Download High Prevalence of Autoimmune Thyroid Disease in Pulmonary

High Prevalence of Autoimmune Thyroid
Disease in Pulmonary Arterial
Hypertension*
James W. Chu, MD; Peter N. Kao, MD, PhD; John L. Faul, MD; and
Ramona L. Doyle, MD, FCCP
Study objectives: An association between thyroid disease and pulmonary arterial hypertension
(PAH) has been reported, yet the pathogenetic relationship between these conditions remains
unclear. Because immune system dysfunction may underlie this association, we sought to
determine the prevalence of autoimmune thyroid disease (AITD) in patients with PAH.
Design and setting: Prospective observational study at a single academic institution.
Patients: Sixty-three consecutive adults with PAH (ie, sustained pulmonary artery systolic pressure,
> 25 mm Hg) were evaluated for clinical, biochemical, and serologic features of AITD.
Measurements: Thyroid gland dysfunction was determined by clinical examination for goiter, and by
biochemical measurements of thyrotropin and free thyroxine. Immune system dysfunction was
determined by serologic measurements of antibodies to thyroglobulin and thyroid peroxidase.
First-degree family history of AITD also was ascertained in order to investigate for genetic clustering
of autoimmunity.
Results: Thirty-one patients (49%; 95% confidence interval [CI], 37 to 62%) received diagnoses of
AITD. Eighteen patients were newly diagnosed, and 9 patients required the initiation of pharmacologic treatment. There was no chronologic relationship between the diagnosis or treatment of PAH
and that of AITD. Sixteen patients (25%; 95% CI, 15 to 36%) had 24 first-degree family members with
AITD.
Conclusions: Approximately half of the patients with PAH have concomitant AITD. These two
conditions may be linked by a common immunogenetic susceptibility, and the elucidation of this
association may advance the understanding of the pathophysiology and treatment of PAH. Systematic
surveillance for occult thyroid dysfunction in patients with PAH may prevent the hemodynamic
exacerbation of right heart failure.
(CHEST 2002; 122:1668 –1673)
Key words: autoimmune thyroiditis; Graves disease; pulmonary hypertension; thyroid diseases
Abbreviations: AITD ⫽ autoimmune thyroid disease; FT4 ⫽ free thyroxine; PAH ⫽ pulmonary arterial hypertension;
PPH ⫽ primary pulmonary hypertension; TgAb ⫽ thyroglobulin antibodies; TPOAb ⫽ thyroid peroxidase antibodies;
TSH ⫽ thyrotropin
rimary pulmonary hypertension (PPH) is a rare
P progressive
disorder of the pulmonary vasculature that causes early death from right heart failure.1
*From the Divisions of Endocrinology and Metabolism (Dr. Chu)
and Pulmonary and Critical Care Medicine (Drs. Kao, Faul, and
Doyle), Department of Medicine, Stanford University School of
Medicine, Stanford, CA.
Presented in part as a poster at the American Association of
Clinical Endocrinologists 10th Annual Meeting and Clinical
Progress, San Antonio, TX, May 2, 2001.
This research was supported by a grant from the Vera M. Wall
Center for Pulmonary Vascular Disease at Stanford University
and by National Institutes of Health grants DK07217-24 and
HL07708-10 (to Dr. Chu), and GCRC M01-RR00070.
Manuscript received January 17, 2002; revision accepted April 8,
2002.
Correspondence to: Ramona L. Doyle, MD, FCCP, Division of
Pulmonary and Critical Care Medicine, Room H3147, Stanford
University Medical Center, Stanford, CA 94305-5236; e-mail:
[email protected]
This disorder has commanded a great deal of attention
as a result of its elusive pathophysiology, poor prognosis, and limited treatment options. The idiopathic form
of PPH is extremely rare (incidence, one case per
million population per year), but similar forms develop
in association with collagen vascular disease,2,3 liver
disease,4 HIV infection,5 anorexigen usage,6 and drug
abuse.7 The exposure-associated forms of pulmonary
hypertension and idiopathic PPH are precapillary in
nature, and they are clinically and histopathologically
indistinguishable from each other.1,2 All of these conditions have been classified as related forms of pulmonary arterial hypertension (PAH) by a World Health
Organization consensus symposium,8 but the common
underlying disease mechanism remains obscure despite
intensive research.
