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(Chest. 2006;130:526-532.)
© 2006 American College of Chest Physicians

Prevalence of Hypothyroidism and Graves Disease in Sarcoidosis*

Alessandro Antonelli, MD; Piera Fazzi, MD; Poupak Fallahi, MD; Silvia Martina Ferrari, PhD and Ele Ferrannini, MD

* From the Metabolism Unit (Drs. Antonelli, Fallahi, and Ferrannini, and Ms. Ferrari), Department of Internal Medicine, and Respiratory Pathophysiology Section (Dr. Fazzi), Cardiac and Thoracic Department, University of Pisa, Pisa, Italy.

Correspondence to: Alessandro Antonelli, MD, Department of Internal Medicine, University of Pisa, via Roma, 67, 56100, Pisa, Italy; e-mail: a.antonelli{at}med.unipi.it

Abstract

Background: The association of sarcoidosis (S) and thyroid autoimmunity has been reported by several studies in a wide range of variability. The aim of our study was to evaluate the prevalence of clinical and subclinical thyroid disorders in patients with S vs gender-matched and age-matched control subjects.

Methods: Thyroid hormones and antithyroid antibodies, thyroid ultrasonography and fine-needle aspiration were performed in 111 patients with S who had been consecutively referred to the Respiratory Pathophysiology Section of the University of Pisa, and the results were compared to 333 gender-matched and age-matched control subjects from the same geographic area.

Results: The odds ratio for subclinical hypothyroidism for female patients with S vs control subjects was 2.7 (95% confidence interval [CI], 1.3 to 5.9); for anti-thyroid peroxidase antibody titer (AbTPO) positivity, 2.2 (95% CI, 1.2 to 3.9); and for thyroid autoimmunity, 1.9 (95% CI, 1.1 to 3.2). The mean values of thyroid-stimulating hormone and AbTPO were higher in female S patients than in control subjects (p < 0.01). A significantly higher prevalence of clinical hypothyroidism (four patients) and Graves disease (three patients) was observed in female S patients than in control subjects (none; p = 0.005 and 0.0026, respectively). Two cases of papillary thyroid cancer were detected in S patients. No significant difference between S patients and control subjects was detected for free triiodothyronine and thyroxine, antithyroglobulin autoantibodies, thyroid volume and nodularity, and subclinical hyperthyroidism.

Conclusions: Thyroid function, AbTPO antibodies, and ultrasonography should be tested as part of the clinical profile in female S patients. Subjects who are at high risk (female subjects, those with positive AbTPOs, and those with hypoechoic and small thyroid) should have thyroid function follow-up and appropriate treatment in due course.

Key Words: autoimmune thyroiditis • antithyroid peroxidase antibody • Graves disease • hypothyroidism • sarcoidosis • thyroid cancer • thyroid ultrasonography

Sarcoidosis is a multisystem disorder of unknown cause.12 The diagnosis is established when clinicoradiologic findings are supported by histologic evidence of noncaseating epithelioid cell granulomas; granulomas of known causes must be excluded.34

The association of sarcoidosis (S) and thyroid autoimmunity5678910 has been reported by several studies, with a wide range of variability. However, from a review of the literature the following considerations arise: (1) many studies do not have an appropriate control group to evaluate the relative risk of hypothyroidism56; (2) among the studies reporting a higher prevalence of thyroid autoimmunity in S patients than in control subjects, discrepant results have been reported about the prevalence of different antithyroid autoantibodies5678; (3) a high prevalence of clinical thyroid dysfunction (ie, Hashimoto thyroiditis, often without reporting the results of thyroid hormone detection in the absence of levothyroxine treatment) has been reported by some studies,67 but it has not been found in others8; (4) thyroid ultrasonography that had been progressively becoming one of the most important tools for the diagnosis of thyroid disorders has been evaluated in S patients in only two studies711; (5) furthermore, no study has taken into account iodine intake, which is a major determinant of thyroid disorders and have not included a complete thyroid workup; and (6) no study evaluated separately patients who were in treatment from patients who were not receiving corticosteroids, which are well-known immunosuppressive agents. For other thyroid disorders, such as hyperthyroidism and Graves disease,111213 central hypothyroidism,14 thyroid nodules,11 thyroid cancer,1215 and S of the thyroid,1216 only anecdotal reports are present in the literature.17 The aim of our study was to evaluate the prevalence of clinical and subclinical thyroid disorders in a wide group of patients with S by assessing thyroid morphology during ultrasound examination and by detecting thyroid hormones as well as the presence of antithyroid antibodies, and comparing their findings with those in a gender-matched (the prevalence of thyroid autoimmune disorders is four to eight times higher in women than in men18) and age-matched control group from the same geographic area who had a well-defined iodine intake, which is a major determinant of thyroid function and morphology.19

Methods and Materials

Patients
S Patients:
A total of 111 S patients who had been consecutively referred to the Respiratory Pathophysiology Section of the University of Pisa were recruited into the study. S was diagnosed according to the accepted criteria123; only patients with biopsy-proven cases of S have been included. Thyroid evaluation was performed before the start of corticosteroid treatment in S patients.

