- Email: [email protected]
High Prevalence of Hypothyroidism in Patients with Primary Pulmonary Hypertension
High Prevalence of Hypothyroidism in Patients with Primary Pulmonary Hypertension AMANDA L. CURNOCK, MBBS; RAED A. DWEIK, MD; BARBARA H. HIGGINS, RN; HUSSEIN F. SAADI, MD; ALEJANDRO C. ARROLlGA, MD
ABSTRACT: Purpose: To characterize the prevalence of hypothyroidism in a population with primary pulmonary hypertension (PPH). Methods: Retrospective record review of 41 patients with PPH seen between 1991 and 1997 at a tertiary care center. Data abstracted included: history of previous thyroid disease, intake of thyroid supplement, and thyroid function tests. Hypothyroidism was defined as a serum thyroid stimulating hormone (TSH) level higher than 5.5 U/L, intake of thyroid supplement, or low serum thyroxine level. Results: Of the 40 patients with PPH included in the study (11 men and 29 women), ages ranged from 11 to 76 years (mean 43.5 years). The mean pulmonary artery pressure was 58.7 mm Hg. Thirty-three
patients had normal serum TSH levels (3 of whom were on levothyroxine supplement); 1 had low TSH; 5 had high TSH (range, 6.8-9.9 U/L, mean 8.4 U/L), and 1 had low thyroxine (T4 < 1.0 ILgldL). Nine of 40 patients (22.5%) had evidence of hypothyroidism, whichis much more than expected in the general population of similar age range (2.8% in men, 7.5% in women) (p = 0.002). Conclusions: The prevalence of hypothyroidism in patients with PPH is high (22.5%). Patients with PPH should be investigated for the possibility of coexisting hypothyroidism. KEY INDEXING TERMS: Primary pulmonary hypertension; Hypothyroidism; Autoimmunity [Am J Med Sci 1999;318(5):
P
factors.! Few studies with a limited number of patients have looked into the association between hypothyroidism and PPH.5-7 The aim of our study is to define the prevalence of clinical and subclinical hypothyroidism in a cohort of patients with PPH.
rimary pulmonary hypertension (PPH) is defined clinically as the presence of pulmonary artery pressure higher than 25 mm Hg at rest or 30 mm Hg during exercise, in the presence of a normal pulmonary artery occlusion pressure and absence of any other causes of pulmonary hypertension. PPH is an uncommon and progressive disorder that if left untreated has a very poor prognosis. The survival at 1 year is 68% and at 5 years is 34%, according to the National Prospective Registry for PPH.l,2 The most common causes of death are right ventricular failure (63%), pneumonia (7%), and sudden death (7%).1,2 The pathogenesis ofPPH remains unclear, although the debate has centered on the role of increased pulmonary vasomotor tone. It has been suggested that a predisposition of patients is necessary together with the presence of stimuli that may initiate the development of characteristic vascular lesions. 1,3,4 Different noxious stimuli have been considered, including hypoxia, drugs, increased pulmonary blood flow, viral infections, and autoimmune
Departments of General Internal Medicine (ALC, HFS), Pulmonary and Critical Care Medicine (RAn, BHH, ACA), and Endocrinology (HFS), The Cleveland Clinic Foundation, Cleveland, Ohio. Submitted December 9, 1998; accepted in revised form February 4,1999. Correspondence: Alejandro C. Arroliga, M.D., FCCP, Department of Pulmonary & Critical Care MedicineIG-62, 9500 Euclid Avenue, Cleveland, OR 44195 (E-mail: arrolia@Ccforg). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
289-92.]
