Association Between Non-Infectious Uveitis and Thyroid Dysfunction: A Case Control Study

Abstract

Background:

Several reports suggested a relation between uveitis and thyroid disease or dysfunction. However, no study has investigated the association between uveitis and thyroid dysfunction. The purpose of this study was to compare the prevalence of thyroid dysfunction in patients with and without non-infectious uveitis.

Methods:

This was a retrospective, case-control study.

Results:

Two hundred thirty-five non-infectious uveitis patients (uveitis group) and 600 controls (control group) were included in the study, of whom 492 (58.9%) were females. No differences were demonstrated between the uveitis and control groups with regard to baseline characteristics, including age, sex, and the presence of systemic diseases such as diabetes, hypertension, and cardiac disease. Rheumatologic and gastrointestinal disease were more common in the uveitis group (p < 0.001 and p = 0.007, respectively). Overall, thyroid dysfunction was noted in 61 (7.3%) patients, of whom 55 had hypothyroidism and six had hyperthyroidism. Seventeen out of 235 (7.2%) uveitis patients and 44/600 (7.3%) controls were diagnosed with thyroid dysfunction—a similar proportion in both groups (p = 0.96). Of these, all uveitis patients and 38 (86.4%) patients in the control group had a diagnosis of hypothyroidism (p = 0.63). A higher percentage of women was found among uveitis patients with thyroid dysfunction compared with uveitis patients without thyroid dysfunction (p = 0.002). The most common uveitis type was anterior uveitis. No significant difference was found in uveitis types between patients with or without a diagnosis of thyroid dysfunction.

Conclusions:

The prevalence of thyroid dysfunction was similar in both groups, and no association was found between non-infectious uveitis and thyroid dysfunction in this study. These findings suggest there is no need for routine thyroid function evaluation in patients with non-infectious uveitis.

Introduction

Noninfectious uveitis is an immune-mediated ocular disease, which may present an ocular manifestation of a systemic disease. It is characterized by an intraocular inflammation of the uvea (consisting of the iris, ciliary body, and choroid), and may involve other parts of the eye such as the vitreous, retina, and optic nerve (1). There is a known association between uveitis and several systemic diseases. Their prevalence varies among different geographical regions and ethnic groups, and may be influenced by genetic and environmental factors (2,3). Understanding the underlying etiology of uveitis is essential for understanding disease pathogenesis and selecting the appropriate treatment. Therefore, uveitis patients undergo a comprehensive systemic evaluation and extensive laboratory investigations.

Search of the PubMed database of English publications revealed several reports regarding uveitis and thyroid dysfunction and or disease. Initially described by O'Rourke et al. in 1960 (4), it was suggested that patients with uveitis have a decreased peripheral utilization of thyroid hormone. Cantor et al. (5) found decreased thyroxine (T4) levels in some patients with uveitis, while Mizoguchi et al. (6) found Graves' disease in 2.3% of uveitis patients. In addition, specific uveitis entities were found to be related to thyroid disease or dysfunction (7 –25): Tubulointerstitial nephritis and uveitis (TINU) syndrome was associated mainly with hyperthyroidism (7 –11). One study (11) also described hypothyroidism in Chinese adults with TINU, and Hashimoto's thyroiditis was the major cause of the thyroid abnormalities in this study. Patients with Vogt–Koyanagi–Harada's (VKH) syndrome were found to have hyper- and hypothyroidism (12 –18), while human T-cell leukemia virus type 1 (HTLV-1)-associated uveitis was found to be correlated only with Graves' disease (19 –25).

Although these studies suggest an association between uveitis and thyroid dysfunction, no study to date has evaluated the prevalence of thyroid dysfunction among non-infectious uveitis patients compared to a control group of healthy subjects. Therefore, the purpose of this study was to investigate the association between non-infectious uveitis and thyroid dysfunction in a large case-control study.