Control Group-General Population:
Each of the S patients who was eligible for the study was matched, by sex and age, one to three with a control group of subjects of the background population from the same geographic area (northwest Tuscany). This control group was extracted from a larger random sample of 1,640 subjects (who were enrolled without any selection in relation to the presence or absence of previously recognized thyroid disorders) in a population-based survey of thyroid disorders.20 Iodine intake differs within Tuscany, and reliable data on local iodine intake based on urinary iodine excretion are available.19 The extraction of either control group from the original populations was performed by finding the closest age match (± 3 years) to each subject within either gender. When more than one age match was available per subject, the choice was made at random. Subjects with a history of rheumatic diseases were excluded from the control group.

All patients and control subjects underwent a complete clinical evaluation, with special attention paid to risk factors for thyroid disorders (ie, a family history of thyroid disease and residence in iodine-deficient areas). The demographic characteristics of patients with S or control subjects are reported in Table 1 . The S patients and control subjects had similar distributions by sex and age by the matching procedure. The majority of S and control subjects had resided in an iodine-deficient area for ≥ 20 years, without a significant difference among the two groups (Table 1).


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  		Table 1. Demographic Characteristics of Patients With S or Control Subjects*

 
Methods
Ultrasonography of the Neck and Fine-Needle Aspiration:
An ultrasound examination of the thyroid (model AU5 with a sectorial 7.5-MHz transducer; Esaote; Florence, Italy) was carried out in all subjects by a single physician, who was blinded to the laboratory findings. The following parameters were evaluated: (1) the thyroid volume212223; (2) the structural abnormalities in the thyroid tissue, scored as previously reported (0, 1, or 2) 212223; and (3) the presence or absence of thyroid nodules. Subject with nodules having a diameter of > 10 mm underwent fine-needle aspiration (FNA).212223

Thyroid Blood Flow:
Thyroid blood flow by color-flow Doppler scanning was studied and scored (0, I, II, and III) in all patients,2223 as previously reported.

Laboratory Evaluation:
The laboratory evaluation included the measurement of serum levels of thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), antithyroglobulin (AbTg), antithyroid peroxidase antibody titers (AbTPOs), and anti-TSH-receptor autoantibodies (TRAbs). Circulating FT3 and FT4 were measured by commercial radioimmunoassay kits (AMERLEX-MAB FT3/FT4 Kit; Amersham Biosciences; Little Chalfont, UK). Measurements of serum levels of TSH (DiaSorin; Stillwater, MN), and AbTPO (positivity, > 100) and AbTg (ICN Pharmaceuticals; Costa Mesa, CA) [positivity, > 100 UI/mL] were evaluated by immunoradiometric assay methods. TRAb levels were measured in patients with the use of a radioreceptor assay (Radim; Milan, Italy) [normal range, 0 to 1 UI/mL].

Values are given as the mean ± SD for normally distributed variables. The study was approved by the institutional ethics committee, and all subjects gave their informed written consent to participate.

Statistical Analysis
Since female gender is a well-recognized risk factor for thyroid disorders,18 levels of TSH, FT3, FT4, AbTPO, and AbTg were compared only among subjects of the same gender. Mean group values were compared by using one-way analysis of variance for normally distributed variables. The {chi}2 test or the odds ratio were used to compare categoric variable.

