More than 10 million Americans have thyroid disease, and another 13 million are estimated to have undiagnosed thyroid problems.1,2 In 1985, the incidence of thyroid dysfunction was approximately 0.4% of the entire United States population.1,2 A February 2000 research study found that the estimated number of people with undiagnosed thyroid disease had significantly increased.3 That study suggested that 10 to 17 million U.S. citizens had undiagnosed thyroid disease.3 Palpating The Thyroid Isthmus Palpating the Main Body
Thyroid disease is typically considered an autoimmune disease.1,2 It rarely occurs in children, and females are eight times more affected than males.1,2 Those men affected generally will have more severe disease, as it is more difficult to control medically.
Although the disease of thyroid dysfunction was discovered as early as 1786, the exact pathophysiology is still unknown.4 In fact, there are more than 40 postulates about the pathophysiology of thyroid disease.5 What is known, however, is that thyroid disease has ocular manifestations.
Here, well review the thyroid glands role in the body, the two forms of thyroid disease, and Graves disease, which has ocular manifestations. This should help you identify thyroid disease in patients, educate them about the role of the thyroid gland, monitor for ocular manifestations and refer the patient to other health professionals.
The Thyroid Gland
The thyroid gland is a small bow-tie or butterfly-shaped gland in the neck. It wraps around the trachea and is located dorsally and inferiorly to the laryngeal prominence. Two lobes to the gland (right and left) join via an isthmus. The thyroid gland weighs approximately 20 grams and is palpable just below the cricoid cartilage.3 It is detectable in the process of swallowing in a healthy patient whose head is erect (See Palpitating the Thyroid Isthmus, below). When head position is complicated or palpation is unobtainable, imaging can be performed to measure the gland size (See Palpitating the Main Body, below). The thyroid gland is fixed to the trachea, rises with deglutition, and rolls between the fingers or thumb of the practitioner as the patient swallows.6
1. Have the patient sit and extend neck slightly outward.
2. Standing behind the patient, place two fingers of each hand on the sides of the trachea, just beneath the crinoid. Have the patient swallow.
3. This allows for palpation of the isthmus, which gives you a landmark on where the thyroid gland is located.
Anatomically, enlargement of the gland is of potential consequence because of its location in the neck. It sits in close proximity to the brachiocephalic artery, the left common carotid artery, and the recurrent laryngeal nerve (important surgically, as there is risk to damage speech.)3
1. Move your fingers of your left hand between the trachea and the right sternocleidomastoid while your right fingers are placed behind the same muscle.
2. Displace the trachea to the left, and have the patient swallow. This allows for the right lobes main body to slide under your fingertips.
3. The gland should feel smooth and not be tender.
The thyroid gland is an endocrine organ that is under hypothalamic/pituitary feedback control. The hypothalamus releases thyrotropin-releasing hormone (TRH). This, in turn, initiates the release of thyroid stimulating hormone (TSH) from the pituitary gland. TSH stimulates the thyroid gland to produce specific thyroid hormones. To produce these hormones, however, the thyroid cells require iodine, which is relatively rare in the body. Proper dietary intake is necessary to ensure an adequate iodine supply.2
The thyroid absorbs iodine via food, such as fresh chicken or turkey, iodized salt or supplements and combines it with the amino acid tyrosine. The thyroid then converts the iodine/tyrosine combination into the specific thyroid hormones triiodothyronine (T3) and thyroxine (T4). The 3 and the 4 refer to the number of iodine molecules in each thyroid hormone molecule.