Methods A cohort of patients with PPH seen at The Cleveland Clinic Foundation from 1991 to 1997 was studied retrospectively. The majority of patients were seen by one of the authors (ACA). This group of patients was evaluated in the outpatient area and none of them was hospitalized in weeks before evaluation. The records of patients with PPH were reviewed and the following data were extracted: history and physical findings consistent with thyroid disease, confirmed previous history of hypothyroidism, current intake of levothyroxine supplement, results of thyroid function tests, including thyroid stimulating hormone (TSH) and L-thyroxine (T4 ), age, sex, and mean pulmonary artery pressure as measured by right ventricular catheterization. Primary pulmonary hypertension was defined as mean pulmonary artery pressure of greater than 25 mm Hg at rest. Pulmonary hypertension of secondary cause was ruled out by historytaking, physical examination, and an extensive work-up that included pulmonary function tests, ventilation perfusion scans, a pulmonary angiogram, high-resolution computed tomography, and a transthoracic echocardiogram. Open lung biopsy, transesophageal echocardiogram, and sleep studies were obtained if clinically indicated. Hypothyroidism for the purpose of this study was defined as a level of TSH higher than 5.5 UIL (third-generation assay with normal range of 0.40-5.50 UIL), intake of thyroid supplement given for a previous confirmed diagnosis of primary hypothyroidism, or by the finding of low serum total T4 level (normal range 5-11 JLg/dL).
289
Hypothyroidism and Primary Pulmonary Hypertension
Table 1. Reports of Hypothyroidism in Patients with PPH
Author, year (reference)
Number of Patients with PPH
Age Range (years)
Number of Patients with Hypothyroidism
Prevalence of Hypothyroidism
1 19 4
33 3-70 33-53 24-43 11-76
1 3
NA 15%
Kitamura (1968)7 Chin and Fisher (1986)5 Badesch et al (1993)6 Opravil et al (1997)9 Current report
17 b
40
4a
10%a
4 9
24% 22.5%
NA, case report, prevalence not available. a Prevalence based on a subsequent letter to the editor (Ann Int Med 1994;120:168). b HN-related PPH.
Statistical Analyses The prevalence of hypothyroidism in our population was compared with the general population using an exact binomial test. Comparison between patients with and without hypothyroidism with respect to age and degree of pulmonary artery hypertension was done using the Student t-test and with respect to sex using the Fisher exact test.
(30 patients). The 1 patient with low TSH was excluded. We found no statistical difference between the groups regarding age, mean pulmonary artery pressure using the Student t-test, and gender using the Fischer exact test. Discussion
Results
Forty-one patients with PPH had complete records and thyroid function tests available. One patient with a high TSH value had been treated with amiodarone for a few weeks before obtaining the thyroid function test. That patient was excluded from the study because of the concern that the raised TSH might have been caused by the amiodarone. The group studied comprised 40 patients (41 initial patients minus the patient excluded because of amiodarone intake; 11 men and 29 women, mean age 43.5 ::!:: 15.9 years). Mean pulmonary artery pressure was 5S.7 ::!:: 14.S mm Hg. Thirty-three patients had normal TSH, 3 of whom were on levothyroxine supplement for a prior confirmed diagnosis of hypothyroidism. One patient had a low serum TSH level «0.02 UIL), 5 patients had a high serum TSH levels (mean ofS.4 UIL, range of6.S UIL to 9.9 UIL), and 1 had a low serum T4 level «1 J.Lg/dL) with no available TSH. In our cohort, the point prevalence of hypothyroidism was 22.5% (9 of 40 patients). Using an exact binomial test, we compared this proportion, 9/40 (22.5%) with a constant-the prevalence of clinical and subclinical hypothyroidism in the general population of 1494 people of similar age range, as reported by Tunbridge et aI, where the prevalence of hypothyroidism in men was 2.S% and in women 7.5%.8 Taking a prevalence of 7.5% in this population of age similar to our PPH patients, we found the higher-than-expected point prevalence in our population with PPH to be statistically significant (P = 0.002). The group of patients with clinical or subclinical hypothyroidism (9 patients) was compared with the rest of the group who had normal thyroid function
290