Materials and Methods

This study was a single-center retrospective case-control study. It was performed in accordance with the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board of the Tel Aviv Medical Center (Tel Aviv, Israel). Charts of patients with uveitis seen at the uveitis service at the Tel Aviv Medical Center between 2012 and 2015 were reviewed. The study compared patients with all types of non-infectious uveitis to randomly selected controls seen in the ophthalmology emergency room (ER) and the ophthalmology general clinic within the same time period at a ratio of 1:3 cases to controls. No patients were hospitalized; all were referred from clinics in the community and treated as outpatients. Control patients who were seen in the ER or general clinic and who were diagnosed with uveitis were included in the case group. Only patients older than 18 years of age were included in the study. Patients with missing systemic or ophthalmic data from their medical records and/or patients with systemic or ocular conditions hindering an appropriate examination were excluded. Uveitis was classified per the SUN classification (26). Demographic information collected for both cases and controls included age, sex, and medical history. Patients categorized as having thyroid dysfunction were patients with a current diagnosis of either hypothyroidism or hyperthyroidism, as defined in their medical records by their attending physician or endocrinologist. In addition, these patients were treated with either thyroid hormone replacement therapy or antithyroid medication. Cardiac diseases included cardiac arrhythmia, congestive heart disease, and ischemic heart disease. Rheumatologic diseases included ankylosing spondylitis, Behcet's disease, familial Mediterranean fever (FMF), fibromyalgia, juvenile idiopathic arthritis, non-specific spondyloarthropathy, psoriatic arthritis, reactive arthritis, rheumatoid arthritis, sarcoidosis, spondylitis associated with inflammatory bowel disease, and systemic lupus erythematosus. Gastrointestinal diseases included celiac disease, gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD; i.e., Crohn's disease or ulcerative colitis).

Sample-size calculation

Using Winpepi v11.63 (J.H. Abramson 2003–2016) with the significance level set at 5% and the power at 90%, a minimal sample size was calculated of 800 patients with a 1:3 patients-to-control ratio (i.e., 200 cases and 600 controls) in order to detect a minimal 2.5 odds ratio of thyroid dysfunction between patients with and without uveitis.

Statistical analysis

Data were recorded in Microsoft^® Excel (2010) and analyzed using IBM SPSS for Windows v21 (IBM Corp., Armonk, NY). Continuous variables such as age were compared between subjects using the independent sample t-test, or for small group comparison and ordinal variables, the Mann–Whitney nonparametric test was used. Binary variables were compared between subjects using Fisher's exact test or Pearson's chi-square test. Odds ratios and confidence intervals were calculated for the primary outcome. All tests were two-tailed, and the threshold for statistical significance was defined as p < 0.05.

Results

Baseline characteristics

The study included 835 patients. Of these, 492 (58.9%) were females. The mean age was 47.01 ± 16.56 years. There were 235 patients with non-infectious uveitis and 600 controls. No differences in baseline characteristics were found between the uveitis and control groups. There was a similar distribution of age, sex, and the presence of systemic diseases, including diabetes, hypertension, and cardiac diseases. Rheumatologic diseases were more common in the uveitis group (p < 0.001). Ankylosing spondylitis was the most common rheumatologic disease among uveitis patients, and its prevalence was 6.8% compared with 0.2% in the control group (p < 0.001). FMF was the most common rheumatologic disease among the control group, and its prevalence was similar in both groups. Gastrointestinal diseases were more common in the uveitis group (p = 0.007). IBD was the most common gastrointestinal disease among uveitis patients, and its prevalence was 3.8% compared with 0.7% in the control group (p = 0.002). GERD was the most common gastrointestinal disease among the control group, and its prevalence was similar in both groups (Table 1).

Table 1.

Patients' Baseline Characteristics

	Non-infectious uveitis cases, n = 235	Controls, n = 600	p
Age at examination, years (mean ± SD)	47.96 ± 15.3	46.63 ± 17.0	0.273
Sex-female, n (%)	138 (58.7%)	354 (59.0%)	0.942
Systemic diseases, n (%)
Diabetes	20 (8.5%)	67 (11.2%)	0.259
Hypertension	43 (18.3)	118 (19.7%)	0.651
Cardiac diseases	9 (3.8%)	34 (5.7%)	0.280
Rheumatologic diseases	35 (14.9%)	10 (1.7%)	<0.001
Gastrointestinal diseases	22 (9.4%)	27 (4.5%)	0.007

n, number of eyes; SD, standard deviation.

