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Lymphocytic interstitial pneumonitis in autoimmune thyroid disease
Lymphocytic Interstitial Pneumonitis in Autoimmune Thyroid Disease ROMESH KHARDORI, M.D., M.B., LANIE E. EAGLETON, M.D., NORMAN PETER R. MCCONNACHIE, Ph.D., .Springfiekf, ///hois
Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.
G.SOLER,
M.D., Ph.D.,
any endocrinopathies have an underlying autoimmune component, and sometimes two or more such endocrinopathies may coexist (polyglandular autoimmune syndrome [PGA]). Bloodworth and associates [l] in 1954 suggested an immunologic mechanism in polyglandular disorders, but it was not until 1956 that Roitt and associates [2] actually demonstrated autoantibodies in an endocrine disease. We have previously described lymphocytic mastitis in patients with thyroid disease [3], and a more recent report confirms this association 141. In this article, we report the occurrence of lymphocytic interstitial pneumonitis in four patients with thyroiditis, two of whom also had concurrent diabetes mellitus. This association has previously been described in one patient in a series of 13 cases from the Mayo Clinic [5].
M
CASE REPORTS Four patients were seen during the last 6 years at the Southern Illinois University School of Medicine Medical Clinics who were diagnosed as having lymphocytic pneumonitis in association with thyroid disease. The clinical characteristics of these patients are summarized in Table I, and brief case histories are provided. Patient 1
From the Departments of Medicine (RK, NGS) and Transplant Immunology (PRM), Divisions of Endocrinology and Metabolism (RK, NGS), and Pulmonary Medicine (LEE), Southern Illinois University School of Medicine, Springfield, Illinois. Requests for reprints should be addressed to Romesh Khardori. M.D., M.B., Division of Endocrinology and Metabolism, Department of Medicine, Southern Illinois University School of Medicine, P.O. Box 19230, Springfield. Illinois 62794-9230. Manuscript submitted June 19. 1990, and accepted in revised form October 1. 1990.
A 33-year-old woman presented with progressively worsening dyspnea. She was diagnosed as having Hashimoto’s thyroiditis (biopsy-proven) at 12 years of age and given thyroid hormone replacement. Esophagogastroduodenoscopy for intermittent nausea/vomiting revealed atrophic gastritis and two gastric polyps. Pulmonary function tests showed a restrictive lung disease. An open lung biopsy revealed lymphocytic interstitial pneumonitis. Bronchoalveolar lavage was performed to examine the T-cell subset distribution. Patient 2
A 72-year-old woman presented with increasing dyspnea. Ten years previously, she had been treated with radioactive iodine for Graves’ disease (thyroxine [TJ, 14.2 mg/dL; triiodothyronine [Ts-RIA], 329 ng/dL; 24-hour radioactive iodine uptake, 70% May 1991 The American Journal of Medicine
Volume 90
649
INTERSTITIAL PNEUMONITIS IN THYROID DISEASE / KHARDORI ET AL TABLEI Clinical Characteristics Thyroid
Age
Patient
Sex
(years)
1
F
33
Hashimoto’s
;i 58
Graves’ Graves’ Graves’
Diabetes hlellitus
Disease
-
Other Autoimmune
Disease
Biopsy suggestive of Sjbgren’s syndrome -
Type I Type 1
TABLE II
I Characterization
of T-Cell and Its Subgroups in Bronchoalveolar Lavage (BAL) and Peripheral Blood (Mean f SD)* lymphocyte
BAL Patient Control Peripheral Patient Control
(96)
T-Cell (CD2) (%)
T-Helper (CD4) (96)
T-Suppressor
(CD8) (%)
17.7 f 4t 8f2
52.9 f 5t 70%5
34.5 f 4t 45f4
40.8 f 6t 25f5
39.7 f 5 20-40
62.6 f 6 60-70
43.654 40-60
15.9f3 22-40
blood
* CD4/CD8 ratio: 0.85 @AL): 3.00 (peripheral blood, normal ran.w: 0.9 to 2.9). t p
and uniform). She subsequently required thyroid hormone replacement. During the past 12 years, she had had several exacerbations of dyspnea. One year ago, she was re-evaluated for increasing breathing difficulty and was found to have restrictive lung disease with diffuse pulmonary infiltrates. Open lung biopsy showed lymphocytic interstitial pneumonitis. The patient underwent bronchoalveolar lavage for T-lymphocyte subset examination. Steroid therapy was begun. Patient 3