The association between PPH and hypothyroidism has been suggested before, but previous evidences are limited to case reports or small series 5- 7 ,9 (Table 1). This study is the first report that defines the prevalence of hypothyroidism in a large cohort of patients with PPH. Our study found a high prevalence (22.5%) of hypothyroidism in patients with PPH. This prevalence is higher than the previously suspected 10 to 15% prevalence from case reports 5- 7 and similar to a recent reported prevalence of24% in patients with HIV-associated PPH9 (Table 1). Although a prospective study would have been more definitive in evaluating this association, such studies are hampered by the low prevalence of PPH, which makes a cross sectional cohort study more feasible. Although there is no definitive explanation for the association between hypothyroidism and PPH, several possibilities can be postulated based on what is known about both diseases. Both hypothyroidism and PPH are known to be associated with autoimmune disease. It is possible that the prevalence of hypothyroidism is increased in patients with PPH because both diseases share a similar autoimmune etiology. Autoimmune injury is the most frequent cause of hypothyroidism in the young population. 10 Abnormal thyroid tests are seen in patients with systemic lupus erythematosus l l and patients with Sjogren syndrome have a high prevalence of autoimmune thyroiditis. 12 ,13 Pulmonary hypertension is seen in patients with such autoimmune diseases as scleroderma, systemic lupus erythematosus, and mixed connective tissue disease.1 4 PPH is also associated with autoimmune antibodies in the absence of clinical autoimmune disease.1 5 - 17 Furthermore, several studies have found that some patients with both PPH and hypothyroidism have clinical evidence of November 1999 Volume 318 Number 5
Curnock et 01
connective tissue disease or positive serologic markers of autoimmunity.5,6,9,1s Chin and Fisher described 9 patients with PPH and hypothyroidism; 6 of these 9 patients also had evidence of connective tissue disease. 5 Baedesch et al reported 4 patients with PPH who also had hypothyroidism and lowtiter positive antinuclear antibody tests (1:4 to 1:256).6 More recently, Opravil et al. reported a high prevalence (24%) of hypothyroidism in a cohort of patients with HIV-associated PPH.9 These patients also had a high prevalence of autoantibodies, particularly anticardiolipin and anti-Sjogren syndrome B (SS-B). Although the 24% prevalence of hypothyroidism in the PPH group in the study by Opravil et al. did not achieve statistical significance compared with the 11% prevalence in the control group, this could be because of the small number of subjects (19 in each group) and the unusually high prevalence of hypothyroidism (11%) in the control group. YanaiLandau et al examined sera from 40 patients with PPH for 18 different autoantibodies.1 s Of the 40 patients, 62.4% had circulating autoantibodies and 47.5% had multiple antibodies. Interestingly, they also found a high prevalence (30%) of antithyroglobulin antibodies in their PPH population. 1s Although they did not evaluate for the presence of hypothyroidism, it is likely (based on the high prevalence of hypothyroidism in our study) that at least a subset of PPH patients with hypothyroidism also have antithyroglobulin antibodies. This is particularly important because patients with subclinical hypothyroidism are more likely to progress to clinical hypothyroidism if they have positive thyroid antibodies. s, 19 Thyroid dysfunction has also been linked to vascular reactivity, a phenomenon that may precede PPH.20 Raynaud's phenomenon, which is seen in patients with PPH, also occurs in hypothyroidism and can improve with supplementation of thyroid hormone,21-23 which suggests a causal relationship and raises the intriguing possibility that thyroid hormone may have a vascular stabilizing role. 6 In support of this, hypothyroidism in an animal model has been shown to significantly affect the tissue levels of endothelin-l,24 a potent vasoconstrictor peptide that may contribute to the pathogenesis of PPH.25 Although less supported by the available literature, inflammation may also represent a possible common link between hypothyroidism and PPH. This has recently been suggested by the high levels of neopterin in a group of patients with HIV-associated PPH.9 Regardless of whether an causal link exists, the high prevalence of hypothyroidism in patients with PPH has important clinical implications because hypothyroidism is known to be associated with such respiratory problems as hypoventilation and hypoxTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