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Clinical Investigations
Prior retrospective studies have suggested an association between thyroid dysfunction and the diagnosis9 or treatment10,11 of PAH, and several case
reports12–15 have described patients who received
diagnoses of both pulmonary hypertension and thyroid disease. One study16 has reported a series of
patients with PAH and hyperthyroidism, while four
others11,17–19 have described a high retrospective
prevalence (10 to 24%) of hypothyroidism or elevated levels of thyrotropin (TSH) in patients with
PAH. In another retrospective study,20 a high frequency of thyroglobulin autoantibodies (30%) was
noted in patients with PAH. Each of these studies,
when considered separately, provides limited insight
into the pathogenetic relationship between PAH and
thyroid disease. None accurately determined the
prevalence of thyroid disease in patients with PAH,
as they were either retrospective or consisted solely
of selected cases. All of the retrospective series also
were characterized by incomplete evaluation of
thyroid disease. Some determined the presence of
thyroid disease only by chart review.17,18 Others11,18,19 assessed biochemical thyroid dysfunction
(ie, levels of TSH and free thyroxine [FT4]) but did
not test for the presence of thyroid autoantibodies
and made no distinctions among autoimmune, druginduced, surgical, or other causes of hypothyroidism
or hyperthyroidism. The only study to evaluate for the
presence of thyroglobulin antibodies (TgAbs)20 neither
assessed thyroid function nor measured the more prevalent thyroid-peroxidase antibody (TPOAb). Furthermore, two retrospective reports10,11 speculated on a
causal relationship between prostacyclin treatment of
PAH and the diagnosis of thyroid disease, but both
studies had observational biases and were inconclusive.
The forms of thyroid disease (hyperthyroidism,
hypothyroidism, and TgAbs) that have each been
described to occur in patients with PAH have thus
far been considered distinct associations, without any
unifying explanation. However, taking all of these
reports together, one recognizes that Graves hyperthyroidism,21 Hashimoto hypothyroidism,22 and thyroid autoantibodies represent overlapping conditions
in the autoimmune thyroid disease (AITD) syndrome, which is characterized by shared immune
and genetic features.23 Thus, we hypothesized that
the PAH-thyroid association is derived from a common immunogenetic susceptibility, and we initiated
a prospective study of thyroid disease in patients with
PAH to accomplish three major goals.
First, we sought to accurately determine the prevalence of AITD in patients with PAH by comprehensively evaluating the clinical, biochemical, and
serologic parameters of thyroid disease. We hypothesized that there would be a high frequency of AITD
and prominent familial clustering of AITD in pawww.chestjournal.org
tients with PAH. We also hypothesized that most
detected forms of hypothyroidism and hyperthyroidism would be autoimmune in pathogenesis, rather
than arising from medical or surgical treatment.
Such findings would suggest a common genetic basis
of PAH and AITD, with implications for novel
diagnostic and therapeutic approaches to pulmonary
hypertension. Second, we aimed to clarify the relationship between the diagnosis or treatment of PAH
and that of AITD, since previous studies speculated
that prostacyclin treatment might induce thyroid
dysfunction,10,11 or, alternatively, that hypothyroidism might cause PAH.17 A prospective evaluation of
AITD in patients with PAH would be able to
elucidate the chronologic relationship between such
events. Finally, we sought to identify and to promptly
treat occult thyroid disease in all patients with PAH,
because thyroid hormone imbalance can impact
cardiac function,24,25 potentially perturbing the precarious hemodynamic state of patients with PAH.
Our study is the first prospective evaluation of
thyroid disease in PAH patients and the only one to
examine multiple features of AITD.
Materials and Methods
The Stanford University Human Subjects Committee approved this study, and each patient gave written informed
consent before participating. We enrolled 63 consecutive adult
(age, ⬎ 18 years) patients who had received a diagnosis of PAH
and had received continuing care at the Stanford Hospital Chest
Clinic between August 1999 and December 2001. PAH was
diagnosed by right heart catheterization findings of sustained
mean pulmonary arterial pressures of ⬎ 25 mm Hg at rest and
was categorized according to the World Health Organization
classification.8 Exclusion criteria consisted of secondary causes of
pulmonary hypertension, including those related to left-sided
myocardial or valvular disease, chronic hypoxia, chronic venoocclusive disease, COPD or chronic restrictive pulmonary disease, or interstitial lung disease. These diagnoses were made by
interview, examination, and clinical evaluation, which included
the use of pulmonary function testing, pulmonary angiography,
ventilation-perfusion scintigraphy, high-resolution CT scanning,
polysomnography, and transthoracic echocardiography.