Results

Results in Female S Patients and Female Control Subjects
TSH serum and AbTPO levels were significantly higher in S patients than in the group of female control subjects (Table 2 ). Subclinical hypothyroidism (defined as a TSH level of > 3.6 µU/mL with FT4 and FT3 levels within the normal range) was significantly more common in S than in control subjects, as was clinical hypothyroidism (defined as a TSH level of > 3.6 µU/mL with FT4 levels below the normal range). The mean TSH level was 4.5 ± 2.8 µU/mL (range, 3.7 to 11.7 µU/mL) in S patients with subclinical hypothyroidism, 38.6 ± 50.5 µU/mL (range, 13.7 to 128 µU/mL) in patients with clinical hypothyroidism, and 5.2 ± 2.4 µU/mL (range, 3.6 to 11.4 µU/mL) in control subjects with subclinical hypothyroidism. The prevalence of subjects with positive AbTPOs and a thyroid hypoechoic pattern, which is a sign of inflammatory involvement of thyroid tissue,212223 were more frequent in S patients than in control subjects. Thyroid autoimmunity was diagnosed by ultrasonography in the absence of positive AbTg or AbTPO levels in four women with S and in two control subjects. On the whole, indexes of thyroid autoimmunity (AbTg, AbTPO, or ultrasonographic diagnosis of thyroiditis) were significantly more frequent in S patients than in control subjects (Table 2). In contrast, there was no statistically significant difference in the prevalence of subclinical hyperthyroidism (defined as a TSH level of < 0.2 µU/mL with FT4 and FT3 levels within the normal range) among female patients in the two groups (Table 2). The prevalence of Graves disease21 (presence of a diffuse goiter varying in size from normal to very large was established from the clinical presentation), thyroid hormones (clinical hyperthyroidism defined as a TSH level of < 0.2 µU/mL with FT3 level above the normal range), thyroid autoantibody measurements (presence of TRAb), and/or thyroid ultrasonography (decreased, dishomogeneous echogenicity and diffuse goiter) was significantly higher in female patients with S (Table 2) than in control subjects. No case of clinical hyperthyroidism was observed among control subjects. The thyroid volume was lower, although not significantly, in S patients than in control subjects. Thyroid enlargement (defined as a thyroid volume of > 20 mL) was not significantly different in the two groups, as was the prevalence of thyroid nodules. One case of papillary thyroid cancer (suspected by the findings of FNA and confirmed by histology) was observed in female patients with S, while no case was observed in control subjects.


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  		Table 2. Comparison of Thyroid Status Among Female Patients With S or Control Subjects*

 
Only one case of hypothyroidism with positive TRAb has been detected.910 The odds ratio for subclinical hypothyroidism for female patients with S compared to female control subjects was 2.7 (95% confidence interval [CI], 1.3 to 5.9), for AbTPO positivity it was 2.2 (95% CI, 1.2 to 3.9), and for thyroid autoimmunity it was 1.9 (95% CI, 1.1 to 3.2).

Results in Male S Patients and Male Control Subjects
The prevalence of male patients with S who had positive AbTPOs and the measured values of their AbTPOs were higher than those in control subjects (Table 3 ). Thyroid autoimmunity was diagnosed by ultrasonography in the absence of positive AbTg and AbTPO values in two patients with S and one control subject. On the whole, indexes of thyroid autoimmunity (ie, AbTg or AbTPO levels, or ultrasonographic diagnosis of thyroiditis) were found more frequently in male S patients than in male control subjects. One case of papillary thyroid cancer (suspected by FNA findings and confirmed by histology) was observed in a male patient with S, while no case was observed in control subjects. One case of clinical hypothyroidism was observed in S patients; no case of clinical hyperthyroidism was found.


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  		Table 3. Comparison of Thyroid Status Among Male Patients With S or Control Subjects*

 
General Results
In each group (Table 2, 3), any kind of thyroid disorder had a higher prevalence in women than in men, with the exception of thyroid enlargement (defined as a thyroid volume of > 20 mL). Thyroid enlargement was more frequent in men, as expected since thyroid volume is physiologically higher in men,2122 but no significant difference in prevalence was shown between male S patients and male control subjects (Table 2, 3). Pooling the data of the female and male S patients (Table 4 ), thyroid enlargement was significantly associated with the presence of thyroid nodules, while no association was found with positive AbTPO or AbTg values or hypothyroidism (no relationship was found with the other thyroid parameters). After pooling the data for female and male S patients (Table 5 ), hypothyroidism was significantly associated with the presence of AbTPOs, a low thyroid volume (< 6 mL), a hypoechoic pattern, and the presence of thyroid autoimmunity (no relationship was found with the other thyroid parameters).


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  		Table 4. Relationship Between Thyroid Enlargement (Thyroid Volume > 20 mL) and Other Thyroid Parameters in Patients With S*

 

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  		Table 5. Relationship Between Hypothyroidism (TSH > 3.6 µU/mL) and Other Thyroid Parameters in Patients With S*

 
In S and control subjects with autoimmune thyroid disorders, thyroid blood flow bore no relation to the thyroid status. No cases of central hypothyroidism,14 thyroid S,1216 or euthyroid sick syndrome24 were observed in S patients and control subjects.