The normal thyroid gland does not produce equal amounts of T3 and T4. The pool of T4 is 20 times greater than that of T3, and the half-life of T4 is seven times that of T3.2 Biologically, T3 is the more active hormone because it functions at the cellular level and is several times stronger than T4.3
Once released by the thyroid, T3 and T4 travel through the bloodstream, where they help cells convert oxygen and calories into energy.3 Direct thyroid secretion of T3 is minimal. The remaining T3 needed by the body forms from the mostly inactive T4 by a process sometimes referred to as T4 to T3 conversion or iodination.2 This conversion of T4 to T3 can take place in peripheral tissue and some organs other than the thyroid, including the hypothalamus.2
The thyroid hormones stimulate multiple cellular metabolic tissue reactions throughout the body (see Thyroid Hormone Actions, below). These hormones enhance the generation of body heat. The thyroid gland regulates about 40% of the bodys resting oxygen consumption.2 Normal growth and sexual development of the body will not occur in the absence of the thyroid hormones.2
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Thyroid Hormone Actions |
| Calorigenic (increase of oxygen consumption). Faster growth and metabolism. Increase in number and affinity of cardiac receptors. Increased nitrogen excretion. Increased carbohydrate absorption in GI tract. Higher pulse pressure. Reduced blood cholesterol. Increased basal metabolism. Increased alertness (secondary to stimulation of the sympathetic nervous system). Increased surface epinephrine receptors on cardiac muscle, which increases heart rate, force of contraction, respiration, production of red blood cells, and blood glucose. |
Hyperthyroidism
There are two types of thyroid disease: hyperthyroidism and hypothyroidism. Hyperthyroidism occurs when the thyroid is overactive and releases too much thyroid hormone into the bloodstream (T3 and T4). Thyroid overproduction can result from hormone overproduction (TRH and TSH), immunologic reaction (Graves disease), toxic thyroid nodules, pituitary tumor (excess TSH), pituitary resistance (disruption of feedback loop, leading to excess TSH release), oral ingestion of hormone (i.e. via medications) or, in rare cases, from extra-thyroid hormone production.1
Hyperthyroidism most commonly presents in the second to third decade of life but can present in the fourth and fifth decades as well.2 Ophthalmopathy is common on physical examination. Additional signs include tachycardia, atrial fibrillation(characterized by an irregular radial pulse that is not normalized by exercise), pretibial myxedema (most commonly described as thickened skin), temporal alopecia, goiter and fine/silky hair. Myxedema results from the accumulation of increased amounts of hyaluronic acid and chondroitin sulfate in the dermis in both lesioned and normal skin.
Symptoms of hyperthyroidism include nervousness, sweating, heat intolerance, fatigue, weight loss despite increased appetite, weakness and increased bowel movements.4 If there is not an increased food intake in proportion to the increased demands of the body, the body oxidizes its own tissues, and weight is rapidly lost.7
If you suspect hyperthyroidism after taking the patients case history and conducting her exam, laboratory investigation by the internist or endocrinologist is critical. Signs of Graves disease, an elevated free-T4 level and decreased TSH all demonstrate a hyperthyroid state.2 If both the aforementioned levels are low, the free-T3 (measured T3 in the bloodstream) will likely be elevated.2 Sensitive TSH tests have eliminated the need for TRH tests or thyroid suppression tests in most cases.2
The treatment of hyperthyroidism is complex. Because medical treatment alone is usually inadequate, a combination of drug therapy with radioactive iodine and/or surgical intervention is common. Thionamide agents are the primary drugs used to block the production of T3 and T4. For adults, radioactive iodine (iodine 131) is the most commonly used isotope because it acts locally without disturbing other tissues.2 Iodine 131 is safe; the principal side effect is the early or late development of hypothyroidism. (Hypothyroidism is a risk of all hyperthyroid treatments and not unique to iodine 131.) Adjunctive medical treatment with oral beta-blockers can block many of the stimulating effects of excess thyroid hormone on other organs.
Hypothyroidism
Hypothyroidism results from an underactive thyroid that produces too little thyroid hormone (i.e., insufficient T3 and/or T4). There are three types of hypothyroidism:
Primary hypothyroidism. This is the most common form of hypothyroidism and is due to an intrinsic defect in the anatomical structure. This defect is caused by chronic autoimmune thyroiditis (Hashimotos disease); surgical or radioiodine treatment for Graves disease; irradiation of a neck neoplasm; subacute thyroiditis; dietary deficiency of iodine (endemic goiter); drugs, such as lithium; or a congenital biosynthetic defect.2 The incidence of primary hypothyroidism is 4,000 to 6,000 births without geographic predilection.
Secondary hypothyroidism. This is due to insufficient delivery of TSH by the pituitary gland.
Tertiary hypothyroidism. This occurs when the hypothalamus delivers insufficient TRH to the pituitary gland, resulting in low TSH. Physical examination reveals bradycardia, intolerance to cold, constipation, slowing of activities, weight gain despite reduced appetite, fatigue, depression, myxedema and dry skin.