A 58-year-old woman with type I diabetes mellitus controlled with insulin presented with a 4month history of worsening of dyspnea. She had been taking thyroid hormone replacement therapy for the last 6 years following treatment of Graves’ disease with radioactive iodine. The patient had symmetric pulmonary infiltrates, and results of pulmonary function tests showed a restrictive pattern. An open lung biopsy revealed lymphocytic interstitial pneumonitis. Earlier, her dyspnea had been presumed to be of cardiac origin, and cardiac catheterization was performed that revealed normal chamber pressures and a pulmonary capillary wedge pressure of 9 mm Hg. Bronchoalveolar lavage was performed. Patient 4
A 58-year-old man with a 20-year history of diabetes mellitus and frequent episodes of diabetic ketoacidosis was diagnosed to have concurrent hyper650
May 1991 The American Journal of Medicine
Volume 90
thyroidism (Td, 14 pg/dL; Ts-RIA, 230 ng/dL; T3 resin uptake, 36%) and given antithyroid medication (propylthiouracil, 300 to 600 mg/day). He had several recurrences and eventually received radioactive iodine treatment. Two years after administration of radioiodine therapy, he became hypothyroid and required thyroid hormone replacement. During each exacerbation of hyperthyroidism, he had recurrent lymphocytic interstitial pneumonitis (biopsy-proven). He underwent bronchoalveolar lavage for T-lymphocyte subset characterization.
METHODS Laboratory studies were conducted when patients were not taking any immunosuppressants. Blood samples were drawn for autoantibody screening, thyroid hormone estimation, T-lymphocyte subtyping studies, and angiotensin-converting enzyme estimation. Levels of the following autoantibodies were measured: rheumatoid factor, antinuclear antibody, and anti-DNA, antimicrosomal, anti-smooth muscle, anti-mitochondrial, antithyroglobulin, anti-SS-A/SS-B (anti-Ro/anti-La), antiparietal cell, and islet cell antibody. The thyroid hormones (T4 and T& and thyroid antibodies were measured as described previously [3], and other antibodies were measured by a commercial laboratory using standard assay procedures [6]. The peripheral blood and the bronchoalveolar T lymphocyte were subtyped using monoclonal antibodies and fluorescence microscopy [7]. The results are shown in Table II. Our efforts to docu-
INTERSTITIAL
PNEUMONITIS
IN THYROID
DISEASE
/ KHARDORl
ET AL
Figure 1. Lung tissue obtained at lung biopsy in which interstitial lymphocytic infiltration is visible (hematoxylin and eosin stain, original magnification X 250, reduced by 35%) (inset: low-power field X 100).
ment circulating antilung tissue antibodies were unsuccessful. Each patient participated in a series of pulmonary function tests to measure airway reactivity (methacholine challenge, histamine challenge, and metabisulfite, aspirin,. and tartrazine challenge), lung volume (using body plethysmography), flow rate (forced expiratory volume in 1 second/forced vital capacity and maximal mid-expiratory flow rate), and diffusing capacity (single-breath carbon monoxide corrected for patients’ hemoglobin levels). Additionally, flow volume loops were analyzed in each patient. Arterial blood gases were routinely analyzed in our pulmonary laboratory. Exercise stress tests could not be performed due to patient refusal. Fiberoptic bronchoscopy was performed with topical 1% lidocaine anesthesia following premedication with 30 mg of codeine, 1 mg of atropine given intramuscularly, and 10 mg of diazepam given intravenously. Lung lavages were performed by instillation of 4 to 8 aliquots of 20 mL of bacteriostatic saline via the fiberoptic bronchoscope wedged into the middle lobe of the lung with the patient in the supine position.