emia,26-2s which may worsen existing pulmonary hypertension. In summary, the identification of the pathophysiologic link between PPH and hypothyroidism may have significant implications for understanding the etiology of PPH. Until such a link is identified, the high prevalence of hypothyroidism we found in patients with PPH makes a strong argument for testing all patients with PPH for possible coexisting hypothyroidism. Identifying PPH patients with subclinical hypothyroidism may be particularly important for several reasons. Patients with PPH have high prevalence of thyroid antibodies, which is a known risk factor for progression from subclinical to clinical hypothyroidism. Hypothyroidism is known to be associated with respiratory problems that may worsen existing pulmonary hypertension. In conclusion, hypothyroidism is common in patients with PPH and should be looked for and treated. References 1. Rubin LJ. Primary pulmonary hypertension. Chest 1993; 104:236-50. 2. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115: 343-9. 3. Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970;42:1163-84. 4. Edwards WD, Edwards JE. Clinical primary pulmonary hypertension: three pathologic types. Circulation 1977;56: 884-8. 5. Chin RG, Fisher J. Hypothyroidism and pulmonary hypertension: observation and speculation. Cardiovasc Rev Rep 1986;9:789-96. 6. Badesch DB, Wynne KM, Bonvallet S, et al. Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenic link? Ann Intern Med 1993;119:44-6. 7. Kitamura S. Three autopsy cases of chronic thyroiditis associated with other diseases. Acta Pathol Jpn 1968;18:50811. 8. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 1977;7:481-93. 9. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension: a case control study. Am J Respir Crit Care Med 1997;155:990-5. 10. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1996;273:808-12. 11. Miller FW, Moore G, Weintraub BD, et al. Prevalence of thyroid disease and abnormal thyroid function test results in patients with systemic lupus erythematosus. Arthritis Rheum 1987;30:1124-31. 12. Hansen BU, Ericsson DB, Henricksson V, et al. Autoimmune thyroiditis and primary Sjogren's syndrome: clinical and laboratory evidence of the coexistence of the two diseases. Clin Exp Rheumatol 1991;9:137-41. 13. Perez B, Kraus A, Lopez G, et al. Autoimmune thyroid disease in primary Sjogren's syndrome. Am J Med 1995;99: 480-4. 14. Gurubhagavatuia I, Palevsky HI. Pulmonary hypertension in systemic autoimmune disease. Rheum Dis Clin North Am 1997;23:365-94. 15. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmo-
291
Hypothyroidism and Primary Pulmonary Hypertension
16. 17. 18. 19. 20. 21.
nary hypertension: A national prospective study. Ann Intern Med 1987;107:216-23. Rich S, Kieras K, Hart K, et al. Antinuclear antibodies in primary pulmonary hypertension. J Am ColI Cardiol 1986;8: 1307-11. Isern RA, Yaneva M, Weiner E, et al. Autoantibodies in patients with primary pulmonary hypertension: Association with anti-Ku. Am J Med 1992;93:307-12. Yani-Landau H, AmitaI H, Bar-Dayan Y, et aI. Autoimmune aspects of primary pulmonary hypertension. Pathobiology 1995;63:71-5. Woeber KA. Subclinical thyroid dysfunction. Arch Intern Med 1997;157:1065-8. Ohar JM, Robichaud AM, Fowler AA, et al. Increased pulmonary artery pressure in association with Raynaud's phenomenon. Am J Med 1986;81:361-2. Shagan B, Freidman SA. Raynaud's phenomenon in hypothyroidism. Angiology 1976;27:19-25.
292
22. Shagan B, Freidman SA. Raynaud's phenomenon and thyroid deficiency. Arch Intern Med 1980;140:832-3. 23. Lateiwish AM, Feher J, Baraczka K, et aI. Remission of Raynaud's phenomenon after L-thyroxine therapy in a patient with hypothyroidism. J Endocrinol Invest 1992;15:49-51. 24. Lam HC, Wang JP, Lee JK, et al. Tissue contents of endothelin vary according to thyroid hormone status in rat. J Cardiovasc PharmacoI1993;22:S299-302. 25. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9. 26. Scherrer M, Konig MP. Pulmonary gas exchange in hypothyroidism. Pneumologie 1974;151:105-13. 27. Zwillich CW, Pierson DJ, Hofeldt FD, et al. Ventilatory control in myxedema and hypothyroidism. N Engl J Med 1975;202:662-5. 28. Goldman AL. Respiratory abnormalities in hypothyroidism. Compr Ther 1977;3:17-24.
