Thyroid

THE BODY AND THE EYE

THE MEDIATOR OF METABOLISM:

The Far Reaching Effects of Thyroid Disease

Complications involving the thyroid present patients with vague and varying symptoms, and clinicians with a challenging diagnosis. Since the eye is a key indicator for both ocular and systemic thyroid disease, optometrists need a solid understanding of the diagnosis, the effects and the management of thyroid diseases.

Andrew S. Gurwood, O.D., Christopher M. Dente, O.D., Philadelphia

The thyroid gland has been called the great mediator of metabolism. Its complex cascade of reactions forms powerful compounds that are released throughout the body and impact every organ system. While ocular sequelae are important, thyroid disease may manifest effects that are system-wide

xamine the thyroid gland to look for

abnormalities in size or position.

Patients with thyroid abnormalities often report a host of variable and vague symptoms that can challenge even the seasoned clinician. Though patients may be tempted to attribute their symptomatology to stress or fatigue, an insightful practitioner can recognize the prompt need for an appropriate systemic work-up.1

Thyroid eye disease remains an enigma. Certain histopathological features have been documented, but the mechanisms responsible remain unclear. In fact, the ocular condition known as Graves’ disease may exist in the absence of clinical or biochemical thyroid dysfunction. Furthermore, when systemic and ocular conditions exist simultaneously, they may follow completely different clinical courses.2,3 This article will concentrate on systemic thyroid disease. (For a review of thyroid eye disease, see “Your Role in Managing Graves’ Disease,” November 1997.)

The eye may serve as the first diagnostic indicator of impending, beginning or progressing systemic and/or ocular thyroid disease. That’s why optometrists need to be skilled in its detection, differential diagnoses and management.

Thyroid conditions are the subject of this, the second installment in our systemic disease series, “The Body and The Eye.” Understanding the anatomy and physiology of the thyroid gland will enhance our ability to detect the presence of thyroid disease, even in cases of subtle or absent ocular clues. 

Anatomy and Physiology
The thyroid gland is a highly vascularized organ in the anterior triangle of the neck, inferior to the thala- mus and just superior to the pituitary gland.1 Its right and left lobes connect across the midline by a narrow portion of tissue called the isthmus. It weighs 20-30 grams.

Its rich arterial supply originates superiorly as branches of the internal carotid artery on both sides and inferiorly as ascendants of the right and left subclavian artery. These vessels form the superior and inferior thyroid arteries.

The superior and middle thyroid veins drain their contents into the internal jugular vein of both sides. The inferior thyroid veins drain directly into the brachiocephalic truck. The muscles of the neck and skin cover the lateral, superficial surface. The deep, medial surface is molded over the trachea, cricoid muscles, the esophagus, deep neck muscles and the nerves and vasculature of the throat.4-6 

The thyroid gland secretes two significant hormones, triidothyronine (T3) and thyroxine (T4). The thyroid gland is among several organs responsible for regulating metabolism. Its neighbors, the hypothalamus and anterior pituitary, serve to orchestrate proper axial function. 

Changes in temperature, emotional reactions, anxiety, stress and excitement stimulate the sympathetic nervous system, which acts on the hypo- thalamic centers, causing alterations (inhibitory or stimulatory) in the thyroid axis.4 This is a normal endocrine regulation and not a pathological process.

Stimuli trigger an increase or decrease in neurotransmitter activity within the cerebrum. The change in neurotransmitter activity provokes a wave of neuronal impulses, stimulating the hypothalamic center to produce potent chemical messengers. These include thyroid-releasing hormone (TRH), which is synthesized in the paraventricular nucleus and released at the level of the median eminence of the pituitary stalk.

This simple three-amino acid compound travels through the long portal vessels to the anterior pituitary gland where it binds to surface receptors on thyrotroph cells. Once bound, channels in the cell membrane open, allowing the passage of calcium ions into the cytoplasm. This cascade ultimately results in the synthesis and immediate release of preformed thyroid-stimulating hormone (TSH) from the anterior pituitary glands.1,4,7,8

When TSH binds to receptors located on the surface of the thyroid gland, a series of events is triggered. The chemical cascade—increased blood flow to the gland, increased iodide uptake (via a ATPase pump), increased activity of cAMP (cyclic adenosine monphosphate), oxidation of iodide by peroxidases, and iodination of tyrosine residues—concludes with the production and release of T3 and T4.

T3 is the biologically active form due to its ability to bypass the liver.1,4,9 As T3 and T4 are released, they bind to specific transport carriers. TSH binding to receptors leads to release of T3 and T4.

Once in the system, T4 and T3 molecules cause increased basal metabolism, increased oxygen consumption within the mitochondria, increased alertness (secondary to its stimulation of the sympathetic nervous system), and increased surface epinephrine receptors on cardiac tissue. This boosts the heart rate and force of contraction, and increases respiration, production of blood cells, and blood glucose levels.