Thyroid dysfunction and uveitis

Overall, thyroid dysfunction was found in 61 (7.3%) patients, of whom 55 had hypothyroidism and six had hyperthyroidism. While comparing the prevalence of thyroid dysfunction between cases and controls, 17/235 (7.2%) uveitis patients and 44/600 controls (7.3%) had a diagnosis of thyroid dysfunction (p = 0.96). Hypothyroidism was found to be the most common thyroid disorder in both groups. All uveitis patients and 38 (86.4%) patients in the control group were diagnosed with hypothyroidism (p = 0.63; Table 2).

Table 2.

Association Between Non-Infectious Uveitis and Thyroid Dysfunction

				CI
	Non-infectious uveitis cases, n = 235	Controls, n = 600	OR	Lower	Upper	p
Thyroid dysfunction, n (%)	17 (7.2%)	44 (7.3%)	1.015	0.568	1.815	0.960
Hypothyroidism, n (%)	17 (7.2%)	38 (6.3%)	0.867	0.479	0.569	0.637
Hyperthyroidism, n (%)	0	6 (1.0%)				0.124

OR, odds ratio; CI, confidence interval.

Characteristics of non-infectious uveitis diagnoses are shown in Table 3. In regard to the characteristics of non-infectious uveitis patients with and without thyroid dysfunction, no difference was found in age or the presence of bilateral ocular disease. A higher percentage of women was found among uveitis patients with thyroid dysfunction compared with uveitis patients without thyroid dysfunction (p = 0.002). No difference was found in the rate of underlying systemic diseases, including diabetes, hypertension, cardiac diseases, rheumatologic diseases, or gastrointestinal diseases.

Table 3.

Non-Infectious Uveitis Diagnoses

Diagnosis ^a	Number out of 235 (%) ^a
Behcet's	5 (2.1%)
Birdshot chorioretinopathy	4 (1.7%)
Fuchs' heterochromic iridocyclitis	3 (1.3%)
Idiopathic	180 (76.6%)
Posner Schlossman	1 (0.4%)
Rheumatoid arthritis	4 (1.7%)
Sarcoidosis	6 (2.5%)
Seronegative spondyloarthropathy^b	32 (13.6%)
VKH	2 (0.8%)

Two patients had more than one known cause.

Seronegative spondyloarthropathy included ankylosing spondylitis, reactive arthritis, psoriatic arthritis, spondylitis associated with inflammatory bowel disease, and undifferentiated spondyloarthropathy.

VKH, Vogt–Koyanagi–Harada.

Among uveitis patients, 179 (76.2%) patients had anterior uveitis, 31 (13.2%) had intermediate uveitis, 24 (10.2 %) had panuveitis, and one (0.4%) had posterior uveitis. No difference in the type of uveitis was found between uveitis patients with or without thyroid dysfunction (Table 4).

Table 4.

Characteristics of Non-Infectious Uveitis Patients in Relation to the Presence of Thyroid Dysfunction

	Non-infectious uveitis cases with hypothyroidism, n = 17	Non-infectious uveitis cases with no thyroid dysfunction, n = 218	p
Age at examination, years, mean ± SD	53.88 ± 16.7	47.5 ± 15.1	0.097
Sex (female), n (%)	16 (94.1%)	122 (56.0%)	0.002
Bilateral eye disease, n (%)	5 (29.4%)	53 (24.3%)	0.574
Systemic diseases, n (%)
Diabetes	0 (0%)	20 (9.2%)	0.374
Hypertension	5 (29.4%)	38 (17.4%)	0.207
Cardiac diseases	0 (0%)	9 (4.1%)	1.000
Rheumatologic diseases	2 (11.8%)	33 (15.1%)	1.000
Gastrointestinal diseases	2 (11.8%)	20 (9.2%)	0.665
Uveitis type, n (%)
Anterior uveitis	15 (88.2%)	164 (75.2%)	0.374
Intermediate uveitis	1 (5.9%)	30 (13.8%)	0.707
Posterior uveitis	0 (0%)	1 (0.5%)	1.000
Panuveitis	1 (5.9%)	23 (10.6%)	1.000

Discussion

This study examined the association between non-infectious uveitis and thyroid dysfunction. It is the first case-control study assessing this subject. A similar proportion of thyroid dysfunction was found among patients with or without uveitis and did not confirm an association between non-infectious uveitis and thyroid dysfunction.