November 1999 Volume 318 Number 5
ABSTRACT: Purpose: To characterize the prevalence of hypothyroidism in a population with primary pulmonary hypertension (PPH). Methods: Retrospective record review of 41 patients with PPH seen between 1991 and 1997 at a tertiary care center. Data abstracted included: history of previous thyroid disease, intake of thyroid supplement, and thyroid function tests. Hypothyroidism was defined as a serum thyroid stimulating hormone (TSH) level higher than 5.5 U/L, intake of thyroid supplement, or low serum thyroxine level. Results: Of the 40 patients with PPH included in the study (11 men and 29 women), ages ranged from 11 to 76 years (mean 43.5 years). The mean pulmonary artery pressure was 58.7 mm Hg. Thirty-three
patients had normal serum TSH levels (3 of whom were on levothyroxine supplement); 1 had low TSH; 5 had high TSH (range, 6.8-9.9 U/L, mean 8.4 U/L), and 1 had low thyroxine (T4 < 1.0 ILgldL). Nine of 40 patients (22.5%) had evidence of hypothyroidism, whichis much more than expected in the general population of similar age range (2.8% in men, 7.5% in women) (p = 0.002). Conclusions: The prevalence of hypothyroidism in patients with PPH is high (22.5%). Patients with PPH should be investigated for the possibility of coexisting hypothyroidism. KEY INDEXING TERMS: Primary pulmonary hypertension; Hypothyroidism; Autoimmunity [Am J Med Sci 1999;318(5):
P
factors.! Few studies with a limited number of patients have looked into the association between hypothyroidism and PPH.5-7 The aim of our study is to define the prevalence of clinical and subclinical hypothyroidism in a cohort of patients with PPH.
rimary pulmonary hypertension (PPH) is defined clinically as the presence of pulmonary artery pressure higher than 25 mm Hg at rest or 30 mm Hg during exercise, in the presence of a normal pulmonary artery occlusion pressure and absence of any other causes of pulmonary hypertension. PPH is an uncommon and progressive disorder that if left untreated has a very poor prognosis. The survival at 1 year is 68% and at 5 years is 34%, according to the National Prospective Registry for PPH.l,2 The most common causes of death are right ventricular failure (63%), pneumonia (7%), and sudden death (7%).1,2 The pathogenesis ofPPH remains unclear, although the debate has centered on the role of increased pulmonary vasomotor tone. It has been suggested that a predisposition of patients is necessary together with the presence of stimuli that may initiate the development of characteristic vascular lesions. 1,3,4 Different noxious stimuli have been considered, including hypoxia, drugs, increased pulmonary blood flow, viral infections, and autoimmune
Departments of General Internal Medicine (ALC, HFS), Pulmonary and Critical Care Medicine (RAn, BHH, ACA), and Endocrinology (HFS), The Cleveland Clinic Foundation, Cleveland, Ohio. Submitted December 9, 1998; accepted in revised form February 4,1999. Correspondence: Alejandro C. Arroliga, M.D., FCCP, Department of Pulmonary & Critical Care MedicineIG-62, 9500 Euclid Avenue, Cleveland, OR 44195 (E-mail: arrolia@Ccforg). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
289-92.]
Methods A cohort of patients with PPH seen at The Cleveland Clinic Foundation from 1991 to 1997 was studied retrospectively. The majority of patients were seen by one of the authors (ACA). This group of patients was evaluated in the outpatient area and none of them was hospitalized in weeks before evaluation. The records of patients with PPH were reviewed and the following data were extracted: history and physical findings consistent with thyroid disease, confirmed previous history of hypothyroidism, current intake of levothyroxine supplement, results of thyroid function tests, including thyroid stimulating hormone (TSH) and L-thyroxine (T4 ), age, sex, and mean pulmonary artery pressure as measured by right ventricular catheterization. Primary pulmonary hypertension was defined as mean pulmonary artery pressure of greater than 25 mm Hg at rest. Pulmonary hypertension of secondary cause was ruled out by historytaking, physical examination, and an extensive work-up that included pulmonary function tests, ventilation perfusion scans, a pulmonary angiogram, high-resolution computed tomography, and a transthoracic echocardiogram. Open lung biopsy, transesophageal echocardiogram, and sleep studies were obtained if clinically indicated. Hypothyroidism for the purpose of this study was defined as a level of TSH higher than 5.5 UIL (third-generation assay with normal range of 0.40-5.50 UIL), intake of thyroid supplement given for a previous confirmed diagnosis of primary hypothyroidism, or by the finding of low serum total T4 level (normal range 5-11 JLg/dL).