The Feedback Loop
A feedback loop involving all the thyroid hormones—TRH, TSH, T3, T4—maintains the delicate balance of the thyroid axis.1,4,7,8,10 A host of entities can disrupt the thyroid axis and lead to systemic complications of end organs. Among them: thyrotoxicosis (secondary to hyperthyroidism), diffuse goiter (Graves’ disease), toxic mutinodular goiter, toxic adenoma, thyrotoxicosis factitia, subacute thyroiditis, silent thyroiditis and excessive thyroid hormone replacement. Symptoms may occur despite laboratory confirmation of a healthy thyroid (as in Euthyroid Sick Syndrome).

The thyroid gland requires iodine by ingestion of food, water or dietary supplements. Iodine couples with tyrosine to form mono-iodothyrosine and di-iodotyrosine, precursors of T3 and T4. To form normal quantities of T4, the body requires 1 mg/week of iodine.

Parathyroid Glands
The parathyroid glands (four) are situated between the dorsal borders of the lateral lobes of the thyroid gland. These small glands manufacture and secrete parathyroid hormone (PTH). PTH is assembled within the Golgi and stored in secretory granules. When serum calcium levels drop, PTH is secreted. Its effects extend to bone, kidneys, and the gastrointestinal tract, where it serves to regulate calcium levels. While these glands have a limited impact on ocular structures and thyroid function directly, they may produce systemic effects if damaged secondarily to disease or treatment of the thyroid gland.10,11

Diseases of the Thyroid
• Hypothyroidism. This is a relatively common disorder that increases in frequency with age.12,13 Three subsections include: primary hypothyroidism (intrinsic defect in thyroid structure or mechanism), secondary hypothyroidism (secondary to insufficient thyroid-stimulating hormone caused by failure of the pituitary gland) and tertiary hypothyroidism (inadequate TSH levels from normal pituitary secondary to insufficient secretion of thyroid-releasing hormone from the hypothalamus ).12,13

Primary hypothyroidism is the most common form of thyroid inadequacy. It occurs in approximately one in 4,000-6,000 births with no geographic predilection. As with all thyroid disease, hypothyroidism affects women more commonly than men.

The most common type of hypothyroidism is the atrophic autoimmune variant, whose etiology is typically rooted to late stage Hashimoto’s thyroiditis (an autoimmune thyroid disorder). Destruction of the gland by infection, virus or other processes, such as ablation via irradiation, radioiodine therapy and subtotal or near-total thyroidectomy, are common causes of hypothyroidism.1,7,8,10

Hypothyroidism can produce signs and symptoms of weight gain, fatigue, cold intolerance, neck swelling, hoarseness, angina, shortness of breath, depression, dry skin, and constipation. Since hypothyroidism has been associated with both hypercholesterolemia and anemia, these patients should have periodic blood work-ups. Symptoms associated with severe and potentially fatal thyroid deficiency are termed myxedema. These typically include swelling of the hands, feet, face and periorbital tissue.12,13 

Patients with hypothyroidism may present with eye signs that can include lid swelling (particularly the lower lids), facial and periorbital swelling, and signs of hypercholesterolemia associated with anemia, such as arteriole nicking, banking and funduscopic microvascular changes (intraretinal hemorrhages and cotton wool spots).5

The laboratory diagnosis of primary hypothyroidism is straightforward. Laboratory testing in patients with hypothyroidism reveals markedly low levels of plasma thyroxine (T4), low levels of thyroid hormone binding ratio (THBR), normal being 0.085:110, or increased serum levels of TSH (the body’s attempt to compensate). However, many clinicians often miss this diagnosis because of its many nonspecific symptoms. Referral of suspected patients to their family physician or endocrinologist for plasma thyroxine, THBR and plasma TSH levels1,10,12 is appropriate.

Primary hypothyroidism is a rewarding disease to treat. Systemic therapy is simple and efficacious. Unfortunately, many patients wait too long, avoid or discontinue therapy and sink into a profound state of myxedema. For this reason, continual follow-up and encouragement are necessary.

Standard treatment for hypothyroidism consists of daily T4 replacement with an average dose of 100µg, to bring TSH levels within a normal range. The levels are checked every three to four weeks and dosage is adjusted until TSH levels are acceptable.14

Other treatment options include desiccated thyroid or purified thyroglobulin (65mgs) and triidothyronine (25µg). These preparations are readily absorbed in the intestinal tract,12,13 and therapy is almost always given orally.

