Thyroid Eye Disease: Is There a Biomarker for Muscle Enlargement?
—Investigators retrospectively reviewed medical records of patients with thyroid eye disease to determine the most useful biomarker for extraocular muscle enlargement.
According to a new study, thyroid-stimulating antibody (TSAb) levels may be associated with muscle enlargement and the number of muscles affected in patients with thyroid eye disease (TED).1
TED is usually associated with autoimmune thyroid diseases, namely Graves disease and Hashimoto disease.2 Up to half of patients with Graves disease may have TED.2
Characteristic clinical features of TED are increased orbital fat and enlargement of extraocular muscles and lacrimal glands.2 Muscle enlargement in TED can lead to diplopia and compressive optic neuropathy, compromising visual function.2
Several autoantibodies are often detectable in autoimmune thyroid diseases, such as TSAb, TRAb, antithyroid peroxidase antibody (ATPO), and antithyroglobulin antibody (ATG).3,4 Of these, TSAb and TRAb are known to be associated with TED.4
The authors of the new study noted that the best biomarker for TED is unclear, and the role of ATPO and ATG is largely unknown. “Moreover, no study has examined the association between muscle enlargement and these 4 thyroid autoantibodies (TRAb, TSAb, ATPO, and ATG),” they wrote.
In the new study, the researchers evaluated the association of thyroid autoantibodies, TSH, age, sex, and smoking history with muscle thickness in patients with TED.
Study design
The researchers retrospectively examined the medical records of patients with a TED diagnosis at the Saitama Medical Center in Kawagoe, Saitama Prefecture, Japan, between April 1, 2017, and March 31, 2023. Inclusion criteria were orbital magnetic resonance imaging (MRI) results and TSH, TH, TRAb, TSAb, APTO, and ATG measurements. Patients with a history of steroid and immunosuppressant use were excluded.
Three independent researchers measured muscle thickness on magnetic resonance imaging (MRI) and the average value was used for analysis. Ten extraocular muscles were measured from each eye. Normal control muscle size measurements were obtained from control patients with unilateral eyelid or orbital tumors who had undergone bilateral orbital MRI. Enlargement was defined as muscle thickness greater than 2 standard deviations (SD) above the mean of controls.
Regression analysis was used to determine associations between muscle characteristics and factors such as age, sex, smoking history, and hormone and antibody levels.
Patients
A total of 41 patients with TED met the study criteria. Of these, 9 were men and 32 were women. The mean (SD) age was 55.2 (13.9) years. The control group included 44 patients with a mean (SD) age of 61.4 (14.8) years. Unlike the TED group, the control group had more men than women (24 vs 20).
In the TED group, eye disease clinical characteristics included eyelid swelling in 30 patients, eyelid retraction in 25 patients, ocular movement disorder in 21 patients, proptosis in 18 patients, and optic neuropathy in 1 patient.
Among those with TED, oral medication was the most common treatment for thyroid dysfunction (24 patients), followed by radioisotope therapy in 2 patients and surgery in 1 patient. Another 15 patients were untreated.
Autoantibodies were detected in most patients in the TED group. A total of 92.7% were positive for TSAb, 78.0% for TRAb, 41.5% for ATPO, and 41.5% for ATG.
Muscle phenotypes
Of 41 patients with TED, 29 (70.7%) had at least 1 muscle that met the definition of enlargement. The average number of muscles enlarged was 2.1.
Muscle enlargement was bilateral in 17 (58.6%) patients and unilateral in 12 (41.4%) patients with enlargement.
Among the 29 patients with muscle enlargement, 23 (79.3%) had asymmetric enlargement, and 6 (20.7%) had symmetric enlargement.
The muscle most often affected, the inferior rectus, was enlarged in 13 right eyes (31.7%) and 14 left eyes (34.1%). Four other muscles were also enlarged in some eyes: the superior rectus in 10 right eyes (24.4%) and 10 left eyes (24.4%); the medial rectus in 9 right eyes (22.0%) and 9 left eyes (22.0%); the superior oblique in 6 right eyes (14.6%) and 8 left eyes (19.5%); and the lateral rectus in 4 right eyes (9.8%) and 4 left eyes (9.8%). No patient had enlargement in all 10 muscles.
Factors associated with muscle phenotypes
On multiple regression analysis, older age was significantly associated with total extraocular muscle thickness (coefficient, 0.153; 95% confidence interval [CI], 0.046-0.260; P =0.006). The concentration of TSAb was also positively associated with total extraocular muscle thickness (coefficient, 0.002; 95% CI, 0.001-0.003; P <0.001).
Similarly, older age (coefficient, 0.068; 95% CI, 0.026-0.110; P =.002) and TSAb concentration (coefficient, 0.001; 95% CI, 0.0004-0.0012; P <.001) were also associated with the number of extraocular muscles enlarged.
The investigators also evaluated these associations with the laterality and symmetry of extraocular muscle enlargement. Neither age nor TSAb concentration was associated with bilateral vs unilateral extraocular muscle enlargement or symmetric vs asymmetric extraocular muscle enlargement.
Detecting extraocular muscle enlargement in thyroid eye disease
Based on previous research, the researchers expected they would find that older age was associated with extraocular muscle enlargement.2 Orbital fat accumulation may be more common in younger patients.2
They wrote that their findings suggested that TSAb could be a biomarker for extraocular muscle enlargement in patients with TED.
While the TRAb assay can be performed more quickly in a hospital setting than the TSAb assay which is typically outsourced and takes days to result, the authors said that TSAb measurements should not be overlooked. “Although internists first measure TRAb, for which results are readily available, the findings of this study suggest that the primary measurement of TSAb is important for early detection and treatment of extraocular muscle enlargement in patients with TED,” they wrote.
According to the researchers, the study's limitations include the retrospective design, small sample size, lack of treatment consideration, and use of thickness to measure extraocular muscle enlargement rather than other parameters, such as volume, cross-sectional area, or signal intensity.
They suggested that future studies should be prospective and include larger sample sizes.
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