All types of hypothyroidism have been associated with hypercholesterolemia and anemia, so periodic blood panels are needed. Primary hypothyroidism that occurs at birth results in developmental abnormalities, such as stunted physical growth, and is termed cretinism.7
The treatment of hypothyroidism is far more straightforward than hyperthyroidism. These patients are prescribed levothyroxine, a synthetic T4 that converts to free T3 pe-ripherally when needed. Both thyroid hormones are then available to the body and tissues, even though the medication only includes one.2
Graves Ophthalmopathy
The ocular effects of thyroid disease are known collectively as Graves ophthalmopathy. This condition refers to the inflammatory response and its sequelae in and around the orbit associated with autoimmune thyroid disease. It is also known as thyroid-related ophthalmopathy or thyroid eye disease and is most frequently linked with hyperthyroidism (termed von Basedows disease in Europe).1
Graves ophthalmopathy can be secondary to hypothyroidism. No information is readily available in the literature about the epidemiology of ocular involvement from hypothyroidism.2
Graves disease, first reported in 1835 by Irish physician Robert James Graves, presents with lid retraction, lid lag, lagophthalmos, periorbital edema, punctate epithelial erosions, corneal ulceration, photophobia, and conjunctival edema and hyperemia. It also presents with extraocular muscle re-striction, diplopia, proptosis, elevated IOP (especially in upgaze), decreased visual acuity, visual field loss and decreased color vision.5
An enlarged thyroid gland (goiter) and bilateral exophthalmos are the most characteristic signs of Graves disease, and are present in approximately one-third of patients at the time of Graves diagnosis.5 When there is diffuse enlargement of the gland, a quiver may often be palpable and a bruit audible over the thyroid (confirming thyroid gland over-activity).5
Graves disease usually manifests in patients younger than age 40 as orbital fat expansion and proptosis in the absence of infiltration of the extraocular muscles and corresponding eyelid retraction. Patients older than age 70 usually manifest severe extraocular muscle involvement resulting in diplopia and compressive optic neuropathy.8
Graves disease has a female preponderance, which ranges from 3:1 to 6:1 depending on the decade of age.2 Women generally develop the disease earlier and have less progression than men, who are more prone to developing a progressive ophthalmopathy. It can develop in patients who are euthyroid (ie., have normal thyroid gland function) or hyperthyroid. There is a temporal relationship between hyperthyroidism and ophthalmopathy in which 20% of patients have eye findings that precede the hyperthyroidism, 40% develop the signs and symptoms concurrently, and 40% develop them after hyperthyroidism occurs.9,10 Regardless of which occurs first, most cases become apparent within 18 months of the other.11
NO SPECS
Many classification systems de-tailing the ocular findings associated with Graves disease have been proposed and used through the years. The first one to gain notoriety was the NO SPECS system first put forward by S.C. Werner, M.D., and the American Thyroid Association in 1969 (and later updated in 1977).12 The acronym stands for:
No signs or symptoms.
Only signs of lid retraction and stare.
Soft tissue involvement.
Proptosis of 3mm or greater.
Extraocular muscle involvement.
Corneal involvement and vision loss.
Secondary to optic nerve disease.
Soft tissue involvement is the most common finding from the NO SPECS classification. It consists of conjunctival chemosis, hyperemia, lagophthalmos, prolapsed orbital fat and periorbital injection. These findings lead to patient complaints of excessive tearing, epiphora, photophobia, foreign-body sensation and/or mild pain that can be localized from the anterior eye to the retrobulbar space.
Proptosis, or exophthalmos, greater than 2mm above the average normal limit, should prompt you to consider a thyroid work-up. Proptosis occurs in 20% to 30% of patients who have Graves disease and is clinically apparent bilaterally in 80% to 90% of those affected.13 However, proptosis of up to 25mm has been found as a familial trait.14 The proptosis in Graves disease can be asymmetric, giving a false clinical impression of a unilateral presentation.
Extraocular muscle involvement is the second most common finding among the NO SPECS classification. Ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) have shown that extraocular muscle (EOM) enlargement is present in 60% to 98% of patients who have Graves disease.14,15 The primary cause of the enlargement is secondary to lymphocytic infiltration, fibroblast proliferation and subsequent edema of the muscle belly. With time, this process is followed by restrictive fibrosis and tethering of the EOMs. Limitation of upward gaze is four times more common than all other movements combined followed by abduction and infraduction.16
The inferior rectus is generally affected first, followed closely by the medial rectus. The superior and then lateral recti are affected in later stages. The EOMs at late stage are typically bilaterally affected, yet asymmetric. There is a resulting muscle stiffness that causes limitation of eye elevation and abduction.