RESULTS The hemogram and urinalysis revealed no significant abnormality except glycosuria in the two patients with diabetes mellitus. The angiotensin-converting enzyme levels were normal (less than 76 U/L). The results of the pulmonary function tests showed restrictive lung disease. The pressure-volume curve showed very stiff lungs and generated high pressure at low volumes. The curve shifted
downwards to the right, indicating an interstitial lung process. Methacholine and histamine challenge did not reveal airway reactivity. The results of challenge with metabisulfite, aspirin, and tartazrine were negative. The lung biopsies were performed at three different medical centers at Denver, St. Louis, and Springfield. The lungs were described as stiff and nodular. One experienced pulmonary pathologist who was unaware of the diagnosis made elsewhere reviewed all the slides and confirmed the histologic diagnosis. Lymphocytic infiltration in the interstitium compatible with lymphocytic interstitial pneumonitis was demonstrated in all patients. Figure 1 provides a representative histologic view. The bronchoalveolar lavages were performed at our center and showed an overall increase in lymphocytes (Table II). However, the total T-cell percentage was lower, with a shift in favor of CD& (cytotoxic-suppressor) T cells. All these changes were statistically significant (p
COMMENTS Autoimmune thyroid disease, an integral component of PGA, has been associated with a variety of disorders including insulin-dependent diabetes mellitus, Addison’s disease, hypoparathyroidism, and hypogonadism [3-121. Association of pulmonary disease and autoimmune thyroid disease has May 1991
The American
Journal
of Medicine
Volume
90
651
not been emphasized in the literature. Our report suggests an association between interstitial lung disease and autoimmune thyroid disease that clinicians need to be aware of. Lymphocytic interstitial pneumonia has been reported in association with rheumatoid arthritis and lupus erythematosus [13,14]. Involvement of pulmonary connective tissue has been described in autoimmune disorders such as Sjiigren’s syndrome, primary biliary cirrhosis, and diabetes mellitus [15,16]. Given these previous relationships, the association of lymphocytic interstitial pneumonitis with autoimmune thyroid disease is not difficult to reconcile. The concomitant remissions and exacerbation of the pneumonitis and thyrotoxicosis in Patient 4 further supports a link between lymphocytic interstitial pneumonia and autoimmune thyroid disease in these patients. In the other three cases, there is evidence of smoldering lung disease (dyspnea and abnormal chest radiographs), which was not vigorously investigated by the treating physicians. The T-lymphocyte subset distribution with a relative increase in the number of cytotoxic/suppressor T lymphocytes also favors an ongoing immune event. Normal bronchoalveolar lavage shows about 30% suppressor T lymphocytes, 7% killer T cells, and 5% to 10% B lymphocytes [17]. In our patients, bronchoalveolar lavages showed 41% suppressor T cells and 34% inducer/helper T lymphocytes. This may reflect the recruitment of more suppressor T lymphocytes to contain the immune process. The profile of T-lymphocyte subsets observed in our patients is opposite to what is observed in sarcoidosis-an important clinical entity to consider when dealing with interstitial lung disease [18]. Normal angiotensin-converting enzyme estimation levels further help to exclude this diagnosis. None of our patients received any medications known to cause interstitial lung disease, and they all presented with identical histologic findings. Our patients were receiving bronchodilators, L-thyroxine, insulin, and steroids, which have not been associated with the development of lymphocytic interstitial lung disease. Each of our patients showed improvement in pneumonitis while taking steroid treatment with a
652
May
1991
The American
Journal
of Medicine
Volume
90
return of symptoms/signs when such therapy was withdrawn (dyspnea, worsening of pulmonary function test results). Rapid improvement in symptoms and lung function was noted after reintroduction of corticosteroid therapy. The association with an underlying autoimmune endocrinopathy and the response to immunosuppression thus favor a morethan-casual relationship. It is proposed that lymphocytic interstitial pneumonitis might be a manifestation of underlying immune dysfunction in autoimmune thyroid disease.