289
Hypothyroidism and Primary Pulmonary Hypertension
Table 1. Reports of Hypothyroidism in Patients with PPH
Author, year (reference)
Number of Patients with PPH
Age Range (years)
Number of Patients with Hypothyroidism
Prevalence of Hypothyroidism
1 19 4
33 3-70 33-53 24-43 11-76
1 3
NA 15%
Kitamura (1968)7 Chin and Fisher (1986)5 Badesch et al (1993)6 Opravil et al (1997)9 Current report
17 b
40
4a
10%a
4 9
24% 22.5%
NA, case report, prevalence not available. a Prevalence based on a subsequent letter to the editor (Ann Int Med 1994;120:168). b HN-related PPH.
Statistical Analyses The prevalence of hypothyroidism in our population was compared with the general population using an exact binomial test. Comparison between patients with and without hypothyroidism with respect to age and degree of pulmonary artery hypertension was done using the Student t-test and with respect to sex using the Fisher exact test.
(30 patients). The 1 patient with low TSH was excluded. We found no statistical difference between the groups regarding age, mean pulmonary artery pressure using the Student t-test, and gender using the Fischer exact test. Discussion
Results
Forty-one patients with PPH had complete records and thyroid function tests available. One patient with a high TSH value had been treated with amiodarone for a few weeks before obtaining the thyroid function test. That patient was excluded from the study because of the concern that the raised TSH might have been caused by the amiodarone. The group studied comprised 40 patients (41 initial patients minus the patient excluded because of amiodarone intake; 11 men and 29 women, mean age 43.5 ::!:: 15.9 years). Mean pulmonary artery pressure was 5S.7 ::!:: 14.S mm Hg. Thirty-three patients had normal TSH, 3 of whom were on levothyroxine supplement for a prior confirmed diagnosis of hypothyroidism. One patient had a low serum TSH level «0.02 UIL), 5 patients had a high serum TSH levels (mean ofS.4 UIL, range of6.S UIL to 9.9 UIL), and 1 had a low serum T4 level «1 J.Lg/dL) with no available TSH. In our cohort, the point prevalence of hypothyroidism was 22.5% (9 of 40 patients). Using an exact binomial test, we compared this proportion, 9/40 (22.5%) with a constant-the prevalence of clinical and subclinical hypothyroidism in the general population of 1494 people of similar age range, as reported by Tunbridge et aI, where the prevalence of hypothyroidism in men was 2.S% and in women 7.5%.8 Taking a prevalence of 7.5% in this population of age similar to our PPH patients, we found the higher-than-expected point prevalence in our population with PPH to be statistically significant (P = 0.002). The group of patients with clinical or subclinical hypothyroidism (9 patients) was compared with the rest of the group who had normal thyroid function
290
The association between PPH and hypothyroidism has been suggested before, but previous evidences are limited to case reports or small series 5- 7 ,9 (Table 1). This study is the first report that defines the prevalence of hypothyroidism in a large cohort of patients with PPH. Our study found a high prevalence (22.5%) of hypothyroidism in patients with PPH. This prevalence is higher than the previously suspected 10 to 15% prevalence from case reports 5- 7 and similar to a recent reported prevalence of24% in patients with HIV-associated PPH9 (Table 1). Although a prospective study would have been more definitive in evaluating this association, such studies are hampered by the low prevalence of PPH, which makes a cross sectional cohort study more feasible. Although there is no definitive explanation for the association between hypothyroidism and PPH, several possibilities can be postulated based on what is known about both diseases. Both hypothyroidism and PPH are known to be associated with autoimmune disease. It is possible that the prevalence of hypothyroidism is increased in patients with PPH because both diseases share a similar autoimmune etiology. Autoimmune injury is the most frequent cause of hypothyroidism in the young population. 