Discussion

Discrepant results have been reported about the prevalence of different antithyroid autoantibodies and hypothyroidism.5678910 The results of our study, using more tests and more sensitive methodology, in a larger group of 111 S patients who were matched by gender18 and age with 333 control subjects, who had a similar risk for iodine deficiency, demonstrated a significantly higher prevalence (5% and 17%, respectively) for clinical and subclinical hypothyroidism in female S patients than in control subjects. It should be stressed that the control group was a sample of the general population of central Italy, so the present series is a case-control study and not an epidemiologic survey. However, the prevalence of hypothyroidism in the female control subjects was substantial (7%), was fully in the range of the reported age-adjusted prevalence rates for the Italian population,20 and was similar to that (8%) of other population-based surveys.25 Interestingly, the mean TSH value was significantly higher in female S patients than in female control subjects, which is in agreement with other studies.7

Autoimmune phenomena are often present in patients with S.12 The percentage of antithyroid antibodies ranged from 1.3 to 54.5% in different studies.711 This wide range may be at least partially explained by the application of steroids and immunosuppressive drugs in S patients, by the different gender and age composition,7 and by the iodine intake of S patients. In most of the studies, AbTg antibodies were more common than antimicrosomal antibodies,58 while in the more recent studies67 a higher prevalence of AbTPO was found. In our female control subjects, the prevalence of AbTPO positivity was 19%, which is fully in the range of the reported age-adjusted prevalence rates for the Italian population20 and for other population-based surveys,25 while in S patients the prevalence of AbTPO positivity was 34%, which is significantly higher. The prevalence of AbTg from population studies has been reported2025 to be approximately 10% in female patients (range, 10 to 15%), which is similar to the prevalence observed in our female control subjects (15%), while in S patients the prevalence of AbTg positivity was 12%, which is not significantly different. Altogether, the above-mentioned data indicate a higher prevalence of thyroid autoimmunity in female S patients compared to female control subjects.

The presence of antithyroid antibodies was found in about two thirds of S patients with hypothyroidism. Moreover, hypothyroidism in S patients is significantly associated with a thyroid hypoechoic pattern and a small thyroid volume. These findings suggest that autoimmunity is very important in the pathogenesis of hypothyroidism and in S patients, and that ultrasonography is able to detect the morphologic alterations of thyroid tissue that are associated with a higher risk of hypothyroidism. Only one case of hypothyroidism with positive TRAb test results has been detected, suggesting that this association is not frequent.910

The incidence of hyperthyroidism in patients with S is unknown.1213 In our study, a significantly higher prevalence of Graves disease, which is of clear autoimmune origin, was observed in female S patients, while no significant difference was observed for subclinical hyperthyroidism, which is mainly related to nodular goiter with functionally autonomous nodules. The diagnosis of clinical hypothyroidism and Graves disease in female S patients permitted us to promptly start the appropriate therapies, avoiding the consequences of prolonged thyroid dysfunction.

We did not find any case of central hypothyroidism14 or of euthyroid sick syndrome24 in S patients. In our S patients, FT4 and FT3 levels, thyroid volume,20 and the prevalence of thyroid nodules1120 were not significantly different from those of control subjects.

Single reports1215 of the association of S with thyroid cancer have been published. In our series of S patients, two cases of thyroid papillary cancer were detected, with a higher, even if not statistically significant, prevalence than control subjects. It is difficult to conclude that there is a pathogenetic link between S and neoplasia, although such an association has been suggested by some authors.15 However, our data suggest the need for a careful thyroid follow-up in S patients with thyroid nodules. No case of thyroid granulomatosis1216 was observed, suggesting that this condition occurs infrequently in S patients.

The association of autoimmune disorders is a well-known phenomenon.2627 The pathogenetic base of this association is under debate. However, much evidence accumulated from animal models and available in cases of human disease favors a prevalent T-helper type 1 lymphokine profile in the target organs of patients with S,2829 such as those with thyroid autoimmune disorders.222330 This T-helper type 1 lymphokine prevalence, under the combined action of genetic and environmental conditions, may involve different organs in the same subject, with the appearance of multiple immune-mediated disorders, leading to different clinical disorders.2627

In conclusion, the results of our study in a large group of S patients demonstrate that female patients had a significantly higher prevalence of AbTPOs, ultrasonographic findings of thyroid autoimmunity, clinical and subclinical hypothyroidism, and Graves disease than did a very large group of control subjects with a similar iodine status. Thyroid function should be tested and ultrasonography performed as part of the clinical profile in female S patients. Those patients who are at high risk (ie, female patients, patients with, and patients who are positive AbTPOs, are hypoechoic and have a small thyroid) should have thyroid function follow-up and appropriate treatment in due course.

Footnotes

Abbreviations: AbTg = antithyroglobulin; AbTPO = anti-thyroid peroxidase antibody titer; CI = confidence interval; FNA = fine-needle aspiration; FT3 = free triiodothyronine; FT4 = free thyroxine; S = sarcoidosis; TRAb = anti-thyroid-stimulating hormone receptor autoantibody; TSH = thyroid-stimulating hormone

The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication November 11, 2005. Accepted for publication February 11, 2006.

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