphocyte transformation test (LTT) in the medical literature, measures the proliferative rate of lymphocytes in the presence of beryllium salts. This test is done on peripheral blood lymphocytes or bronchoalveolar (BAL) lymphocytes and can be used to determine if a patient is sensitized to beryllium.

As with other non-routine laboratory tests performed on living cells, logistical and other issues must be considered in advance for the test to be properly done. However, it is possible to arrange for shipment of cells to one of the few laboratories which currently offer this testing service (listed below).

Limitations of LPT

Blood-LPT on Asymptomatic Patients with Normal Pulmonary Function and Chest X-ray

Studies are underway to evaluate the usefulness of blood LPT as a screening test for asymptomatic persons in a number of worker populations.

Blood-LPT on Symptomatic Patients or Patients with Abnormal X-ray or Pulmonary Function Tests

One group reported 93% sensitivity for the blood-LPT in patients with known CBD. However, another group reported that only 48% of patients with known CBD are positive. Therefore, the interpretation of the test in symptomatic patients is also problematic.

BAL-LPT

The LPT on bronchoalveolar lymphocytes has high sensitivity in symptomatic CBD. However, since it requires lymphocytes from a bronchoalveolar lavage, it is only appropriate for symptomatic patients or asymptomatic patients withabnormal lung function or chest x-ray who are undergoing bronchoscopy for diagnostic purposes. In appropriate clinical situations or research settings, the test may also be indicated for asymptomatic individuals with no radiographic or functional abnormalities who are blood-LPT positive. There are reports of a false positive rate of up to 25% for the BAL-LPT test among beryllium-exposed patients with other lung diseases, and the test may be less sensitive in patients with subclinical disease. False negatives also occur in both the blood and BAL-LPT tests. Some are the result of immunosuppression in patients on corticosteroids. Therefore, this test must be used cautiously.

Some researchers have found lung damage in people exposed to beryllium who are not sensitized to beryllium. They believe that this damage was caused by beryllium exposure. Thus, your patient may have lung damage attributable to beryllium even in the absence of beryllium sensitivity.

Laboratories

If you would like the LPT test done for your patient, contact one of the following centers for instructions on sample collection. The clinic directors are knowledgeable about beryllium disease and can also refer you to specialists.

The National Jewish Center for Immunology and Respiratory Medicine Clinical Immunology Laboratory

1400 Jackson St

Denver, CO 80206

(303) 398-1344

Specialty Laboratory, Inc.

2211 Michigan Ave.

Santa Monica, CA 90404

(310)828-6543

Cleveland Clinic

9500 Euclid Ave.

Cleveland, OH 44195

(216)444-2790

The University of Pennsylvania

876 Maloney Building

3400 Spruce Street

Philadelphia, PA 19104

(215)662-6479

Another source of information concerning beryllium disease is:

The Occupational/Environmental Health Clinic

Dept of Family Practice

MetroHealth Medical Center

2500 MetroHealth Drive

Cleveland, Ohio 44109-1998

(216)778-8087

Beryllium Patch Warning

The beryllium patch test should not be used because of false negatives, induction of beryllium sensitivity, and the possibility of severe anaphylactoid reaction.

Pathology

Pathologic changes in CBD include chronic interstitial pneumonitis with mononuclear cell infiltration and non-caseating granulomas. Non-caseating granulomas have also been found in the lymph nodes, liver, skin, spleen, and other tissues. Varying degrees of fibrosis may be present in different parts of the lung.

Other Tests

Active CBD is typically characterized by lymphocytosis in BAL fluid. Some patients may have one or more of the following: elevated serum IgG, elevated serum IgA, high erythrocyte sedimentation rate, erythrocytosis, hyperuricemia, hypercalcemia, or hypercalciuria.

Treatment

Patients with mild CBD may not need any treatment, but should be clinically followed with periodic assessment of symptoms, chest examination, pulmonary function tests, and chest x-rays. The only available treatment is corticosteroids. Improvements in symptoms, signs, clinical course, and radiographic abnormalities have been seen in some patients treated with corticosteroids. Patients presumptively diagnosed ashaving CBD without evidence of beryllium sensitization should be examined for possible systemic involvement by sarcoidosis (e.g., uveitis), since misdiagnosis of sarcoidosis as CBD is more likely in these individuals.

In severe CBD, as in any chronic lung disorder, hypoxemia, pulmonary hypertension, and right heart failure may require supportive measures including supplemental oxygen, diuretics, and possibly digitalis.