Each participant underwent a medical interview and thyroid
examination, provided information about family history, and
contributed blood samples for the evaluation of AITD. TSH
levels (third generation immunometric assay; reference range,
0.40 to 4.00 ␮IU/mL), FT4 levels (immunoradiometric assay;
reference range, 0.73 to 2.01 ng/dL), and the presence and levels
of TPOAbs and TgAbs (immunoradiometric assays; negative,
⬍ 0.3 U/mL; abnormal level, ⬎ 1.0 U/mL) were determined for
each patient. The detection of thyroid dysfunction resulted in
confirmatory testing before the initiation of pharmacologic treatment. All patients had repeat TSH and FT4 testing performed at
follow-up, at intervals of 4 to 6 months.
Graves disease was defined by the finding of sustained hyperthyroidism (ie, low TSH levels and high FT4 levels), a diffuse
goiter, and elevated homogenous uptake on 123I scintigraphy.
Hashimoto disease was defined by the presence of at least two of
the following three criteria: (1) thyroid autoantibodies; (2) reCHEST / 122 / 5 / NOVEMBER, 2002
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peatedly elevated TSH levels; and (3) diffuse goiter. The presence of thyroid autoantibodies or either of the above conditions
defined AITD. None of the patients had been exposed to
amiodarone, interferon-␣, or lithium within the past year, or to
iodinated contrast material within 2 months before the initial
thyroid function testing.
Descriptive statistics include percentages for categoric variables and means ⫾ SD for continuous measures. The ␹2 test with
the Yates correction factor was used to make statistical comparisons.
Results
The mean age of the cohort was 47 years (range,
19 to 79 years), there were 53 women and 10 men,
and PAH had been diagnosed for a mean duration of
2.7 years (range, 0.1 to 11.5 years). At the time of
the initial thyroid function evaluation, 15 patients
were receiving continuous IV epoprostenol (Flolan;
GlaxoSmithKline; Research Triangle Park, NC) by
infusion therapy, 2 patients were taking subcutaneous uniprost (Remodulin; United Therapeutics; Silver Spring, MD), and 1 patient was a heart-lung
transplant recipient. The mean follow-up period was
1.0 years (range, 0.1 to 2.3 years). At the most recent
evaluation, 8 patients were deceased, 30 patients
were receiving therapy with epoprostenol, 2 patients
were receiving therapy with uniprost, 3 patients were
receiving therapy with oral bosentan (Tracleer; Actelion Ltd; Basel, Switzerland), and 1 patient had
received a transplant. Thirty-one of the study patients (49%; 95% confidence interval, 37 to 62%)
were found to have AITD. Sixteen individuals
(8 with AITD) had a total of 24 first-degree family
members who were receiving treatment either for
Graves disease or Hashimoto disease.
AITD affected patients across all subgroups of
PAH (Table 1). The highest prevalence was seen
in the group with idiopathic PPH (67%). Overall,
21 patients were positive for TPOAb, 18 patients
were positive for TgAb, 13 patients were positive for
both, and 5 patients were negative for both. Thirteen
individuals carried prior diagnoses of AITD, while
18 patients were newly diagnosed, with 9 requiring
the initiation of pharmacologic intervention (4 for
Graves disease and 5 for Hashimoto disease). All of
the patients with thyroid dysfunction requiring pharmacologic treatment had autoimmune causes of
hypothyroidism (ie, Hashimoto disease and lymphocytic hypophysitis) or hyperthyroidism (Graves disease) [Table 2].
Thirty-five of the 63 patients had recently (ie,
⬍ 3 months ago) received a diagnosis of PAH. The
longitudinal thyroid test results in this subgroup
provide a valid prospective evaluation of the temporal relationships between the diagnosis or treatment
of thyroid disease and that of PAH. Seventeen of
these 35 patients were found to have AITD. Four
carried prior diagnoses of AITD, 12 received diagnoses of AITD at the initial visit to our institution,
while 1 patient was initially euthyroid with negative
test results for the presence of thyroid autoantibodies and developed Graves disease 9 months after the
initiation of epoprostenol therapy. Of the 12 individuals with occult AITD, 4 were hypothyroid, 4 were
hyperthyroid, and 4 were euthyroid with high-titer
thyroid autoantibodies and goiter.
How does the prevalence of AITD in PAH patients compare with that of the general population?
The percentage of PAH-afflicted patients necessitating medical therapy for AITD (33%) was dramatically higher than the 15% of patients with thyroid
dysfunction in the Colorado cohort26 (p ⬍ 0.0001).