REFERENCES 1. Bloodworth JMB Jr, Kirkendall WM, Carr TL. Addison’s disease associated with thyroid insufficiency and atrophy (Schmidt syndrome). J Clin Endocrinol Metab 1954; 14: 540-53. 2. Roitt IM, Doniach D, Campbell PN, Hudson RV. Autoantibodies in Hashimoto’s disease (lymphadenoid goiter). Lancet 1956; 2: 820-l. 3. Soler NG, Khardori R. Fibrous disease of the breast, thyroiditis, and cheiroarthropathy in type I diabetes meltitus. Lancet 1984; 1: 193-5. 4. Logan WW, Hoffman NY. Diabetic fibrous breast disease. Radiology 1989; 172: 667-70. 5. Strimlan CV. Rosenow EC, Weiland LH, Brown LR. Lymphocytic interstitial pneumonitis: review of 13 cases. Ann Intern Med 1978; 88: 616-21. 6. Peter JB. The use and interpretation of tests in clinical immunology, 6th ed. Santa Monica, California: Specialty Laboratories, Inc., 1989: 1-52. 7. Mishell BB, Shiigi SM, eds. Selected methods in cellular immunology. San Francisco: WH Freeman, 1980: 297-9. 8. Leshin M. Polyglandular autoimmune syndromes: Southwestern Internal Medicine Conference. Am J Med Sci 1985; 290: 77-88. 9. Seinfield ED, Sharma OP. Tass syndrome: unusual association of thyroiditis, Addison’s disease, Sjbgren’s syndrome and sarcoidosis. J R Sot Med 1983; 76: 883-5. 10. Burton JL. Peripheral neuropathy associated with dysproteinemia, skin changes and endocrinopathy. BMJ 1986: 292: 1415-6. 11. Kihara S. Matsuzawa Y, Kubo M, et al. Autoimmune hyperchilomicronemia. N Engl J Med 1989; 320: 1255-9. 12. Usherwood PT. Hypothyroidism and autonomic failure. BMJ 1986; 292: 1050. 13. Benisch B, Peison B. The association of lymphocytic interstitial pneumonia and systemic lupus erythematosus. Mt Sinai J Med 1979; 46: 398-401. 14. Liebow AA. Definition and classification of interstitial pneumonias in human pathology, Alveolar lnterstitium of the Lung. In: Basset F, Georges R, eds. Progress in respiration research, vol 8. Basel: Karger, 1975: 1-33. 15. Rodriguez-Rosin R, Pares A, Bruguera M, et a/. Pulmonary involvement in primary biliary cirrhosis. Thorax 1981; 36: 208-12. 16. Schuyler MR, Niewochner DE, lnkley SR, Kohn R. Abnormal lung elasticity in juvenile diabetes mellitus. Am Rev Respir Dis 1976; 113: 37-41. 17. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis 1987; 135: 25063. 18. Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981: 305: 429-34.
Four patients are described who were found to have autoimmune thyroid disease associated with lymphocytic interstitial pneumonitis. The patients were not receiving any medications known to cause lymphocytic interstitial pneumonitis. Their response to steroid therapy and the relapse of their clinical symptoms after steroid withdrawal support an underlying immunologic dysfunction. It is proposed that lymphocytic interstitial pneumonitis may be yet another manifestation of immune dysfunction in autoimmune thyroid disease.
G.SOLER,
M.D., Ph.D.,
any endocrinopathies have an underlying autoimmune component, and sometimes two or more such endocrinopathies may coexist (polyglandular autoimmune syndrome [PGA]). Bloodworth and associates [l] in 1954 suggested an immunologic mechanism in polyglandular disorders, but it was not until 1956 that Roitt and associates [2] actually demonstrated autoantibodies in an endocrine disease. We have previously described lymphocytic mastitis in patients with thyroid disease [3], and a more recent report confirms this association 141. In this article, we report the occurrence of lymphocytic interstitial pneumonitis in four patients with thyroiditis, two of whom also had concurrent diabetes mellitus. This association has previously been described in one patient in a series of 13 cases from the Mayo Clinic [5].
M
CASE REPORTS Four patients were seen during the last 6 years at the Southern Illinois University School of Medicine Medical Clinics who were diagnosed as having lymphocytic pneumonitis in association with thyroid disease. The clinical characteristics of these patients are summarized in Table I, and brief case histories are provided. Patient 1
From the Departments of Medicine (RK, NGS) and Transplant Immunology (PRM), Divisions of Endocrinology and Metabolism (RK, NGS), and Pulmonary Medicine (LEE), Southern Illinois University School of Medicine, Springfield, Illinois. Requests for reprints should be addressed to Romesh Khardori. M.D., M.B., Division of Endocrinology and Metabolism, Department of Medicine, Southern Illinois University School of Medicine, P.O. Box 19230, Springfield. Illinois 62794-9230. Manuscript submitted June 19. 1990, and accepted in revised form October 1. 1990.