Proptosis and extraocular muscle involvement occasionally must be differentiated from orbital pseudotumor, a task that can be quite difficult at times. Orbital pseudotumor generally has a more insidious onset, erythema and ocular dysmotility. On CT and MRI, the extraocular tendinous insertion sites are spared in Graves disease while they are involved with orbital pseudotumor. Also, there is a possible refractive effect caused by the increase in tissue that fills the potential space of the orbit. This increase in orbital volume may lead to a hyperopic shift, which can reverse with orbital decompression. As such, monitor refractive status closely.17
Increased intraocular pressure in up-gaze can be quantified and is a good in-office test to suggest inferior rectus infiltration and the need for subsequent imaging.18 If IOP changes more than 3mm Hg (when compared with primary position IOP), then further testing is likely required.
IOP elevation likely results from tension on the globe due to restrict- ed extraocular muscles and elevated episcleral venous pressure.19 Additionally, with later staged infiltration, slit-lamp biomicroscopy can demonstrate localized injection over and in front of the insertions of the horizontal rectus muscles.18
Corneal involvement in Graves disease most often results from ex-posure keratopathy and a compromised tear film. Punctate epithelial erosions are a common finding, but few patients progress to ulceration. Given the lid lag and increased palpebral width, increased tear evaporation causes increased osmolarity. Subsequently, dry eye can result.
Optic nerve involvement is the most devastating ocular sequela of Graves disease, but fortunately, this occurs in only 6% of patients.20 The optic nerve becomes compromised by apical compression secondary to the enlargement of the extraocular muscles and orbital connective tissue. Bilateral involvement is usually present although often asymmetric. Unfortunately, about 50% of patients with optic neuropathy at the time of diagnosis are unaware of any vision loss. To best evaluate optic neuropathy, use CT or MRI with coronal views to look for crowding at the orbital apex.
One study found that the course of ophthalmopathy, following treatment of the hyperthyroidism, initially had a rapid progression, peaking after a short interval (six to 24 months). This was followed by a prolonged plateau phase and then a gradual, often incomplete, regression of the eye findings.16
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Ocular Manifestations |
| Eyelids Lid retraction Lid lag Lagophthalmos Periorbital edema Cornea Cornea Exposure Keratitis Punctate epith. erosions Ulceration Photophobia Conjunctiva Edema Hyperemia Extraocular Muscles Restriction Diplopia Proptosis Elevated IOP Especially in upgaze Optic Nerve Decreased visual acuity Visual field loss Decreased color vision |
Treatment
Treatment for Graves ophthalmopathy ranges from local measures to surgical treatment. In most patients, the disease is self-limiting and can be managed with topical lubrication for dry eye symptoms and, if necessary, taping the eyelids shut at night; prisms for diplopia; and sunglasses for photophobia. Patients can also benefit from sleeping with their heads elevated to help reduce the periorbital edema. Eyelid repair can be accomplished by EOM correction or orbital decompression surgery. Thyroid ablation, to correct the underlying thyroid gland overaction, is achieved by high-dose radioiodine.
Your ultimate goal is to return the patient to a euthyroid state. Unfortunately, ablation can paradoxically exacerbate the thyroid eye disease (via Graves ophthalmopathy secondary to a severe hypothyroid state), so consider this management option with caution. The eyelid surgery is primarily for cosmesis but can help stabilize the tear film. EOM surgery is warranted to help alleviate diplopia and is also commonly performed following orbital decompression sur-gery to correct for any secondary diplopia.
Orbital decompression is performed secondary to se-vere proptosis, compressive optic neuropathy or poor cosmesis. The decompression can be approached in three possible ways:
Laterally, which yields the lowest increase in volume.
Superiorly, which yields the largest increase in volume but increases the patients risk of frontal lobe damage, meningitis or a cerebrospinal fluid leak.21
Inferiorly, either transantral or transorbital, which is the most common procedure.
Advantages to the inferior approach are the lack of an external scar; a short hospitalization period and access to the ethmoid space in patients who have optic neuropathy.21 The risks to the inferior approach include induced diplopia, lip numbness, sinusitis, entropion and meningitis.21
The approach to orbital decompression is often determined both by cosmesis and the amount of space needed to increase the volume of the orbit.