Similar to the known prevalence of thyroid dysfunction in iodine-replete countries (27), most of the patients had hypothyroidism (all of the uveitis patients and 86% of the control group). In addition, a significant female preponderance was found among patients with uveitis who also had thyroid dysfunction compared with uveitis patients without thyroid dysfunction. This finding is also compatible with the higher prevalence of thyroid dysfunction among women in the general population (27). An equal distribution of non-infectious uveitis was found between men and women, and the most common uveitis type was anterior uveitis, similar to findings in other uveitis studies (2,3). Rheumatologic and gastrointestinal diseases were significantly more common in the uveitis group compared with controls, as explained by the strong correlation between various rheumatologic and gastrointestinal diseases and uveitis (1). These findings strengthen the external validity of this study.

Few previous publications have demonstrated thyroid-function disorders among patients with uveitis. O'Rourke et al. (4) found a high incidence of decreased basal metabolic rate in patients with uveitis who were studied for thyroid dysfunction. They further noted that there was a decreased turnover of radioactive thyroxine and that the percent of the extrathyroidal organic iodine pool used daily was predominantly subnormal. They suggested that patients with uveitis have a decreased peripheral utilization of thyroid hormone. Cantor et al. (5) collected thyroxine levels in patients with uveitis and found that some exhibited depressed levels. They suggested their results might be affected by decreased thyroxine-binding globulin levels in uveitis patients with toxoplasmosis, tuberculosis, and sarcoidosis. Notably, both aforementioned studies were initiated before the routine use of modern diagnostic tests such as: total and free triiodothyronine, total and free T4, and thyrotropin measurement. Mizoguchi et al. (6) investigated patients with Graves' disease who were treated at the Nagasaky University Hospital at Japan, and they failed to demonstrate any case of uveitis among these patients. They found Graves' disease in 2.3% (5/220) of their uveitis patients, which in four of these patients appeared several months after thyroid functions became uncontrolled. However, they did not have a control group and did not compare the prevalence of Graves' disease in patients with and without uveitis. In the present study, none of the uveitis patients had hyperthyroidism.

Some uveitis entities including TINU, VKH syndrome, and HTLV-1-associated uveitis were found to be related with thyroid dysfunction and may share the same immune mechanism with thyroid disease (7 –25). These findings suggest considering a laboratory evaluation of thyroid function in the diagnostic evaluation of specific uveitic diseases. The present study included two cases of VKH syndrome in which no thyroid dysfunction was found. There were no cases of TINU or HTLV-1-associated uveitis. TINU is a rare syndrome, mainly found among children and young adults. The present study did not include patients younger than 18 years of age, and this may explain why there were no cases of TINU. In addition, no cases of HTLV-1-associated uveitis have been found in Israel to date.

The value of this study is its large sample size and case-control design, allowing sufficient power to reveal the association between non-infectious uveitis and thyroid dysfunction. Thus, the study's inability to reject the null hypothesis and the acceptance of the non-association between thyroid dysfunction and uveitis is reliable. In the field of uveitis, there are no preferred practice guidelines regarding routine testing of thyroid functions in the workup of uveitis. Nevertheless, some ophthalmologists and general physicians commonly send uveitis patients for the evaluation of thyroid function. While reviewing the literature, no comprehensive study was found to support or oppose this decision. The present findings suggest that there is no need for a routine thyroid function evaluation in patients with non-infectious uveitis. Specific uveitis entities such as TINU, VKH syndrome, and HTLV-1-associated uveitis were shown in case reports to be related to thyroid function abnormalities, and in these specific cases, the characterization of thyroid function evaluation should be considered.

Footnotes

Author Disclosure Statement

No competing financial interests exist for any of the authors.

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