A 33-year-old woman presented with progressively worsening dyspnea. She was diagnosed as having Hashimoto’s thyroiditis (biopsy-proven) at 12 years of age and given thyroid hormone replacement. Esophagogastroduodenoscopy for intermittent nausea/vomiting revealed atrophic gastritis and two gastric polyps. Pulmonary function tests showed a restrictive lung disease. An open lung biopsy revealed lymphocytic interstitial pneumonitis. Bronchoalveolar lavage was performed to examine the T-cell subset distribution. Patient 2
A 72-year-old woman presented with increasing dyspnea. Ten years previously, she had been treated with radioactive iodine for Graves’ disease (thyroxine [TJ, 14.2 mg/dL; triiodothyronine [Ts-RIA], 329 ng/dL; 24-hour radioactive iodine uptake, 70% May 1991 The American Journal of Medicine
Volume 90
649
INTERSTITIAL PNEUMONITIS IN THYROID DISEASE / KHARDORI ET AL TABLEI Clinical Characteristics Thyroid
Age
Patient
Sex
(years)
1
F
33
Hashimoto’s
;i 58
Graves’ Graves’ Graves’
Diabetes hlellitus
Disease
-
Other Autoimmune
Disease
Biopsy suggestive of Sjbgren’s syndrome -
Type I Type 1
TABLE II
I Characterization
of T-Cell and Its Subgroups in Bronchoalveolar Lavage (BAL) and Peripheral Blood (Mean f SD)* lymphocyte
BAL Patient Control Peripheral Patient Control
(96)
T-Cell (CD2) (%)
T-Helper (CD4) (96)
T-Suppressor
(CD8) (%)
17.7 f 4t 8f2
52.9 f 5t 70%5
34.5 f 4t 45f4
40.8 f 6t 25f5
39.7 f 5 20-40
62.6 f 6 60-70
43.654 40-60
15.9f3 22-40
blood
* CD4/CD8 ratio: 0.85 @AL): 3.00 (peripheral blood, normal ran.w: 0.9 to 2.9). t p
and uniform). She subsequently required thyroid hormone replacement. During the past 12 years, she had had several exacerbations of dyspnea. One year ago, she was re-evaluated for increasing breathing difficulty and was found to have restrictive lung disease with diffuse pulmonary infiltrates. Open lung biopsy showed lymphocytic interstitial pneumonitis. The patient underwent bronchoalveolar lavage for T-lymphocyte subset examination. Steroid therapy was begun. Patient 3
A 58-year-old woman with type I diabetes mellitus controlled with insulin presented with a 4month history of worsening of dyspnea. She had been taking thyroid hormone replacement therapy for the last 6 years following treatment of Graves’ disease with radioactive iodine. The patient had symmetric pulmonary infiltrates, and results of pulmonary function tests showed a restrictive pattern. An open lung biopsy revealed lymphocytic interstitial pneumonitis. Earlier, her dyspnea had been presumed to be of cardiac origin, and cardiac catheterization was performed that revealed normal chamber pressures and a pulmonary capillary wedge pressure of 9 mm Hg. Bronchoalveolar lavage was performed. Patient 4
A 58-year-old man with a 20-year history of diabetes mellitus and frequent episodes of diabetic ketoacidosis was diagnosed to have concurrent hyper650
May 1991 The American Journal of Medicine
Volume 90
thyroidism (Td, 14 pg/dL; Ts-RIA, 230 ng/dL; T3 resin uptake, 36%) and given antithyroid medication (propylthiouracil, 300 to 600 mg/day). He had several recurrences and eventually received radioactive iodine treatment. Two years after administration of radioiodine therapy, he became hypothyroid and required thyroid hormone replacement. During each exacerbation of hyperthyroidism, he had recurrent lymphocytic interstitial pneumonitis (biopsy-proven). He underwent bronchoalveolar lavage for T-lymphocyte subset characterization.