10 Abnormal thyroid tests are seen in patients with systemic lupus erythematosus l l and patients with Sjogren syndrome have a high prevalence of autoimmune thyroiditis. 12 ,13 Pulmonary hypertension is seen in patients with such autoimmune diseases as scleroderma, systemic lupus erythematosus, and mixed connective tissue disease.1 4 PPH is also associated with autoimmune antibodies in the absence of clinical autoimmune disease.1 5 - 17 Furthermore, several studies have found that some patients with both PPH and hypothyroidism have clinical evidence of November 1999 Volume 318 Number 5
Curnock et 01
connective tissue disease or positive serologic markers of autoimmunity.5,6,9,1s Chin and Fisher described 9 patients with PPH and hypothyroidism; 6 of these 9 patients also had evidence of connective tissue disease. 5 Baedesch et al reported 4 patients with PPH who also had hypothyroidism and lowtiter positive antinuclear antibody tests (1:4 to 1:256).6 More recently, Opravil et al. reported a high prevalence (24%) of hypothyroidism in a cohort of patients with HIV-associated PPH.9 These patients also had a high prevalence of autoantibodies, particularly anticardiolipin and anti-Sjogren syndrome B (SS-B). Although the 24% prevalence of hypothyroidism in the PPH group in the study by Opravil et al. did not achieve statistical significance compared with the 11% prevalence in the control group, this could be because of the small number of subjects (19 in each group) and the unusually high prevalence of hypothyroidism (11%) in the control group. YanaiLandau et al examined sera from 40 patients with PPH for 18 different autoantibodies.1 s Of the 40 patients, 62.4% had circulating autoantibodies and 47.5% had multiple antibodies. Interestingly, they also found a high prevalence (30%) of antithyroglobulin antibodies in their PPH population. 1s Although they did not evaluate for the presence of hypothyroidism, it is likely (based on the high prevalence of hypothyroidism in our study) that at least a subset of PPH patients with hypothyroidism also have antithyroglobulin antibodies. This is particularly important because patients with subclinical hypothyroidism are more likely to progress to clinical hypothyroidism if they have positive thyroid antibodies. s, 19 Thyroid dysfunction has also been linked to vascular reactivity, a phenomenon that may precede PPH.20 Raynaud's phenomenon, which is seen in patients with PPH, also occurs in hypothyroidism and can improve with supplementation of thyroid hormone,21-23 which suggests a causal relationship and raises the intriguing possibility that thyroid hormone may have a vascular stabilizing role. 6 In support of this, hypothyroidism in an animal model has been shown to significantly affect the tissue levels of endothelin-l,24 a potent vasoconstrictor peptide that may contribute to the pathogenesis of PPH.25 Although less supported by the available literature, inflammation may also represent a possible common link between hypothyroidism and PPH. This has recently been suggested by the high levels of neopterin in a group of patients with HIV-associated PPH.9 Regardless of whether an causal link exists, the high prevalence of hypothyroidism in patients with PPH has important clinical implications because hypothyroidism is known to be associated with such respiratory problems as hypoventilation and hypoxTHE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