Regardless of which management option you and the patient choose, encourage those patients who smoke to quit, as there appears to be an association between the quantity of smoking and the severity of the disease. In one study of Graves disease, 47.6% of heavy smokers had moderate to severe ophthalmopathy as compared with 24.7% of non-smokers who had only minor eye changes.22 Also, smoking appears to decrease the effectiveness of treatment for the disease.23
The last 10 to 15 years have yielded little research to improve our understanding of the nature and peculiarities of thyroid dysfunction. Thyroid disease is a complicated disorder, and its specific pathogenesis is still not completely understood.
Nevertheless, it affects a significant number of patients. Ocular signs and symptoms are to be expected, so you may be the first doctor to suspect the disease. Such signs as proptosis and lid retraction should at the very least warrant further evaluation.
Dr. Lievens is an associate professor and the chief of primary care at the Southern College of Optometry where he is the instructor of seven clinical patient care courses. He has also been employed in private practice and at an ophthalmology laser center.
Dr. Kinnaird is an attending optometrist at West Side VA Medical Center in Chicago. He holds faculty appointments at the Illinois College of Optometry, University of Illinois at Chicago, Department of Ophthalmology, and Indiana University College of Optometry.
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2. Marks ES, Adamczyk DT, Thomann KH. Thyroid Dysfunction in: Primary Eyecare in Systemic Disease. Norwalk, Ct.: Appleton and Lange, 1995:162-173.
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9. Gorman CA. Temporal relationship between onset of Graves ophthalmopathy and diagnosis of thyrotoxicosis. Mayo Clin Proc. 1983 Aug;58(8):515-9.
10. Wiersinga WM, Smit T, van der Gaag R, Koornneef L. Temporal relationship between onset of Graves ophthalmopathy and onset of thyroidal Graves disease. J Endocrinol Invest. 1988 Sep;11(8):615-9.
11. Merck Manuals. www.merck.com/mmhe/sec13/ ch163/ch163a.html (Accessed June 27, 2006).
12. Werner SC. Modification of the classification of the eye changes of Graves" disease: recommendations of the Ad Hoc Committee of the American Thyroid Association on diabetes. J Clin Endocrinol Metab 1977;44:203-4.
13. Wiersinga WM, Smit T, van der Gaag R, et al. Clinical presentation of Graves" ophthalmopathy. Ophthalmic Res. 1989;21(2):73-82.
14. Werner SC, Coleman DJ, Franzen LA. Ultrasonographic evidence of a consistent orbital involvement in Graves disease. N Engl J Med 1974 Jun27; 290 (26): 1447-50.
15. Trokel SL, Jakobiec FA. Correlation of CT scanning and pathologic features of ophthalmic Graves disease. Ophthalmology 1981 Jun;88(6):553-64.
16. Rundle FF. Eye Signs of Graves Disease in: The Thyroid. Washington, DC: Butterworths and Co. 1964: 171-197.
17. Chandrasekaran S, Petsoglou C, Billson FA, et al. Refractive change in thyroid eye disease (a neglected clinical sign). Br J Ophthalmol 2006 Mar;90(3):307-9.
18. Neuromuscular Disease Center, Washington University, St. Louis MO. www.neuro.wustl.edu/neuro muscular/ msys/mend.htm#thyroid (Accessed June 29, 2006).
19. Fishman DR, Benes SC. Upgaze intraocular pressure changes and strabismus in Graves ophthalmopathy. J Clin Neuro Ophthalmol 1991 Sep;11(3):162-5.
20. Bartley GB, Fatourechi V, Kadrmas EF, et al. Clinical features of Graves ophthalmopathy in an incidence cohort. Am J Ophthalmol 1996 Mar;121(3):284-90.
21. Gorman CA, Waller RR, Dyer JA. Orbital Decompression Techniques & Transantral Orbital Decompression in: The Eye and Orbit in Thyroid Disease. New York: Raven Press. 1984: 221-252.
22. Bartalena L, Martino E, Marcocci C, et al. More on smoking habits and Graves ophthalmopathy. J Endo-crinol Invest 1989 Nov;12(10):733-7.
23. Bartalena L, Marcocci C, Tanda ML, et al. Cigarette smoking and treatment outcomes in Graves ophthalmopathy. Annals of Int Med 1998 Oct15;129(8):632-5.