METHODS Laboratory studies were conducted when patients were not taking any immunosuppressants. Blood samples were drawn for autoantibody screening, thyroid hormone estimation, T-lymphocyte subtyping studies, and angiotensin-converting enzyme estimation. Levels of the following autoantibodies were measured: rheumatoid factor, antinuclear antibody, and anti-DNA, antimicrosomal, anti-smooth muscle, anti-mitochondrial, antithyroglobulin, anti-SS-A/SS-B (anti-Ro/anti-La), antiparietal cell, and islet cell antibody. The thyroid hormones (T4 and T& and thyroid antibodies were measured as described previously [3], and other antibodies were measured by a commercial laboratory using standard assay procedures [6]. The peripheral blood and the bronchoalveolar T lymphocyte were subtyped using monoclonal antibodies and fluorescence microscopy [7]. The results are shown in Table II. Our efforts to docu-
INTERSTITIAL
PNEUMONITIS
IN THYROID
DISEASE
/ KHARDORl
ET AL
Figure 1. Lung tissue obtained at lung biopsy in which interstitial lymphocytic infiltration is visible (hematoxylin and eosin stain, original magnification X 250, reduced by 35%) (inset: low-power field X 100).
ment circulating antilung tissue antibodies were unsuccessful. Each patient participated in a series of pulmonary function tests to measure airway reactivity (methacholine challenge, histamine challenge, and metabisulfite, aspirin,. and tartrazine challenge), lung volume (using body plethysmography), flow rate (forced expiratory volume in 1 second/forced vital capacity and maximal mid-expiratory flow rate), and diffusing capacity (single-breath carbon monoxide corrected for patients’ hemoglobin levels). Additionally, flow volume loops were analyzed in each patient. Arterial blood gases were routinely analyzed in our pulmonary laboratory. Exercise stress tests could not be performed due to patient refusal. Fiberoptic bronchoscopy was performed with topical 1% lidocaine anesthesia following premedication with 30 mg of codeine, 1 mg of atropine given intramuscularly, and 10 mg of diazepam given intravenously. Lung lavages were performed by instillation of 4 to 8 aliquots of 20 mL of bacteriostatic saline via the fiberoptic bronchoscope wedged into the middle lobe of the lung with the patient in the supine position.
RESULTS The hemogram and urinalysis revealed no significant abnormality except glycosuria in the two patients with diabetes mellitus. The angiotensin-converting enzyme levels were normal (less than 76 U/L). The results of the pulmonary function tests showed restrictive lung disease. The pressure-volume curve showed very stiff lungs and generated high pressure at low volumes. The curve shifted
downwards to the right, indicating an interstitial lung process. Methacholine and histamine challenge did not reveal airway reactivity. The results of challenge with metabisulfite, aspirin, and tartazrine were negative. The lung biopsies were performed at three different medical centers at Denver, St. Louis, and Springfield. The lungs were described as stiff and nodular. One experienced pulmonary pathologist who was unaware of the diagnosis made elsewhere reviewed all the slides and confirmed the histologic diagnosis. Lymphocytic infiltration in the interstitium compatible with lymphocytic interstitial pneumonitis was demonstrated in all patients. Figure 1 provides a representative histologic view. The bronchoalveolar lavages were performed at our center and showed an overall increase in lymphocytes (Table II). However, the total T-cell percentage was lower, with a shift in favor of CD& (cytotoxic-suppressor) T cells. All these changes were statistically significant (p
COMMENTS Autoimmune thyroid disease, an integral component of PGA, has been associated with a variety of disorders including insulin-dependent diabetes mellitus, Addison’s disease, hypoparathyroidism, and hypogonadism [3-121. Association of pulmonary disease and autoimmune thyroid disease has May 1991
The American
Journal
of Medicine
Volume
90
651
not been emphasized in the literature. Our report suggests an association between interstitial lung disease and autoimmune thyroid disease that clinicians need to be aware of. Lymphocytic interstitial pneumonia has been reported in association with rheumatoid arthritis and lupus erythematosus [13,14]. Involvement of pulmonary connective tissue has been described in autoimmune disorders such as Sjiigren’s syndrome, primary biliary cirrhosis, and diabetes mellitus [15,16]. Given these previous relationships, the association of lymphocytic interstitial pneumonitis with autoimmune thyroid disease is not difficult to reconcile. The concomitant remissions and exacerbation of the pneumonitis and thyrotoxicosis in Patient 4 further supports a link between lymphocytic interstitial pneumonia and autoimmune thyroid disease in these patients. In the other three cases, there is evidence of smoldering lung disease (dyspnea and abnormal chest radiographs), which was not vigorously investigated by the treating physicians. The T-lymphocyte subset distribution with a relative increase in the number of cytotoxic/suppressor T lymphocytes also favors an ongoing immune event. Normal bronchoalveolar lavage shows about 30% suppressor T lymphocytes, 7% killer T cells, and 5% to 10% B lymphocytes [17]. In our patients, bronchoalveolar lavages showed 41% suppressor T cells and 34% inducer/helper T lymphocytes. This may reflect the recruitment of more suppressor T lymphocytes to contain the immune process. The profile of T-lymphocyte subsets observed in our patients is opposite to what is observed in sarcoidosis-an important clinical entity to consider when dealing with interstitial lung disease [18]. Normal angiotensin-converting enzyme estimation levels further help to exclude this diagnosis. None of our patients received any medications known to cause interstitial lung disease, and they all presented with identical histologic findings. Our patients were receiving bronchodilators, L-thyroxine, insulin, and steroids, which have not been associated with the development of lymphocytic interstitial lung disease. Each of our patients showed improvement in pneumonitis while taking steroid treatment with a
652
May
1991
The American
Journal
of Medicine
Volume
90
return of symptoms/signs when such therapy was withdrawn (dyspnea, worsening of pulmonary function test results). Rapid improvement in symptoms and lung function was noted after reintroduction of corticosteroid therapy. The association with an underlying autoimmune endocrinopathy and the response to immunosuppression thus favor a morethan-casual relationship. It is proposed that lymphocytic interstitial pneumonitis might be a manifestation of underlying immune dysfunction in autoimmune thyroid disease.