emia,26-2s which may worsen existing pulmonary hypertension. In summary, the identification of the pathophysiologic link between PPH and hypothyroidism may have significant implications for understanding the etiology of PPH. Until such a link is identified, the high prevalence of hypothyroidism we found in patients with PPH makes a strong argument for testing all patients with PPH for possible coexisting hypothyroidism. Identifying PPH patients with subclinical hypothyroidism may be particularly important for several reasons. Patients with PPH have high prevalence of thyroid antibodies, which is a known risk factor for progression from subclinical to clinical hypothyroidism. Hypothyroidism is known to be associated with respiratory problems that may worsen existing pulmonary hypertension. In conclusion, hypothyroidism is common in patients with PPH and should be looked for and treated. References 1. Rubin LJ. Primary pulmonary hypertension. Chest 1993; 104:236-50. 2. D'Alonzo GE, Barst RJ, Ayres SM, et al. Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 1991;115: 343-9. 3. Wagenvoort CA, Wagenvoort N. Primary pulmonary hypertension: a pathologic study of the lung vessels in 156 clinically diagnosed cases. Circulation 1970;42:1163-84. 4. Edwards WD, Edwards JE. Clinical primary pulmonary hypertension: three pathologic types. Circulation 1977;56: 884-8. 5. Chin RG, Fisher J. Hypothyroidism and pulmonary hypertension: observation and speculation. Cardiovasc Rev Rep 1986;9:789-96. 6. Badesch DB, Wynne KM, Bonvallet S, et al. Hypothyroidism and primary pulmonary hypertension: an autoimmune pathogenic link? Ann Intern Med 1993;119:44-6. 7. Kitamura S. Three autopsy cases of chronic thyroiditis associated with other diseases. Acta Pathol Jpn 1968;18:50811. 8. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol 1977;7:481-93. 9. Opravil M, Pechere M, Speich R, et al. HIV-associated primary pulmonary hypertension: a case control study. Am J Respir Crit Care Med 1997;155:990-5. 10. Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1996;273:808-12. 11. Miller FW, Moore G, Weintraub BD, et al. Prevalence of thyroid disease and abnormal thyroid function test results in patients with systemic lupus erythematosus. Arthritis Rheum 1987;30:1124-31. 12. Hansen BU, Ericsson DB, Henricksson V, et al. Autoimmune thyroiditis and primary Sjogren's syndrome: clinical and laboratory evidence of the coexistence of the two diseases. Clin Exp Rheumatol 1991;9:137-41. 13. Perez B, Kraus A, Lopez G, et al. Autoimmune thyroid disease in primary Sjogren's syndrome. Am J Med 1995;99: 480-4. 14. Gurubhagavatuia I, Palevsky HI. Pulmonary hypertension in systemic autoimmune disease. Rheum Dis Clin North Am 1997;23:365-94. 15. Rich S, Dantzker DR, Ayres SM, et al. Primary pulmo-
291
Hypothyroidism and Primary Pulmonary Hypertension
16. 17. 18. 19. 20. 21.
nary hypertension: A national prospective study. Ann Intern Med 1987;107:216-23. Rich S, Kieras K, Hart K, et al. Antinuclear antibodies in primary pulmonary hypertension. J Am ColI Cardiol 1986;8: 1307-11. Isern RA, Yaneva M, Weiner E, et al. Autoantibodies in patients with primary pulmonary hypertension: Association with anti-Ku. Am J Med 1992;93:307-12. Yani-Landau H, AmitaI H, Bar-Dayan Y, et aI. Autoimmune aspects of primary pulmonary hypertension. Pathobiology 1995;63:71-5. Woeber KA. Subclinical thyroid dysfunction. Arch Intern Med 1997;157:1065-8. Ohar JM, Robichaud AM, Fowler AA, et al. Increased pulmonary artery pressure in association with Raynaud's phenomenon. Am J Med 1986;81:361-2. Shagan B, Freidman SA. Raynaud's phenomenon in hypothyroidism. Angiology 1976;27:19-25.
292
22. Shagan B, Freidman SA. Raynaud's phenomenon and thyroid deficiency. Arch Intern Med 1980;140:832-3. 23. Lateiwish AM, Feher J, Baraczka K, et aI. Remission of Raynaud's phenomenon after L-thyroxine therapy in a patient with hypothyroidism. J Endocrinol Invest 1992;15:49-51. 24. Lam HC, Wang JP, Lee JK, et al. Tissue contents of endothelin vary according to thyroid hormone status in rat. J Cardiovasc PharmacoI1993;22:S299-302. 25. Stewart DJ, Levy RD, Cernacek P, et al. Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease? Ann Intern Med 1991;114:464-9. 26. Scherrer M, Konig MP. Pulmonary gas exchange in hypothyroidism. Pneumologie 1974;151:105-13. 27. Zwillich CW, Pierson DJ, Hofeldt FD, et al. Ventilatory control in myxedema and hypothyroidism. N Engl J Med 1975;202:662-5. 28. Goldman AL. Respiratory abnormalities in hypothyroidism. Compr Ther 1977;3:17-24.
November 1999 Volume 318 Number 5