A 45-year-old woman comes to the office because of a 3-month history of worsening bulging of her eyes and persistent double vision. She was diagnosed with Graves disease 6 months ago and is currently taking methimazole. She has a 25-pack-year smoking history and continues to smoke one pack of cigarettes daily. Physical examination shows bilateral proptosis, conjunctival injection, and restricted upward gaze in both eyes. Laboratory studies show a TSH of 0.9 μU/mL (N: 0.5–5.0) and a free T4 of 1.1 ng/dL (N: 0.8–1.8).
Which of the following is the most likely mechanism underlying this patient's ocular findings?
The correct answer is:
A) Accumulation of glycosaminoglycans and orbital fibroblast proliferation
The patient is presenting with Graves orbitopathy which is also known as thyroid-associated ophthalmopathy. The pathogenesis of this condition involves the stimulation of TSH receptor antibodies (TRAb) on orbital fibroblasts. These activated fibroblasts proliferate and secrete high levels of glycosaminoglycans (primarily hyaluronan). The highly hydrophilic nature of glycosaminoglycans leads to osmotic edema, which causes significant swelling of the extraocular muscles and expansion of the retro-orbital fat and connective tissues. This tissue expansion results in proptosis, impaired venous return (resulting in chemosis and injection), and restrictive myopathy causing diplopia. Smoking is the most significant modifiable risk factor for the development and progression of this condition.
Answer choice B: Excessive sympathetic stimulation of the superior tarsal muscles, is incorrect. This mechanism describes the cause of lid lag and "stare" (Dalrymple sign) seen in thyrotoxicosis of any cause. While patients with Graves disease often have lid lag, the proptosis and restriction of extraocular muscles are specific to the autoimmune fibroblast activation seen in Graves orbitopathy, not sympathetic overactivity.
Answer choice C: Lymphocytic infiltration leading to extraocular muscle necrosis, is incorrect. While Graves orbitopathy involves a T-cell-mediated lymphocytic infiltration of the orbital tissues, it does not lead to muscle necrosis. Instead, it leads to inflammation, glycosaminoglycan deposition, and eventually fibrosis.
Answer choice D: Myocyte hypertrophy in response to elevated serum thyroxine, is incorrect. The enlargement of the extraocular muscles in Graves orbitopathy is not due to the hypertrophy of the muscle fibers themselves or the direct effect of thyroid hormones. It is the result of the accumulation of glycosaminoglycans and inflammatory cells within the muscle belly and surrounding connective tissue.
Answer choice E: Type III hypersensitivity reaction with immune complex deposition, is incorrect. Graves disease is primarily a Type II (antibody-mediated) hypersensitivity reaction where antibodies stimulate the TSH receptor. It is not characterized by the deposition of immune complexes or the systemic vasculitis typical of Type III hypersensitivity.
Key Learning Point
Graves orbitopathy is caused by TSH receptor antibodies (TRAb) that stimulate orbital fibroblasts, leading to the accumulation of glycosaminoglycans and subsequent osmotic edema, fat expansion, and extraocular muscle swelling. Smoking is the strongest modifiable risk factor for the progression of the disease.