The frequency of treated AITD in the subgroup of
women (38%) was considerably higher than the 13%
of women requiring treatment for AITD that was
noted in the 20-year longitudinal Whickham survey27
(p ⬍ 0.0001), despite a younger age distribution in
the women with PAH (mean, 46 vs 55 years, respectively). The frequency of the presence of first-degree
family history of AITD (25%) was also significantly
higher in the PAH cohort when compared to the
general population findings (5.5%; p ⬍ 0.001).28
Table 1—Frequency of AITD Characteristics in Patients With PAH*
Type of PAH
No.
Age, mean yr
Female
White
TPOAb (⫹)
TgAb (⫹)
AITD
Rx AITD
FHx AITD
Idiopathic PPH
CTD-associated
Liver disease-associated
Drug abuse-associated‡
Anorexigen-associated
HIV infection-associated
Entire cohort
24
13
6
11
6
3
63
48
49
46
41
52
39
47
20 (83)
13 (100)
4 (67)
8 (73)
6 (100)
2 (67)
53 (84)
16 (67)
9 (69)
5 (83)
10 (91)
6 (100)
2 (67)
48 (76)
12 (50)
1 (8)†
2 (33)
3 (27)
3 (50)
0 (0)
21 (33)
11 (46)
2 (15)†
1 (17)
1 (9)
3 (50)
0 (0)
18 (29)
16 (67)
5 (38)
2 (33)
4 (36)
4 (67)
0 (0)
31 (49)
10 (42)
3 (23)
2 (33)
3 (27)
3 (50)
0 (0)
21 (33)
4 (17)
5 (38)
2 (33)
3 (27)
2 (33)
0 (0)
16 (25)
*Values given as No. (%), unless otherwise indicated. CTD ⫽ connective tissue disease (including systemic lupus erythematosus, scleroderma,
rheumatoid arthritis, etc); FHx AITD ⫽ has first-degree family history of AITD; Rx AITD ⫽ requiring pharmacologic treatment for AITD.
†Seven patients were receiving immunomodulatory agents, which may suppress thyroid autoantibody formation.
‡Either amphetamine and/or cocaine abuse.
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Clinical Investigations
Table 2—Frequency of Specific Diagnoses of Thyroid Disease in 31 Patients With Concurrent PAH and AITD*
Type of PAH
Hashimoto
Disease
Graves
Disease
Euthyroid With
Thyroid Antibodies
6
4
1
1
2
4
5
1
1
2
1
1
1§
14
8
8
Idiopathic PPH
CTD-associated
Liver disease-associated
Drug abuse-associated‡
Anorexigen-associated
HIV infection-associated
Entire cohort
Others
Total AITD
1†
16
5
2
4
4
0
31
1
*See Table 1 for abbreviations not used in the text.
†Patient had received putative diagnosis of lymphocytic hypophysitis and was hypothyroid.
‡Either amphetanine and/or cocaine abuse.
§Patient had received diagnosis of lymphocytic hypophysitis.
Discussion
PAH results from complex, poorly understood
interactions between genetic factors and environmental triggers. Genetic studies identified bone
morphogenetic protein receptor-II mutations in patients manifesting familial and sporadic PPH.29,30
Additional genetic factors potentiating immune dysfunction also may be involved, since the following
features of autoimmune disease are commonly observed in PAH patients: marked female gender
predominance31,32; distinctive human leukocyte antigen haplotypes33,34; high frequency of autoantibodies33,35; concomitant connective tissue disease2,3; and
disease reversal with immunosuppressive therapy.36,37 The results of this study support the presence
of immune dysfunction in PAH-affected individuals,
since 49% had evidence of AITD. The high frequency of PAH patients with first-degree family
histories of AITD, even in those without a personal
history of AITD, further suggests the presence of
immunogenetic clustering.