REFERENCES 1. Bloodworth JMB Jr, Kirkendall WM, Carr TL. Addison’s disease associated with thyroid insufficiency and atrophy (Schmidt syndrome). J Clin Endocrinol Metab 1954; 14: 540-53. 2. Roitt IM, Doniach D, Campbell PN, Hudson RV. Autoantibodies in Hashimoto’s disease (lymphadenoid goiter). Lancet 1956; 2: 820-l. 3. Soler NG, Khardori R. Fibrous disease of the breast, thyroiditis, and cheiroarthropathy in type I diabetes meltitus. Lancet 1984; 1: 193-5. 4. Logan WW, Hoffman NY. Diabetic fibrous breast disease. Radiology 1989; 172: 667-70. 5. Strimlan CV. Rosenow EC, Weiland LH, Brown LR. Lymphocytic interstitial pneumonitis: review of 13 cases. Ann Intern Med 1978; 88: 616-21. 6. Peter JB. The use and interpretation of tests in clinical immunology, 6th ed. Santa Monica, California: Specialty Laboratories, Inc., 1989: 1-52. 7. Mishell BB, Shiigi SM, eds. Selected methods in cellular immunology. San Francisco: WH Freeman, 1980: 297-9. 8. Leshin M. Polyglandular autoimmune syndromes: Southwestern Internal Medicine Conference. Am J Med Sci 1985; 290: 77-88. 9. Seinfield ED, Sharma OP. Tass syndrome: unusual association of thyroiditis, Addison’s disease, Sjbgren’s syndrome and sarcoidosis. J R Sot Med 1983; 76: 883-5. 10. Burton JL. Peripheral neuropathy associated with dysproteinemia, skin changes and endocrinopathy. BMJ 1986: 292: 1415-6. 11. Kihara S. Matsuzawa Y, Kubo M, et al. Autoimmune hyperchilomicronemia. N Engl J Med 1989; 320: 1255-9. 12. Usherwood PT. Hypothyroidism and autonomic failure. BMJ 1986; 292: 1050. 13. Benisch B, Peison B. The association of lymphocytic interstitial pneumonia and systemic lupus erythematosus. Mt Sinai J Med 1979; 46: 398-401. 14. Liebow AA. Definition and classification of interstitial pneumonias in human pathology, Alveolar lnterstitium of the Lung. In: Basset F, Georges R, eds. Progress in respiration research, vol 8. Basel: Karger, 1975: 1-33. 15. Rodriguez-Rosin R, Pares A, Bruguera M, et a/. Pulmonary involvement in primary biliary cirrhosis. Thorax 1981; 36: 208-12. 16. Schuyler MR, Niewochner DE, lnkley SR, Kohn R. Abnormal lung elasticity in juvenile diabetes mellitus. Am Rev Respir Dis 1976; 113: 37-41. 17. Reynolds HY. Bronchoalveolar lavage. Am Rev Respir Dis 1987; 135: 25063. 18. Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte activity at sites of disease activity. N Engl J Med 1981: 305: 429-34.