The 49% prevalence of AITD in PAH patients is
striking, exceeding the frequency found in any of
several well-characterized autoimmune diseases that
are associated with AITD. These include type 1
diabetes mellitus, Addison disease, and pernicious
anemia, which aggregate in the polyglandular autoimmune syndromes.38 Also associated with AITD are
nonendocrine disorders including myasthenia gravis39 and the collagen vascular diseases.40 Of these
various conditions, connective tissue diseases have
been described previously to associate separately
with either AITD41,42 or PAH,2,3 and, notably, 13
individuals in this cohort had concomitant diagnoses
of AITD, PAH, and collagen vascular disorders. The
potential immunogenetic overlap between PAH and
AITD is further supported by data on the use of
interferon-␣, which has been shown to induce autoimmune disorders,43 most commonly AITD,44 and is
www.chestjournal.org
also associated with the development of PAH.45 With
multiple lines of evidence suggesting immune dysfunction in PAH patients, the role of immunoregulatory agents in treating early PAH should be examined. Currently, only incidental data exist on the
efficacy of immunosuppressive agents to attenuate
elevated pulmonary artery pressures in patients with
pre-existent autoimmune connective tissue disorders.36,37
This report is the first prospective and systematic
evaluation of thyroid dysfunction in PAH patients
with the use of clinical, biochemical, and serologic
parameters of AITD. The collective AITD prevalence of 49% is the highest reported frequency of
thyroid dysfunction in PAH patients, yet the prevalence of individual measurements of thyroid disease
resembles those of previous observations, supporting
the general applicability of these findings. For example, our presurvey prevalence of hypothyroidism
(19%) was within the range of retrospectively determined rates of 10 to 24%.17–19 The TgAb prevalence
(29%) in this cohort is virtually identical to the
previously reported 30% rate.20 Despite the high
overall prevalence of AITD, it may yet be an underestimation, because six patients without thyroid disease were treated with immunosuppressants, which
can mitigate the development of AITD.46
On the basis of retrospective analyses, previous
authors have speculated that prostacyclin treatment
of PAH patients may lead to thyroid disease10,11 or,
alternatively, that thyroid dysfunction may lead to
PAH.17,18 However, the results from this study demonstrate a lack of chronologic relationship between
the diagnosis or treatment of AITD and either PAH
diagnosis or prostacyclin therapy initiation. Of the 35
patients in this cohort who were newly diagnosed
with PAH, and thus could be validly assessed for
thyroid dysfunction on a prospective basis, 17 patients were confirmed to have AITD, but only 1 of
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these patients developed thyroid disease after the
initiation of prostacyclin therapy. Of the 12 patients
with newly diagnosed PAH who were also newly
found to have AITD, 4 were hypothyroid, 4 were
hyperthyroid, and 4 were euthyroid with thyroid
autoantibodies. This suggests that the pathogenesis
of PAH does not derive from the particular direction
of disturbance in thyroid hormone concentrations.
However, it is possible that abnormal circulating
levels of thyroid hormone may have exacerbated
right heart dysfunction,47 leading to an earlier diagnosis of PAH in several patients.
A substantial 29% of the entire cohort of patients
were newly diagnosed with AITD, and half of these
patients had abnormal results of thyroid function
tests, requiring the initiation of pharmacologic treatment. These findings strongly advocate for a systematic, comprehensive evaluation of thyroid disease in
all patients with PAH, including the assessment of
both serologic and biochemical parameters. Thyroid
autoantibodies are important, because high titers in
the euthyroid individual indicate incipient AITD,
which may portend future thyroid dysfunction,27 and
should prompt frequent thyroid function monitoring
in the patient with PAH. Biochemical tests for TSH,
FT4, and free triiodothyronine concentrations are
critical for discovering occult thyroid disease, since
objective findings of dysthyroidism are often nonspecific and subtle, and may be masked by severe
symptoms that are associated with pulmonary hypertension. The most commonly detected thyroid function abnormality, subclinical hypothyroidism (ie, elevated TSH levels and normal FT4 levels) may not
often need to be treated in the healthy ambulatory
individual,48 but in the patient with PAH with a
tenuous cardiac reserve, appropriate thyroxine treatment may improve hemodynamic function. In our
cohort, symptomatic improvement was reported by
the nine patients with newly diagnosed hypothyroidism or hyperthyroidism after the treatment of thyroid disease, but the concomitant initiation or modification of PAH therapy during the time interval (ie,
⬎ 1.5 months) required for the achievement of
euthyroidism confounded these observations. However, one would generally expect improved circulatory and respiratory function with the restoration of
normal thyroid function.24,25
In summary, this study has demonstrated a dramatic association between AITD and PAH, with
evidence for a common immunogenetic susceptibility. The approach of identifying in PAH-affected
patients the collective syndrome of AITD, rather
than its separate components, provides a unifying
explanation for previously observed associations
among PAH and hypothyroidism, hyperthyroidism,
or the presence of thyroid autoantibodies. Future
studies should focus on discovering the immunogenetic overlap between AITD and PAH, such as
common human leukocyte antigen alleles, susceptibility loci, autoantibodies and/or autoantigens, and
the mechanisms of immune dysfunction. Such an
improved understanding of the genetic and immune
factors causing PAH may ultimately lead to novel
effective approaches in diagnosis and treatment.
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