The only serious danger in treating primary hypothyroidism with thyroid hormone is cardiac stress. In susceptible cases, myocardial infarction or arrhythmias can arise as a consequence of drug therapy. Care and experience are required as thyrotoxicosis (refers to all causes of excess thyroid hormone) may result when doses of thyroid hormone exceed 100µg.5,12

Secondary and tertiary hypothyroidism (secondary to pituitary failure) are similar to primary hypothy- roidism. In fact no clear differentiation can be made on clinical grounds alone.12,13 Patients with hypopituitarism typically produce very low levels of TSH and possess small thyroid glands. The most useful diagnostic course in such cases is to refer the patient to the internist or endocrinologist for plasma thyroxine and TSH levels. Treatment for secondary and tertiary hypothyroidism is TSH and adrenocortical replacement therapy. Optometrists play a supportive role in therapy, by monitoring the condition.9

• Nontoxic goiter. Nontoxic goiter (enlargement of the thyroid gland) is the most common endocrine disease.12 It is classified and characterized as thyroid enlargement that is neither associated with thyrotoxicosis nor due to thyroid neoplasm.12 It is six times more common in women than men. Susceptibility to goiter is inherited and thought to be from one or more biosynthetic defects in thyroid hormone synthesis or secretion. 12,13

Endemic goiter is most prevalent in under-developed regions. The primary cause is deficient dietary iodine intake. Treatment typically consists of iodine supplements.7 Clinicians must exercise great care when adding iodine to diets of these patients. Epidemiological studies have document- ed a transient pronounced increase in thyrotoxicosis incidence when iodine supplementation is introduced to iodine deficient areas.12 However, a lack of prompt treatment can result in glands that may become disfigured, sometimes exceeding 1kg in weight.12

The treatment of sporadic nontoxic goiter is to gently suppress TSH concentration through careful administration of low dosages of thyroid hormone.12 The optometrist must monitor these patients for therapeutic compliance and ocular signs.

• Toxic Nodular Goiter (Plummer’s Disease). The pathophysiology of this disease results from one or more nodules in the thyroid gland that produce excess amounts of thyroid hormone. These nodules are benign tumors that are not under the control of TSH. This variant typically is seen in elderly patients with preexisting goiters. Signs and symptoms of ophthalmopathy are most always absent. The disease is diagnosed in the same manner as non-toxic goiter and the treatment of choice is radioactive iodine (131I) therapy.1

• Thyroiditis. Thyroiditis indicates thyroid inflammation. The pathological, clinical and laboratory features of various forms of this disease are mysteries. Thyroid inflammation may cause local neck symptoms, ear pain, constitutional complaints and abnormalities of thyroid hormone production.5

Subacute thyroiditis or DeQuervain’s thyroiditis is believed to arise from a viral infection of the thyroid gland. It is often preceded by an upper respiratory tract infection. The cardinal symptom is pain, which may be referred to the throat (sore throat), ear or lateral neck. Constitutional symptoms include low-grade fever, sweats, fatigue and malaise. Clinically, the thyroid gland is often enlarged, firm and tender on palpitation. The inflamed gland releases pre-formed hormone, which induces a transient hyperthyroidism (thyrotoxicosis).

The disease is self-limiting and resolves within several months.1,5 The diagnosis of subacute thyroiditis is confirmed by detection of abnormal thyroid hormone concentrations, elevated Westegren erythrocyte sedimentation rate (E.S.R.) and markedly decreased thyroidal radioactive uptake. Typically there is no treatment for the thyroid dysfunction. In most cases, it returns to normal once the event passes. Supportive therapies to treat the inflammatory and constitutional signs include aspirin, NSAIDs and in rare cases, systemic steroids.13

Hashimoto’s thyroiditis (also called autoimmune thyroiditis) is now thought to be almost identical to Graves’ disease with respect to immunohereditary mechanisms. It typically presents with a medium-sized goiter, lymphocytic infiltration, autoantibodies and hypothyroidism. It is much more prevalent in women (8:1) and is most frequently seen in patients age 30-50 years old. The inflammation is of the cell-mediated variety.

The antibodies bind to thyroid-stimulating hormone (TSH) receptors and incite the release of TSH from the anterior pituitary. Increased circulating TSH levels, through feedback mechanisms, retard T3 and T4 release, resulting in a hypothyroid state. Hashimoto’s thyroiditis is frequently found in the compa- ny of other autoimmune diseases such as Sjögren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis and type I diabetes mellitus.1,3,4,12
Treatment consists of hormone replacement to stabilize thyroid functioning and decrease the size of the goiter. Surgical removal of the gland is an option in cases that cause disfigurement or where there’s obstruction of tracheal or esophageal function.1

• Hyperthyroidism. This develops when the thyroid produces too much hormone. It can be induced by an immunologic reaction (Graves’), inflammation of the gland (thyroiditis), toxic thyroid nodules (abnormal tissue growth), pituitary tumor (tumor produces excess TSH) and pituitary resistance (disruption of the feedback loop leading to excess TSH release). Thyrotoxicosis produces signs and symptoms that include nervousness, anxi- ety, weight loss, restlessness, cardiac arrhythmia and fatigue. One complication of hyperthyroidism is called thyroid storm. This life-threatening situation results in fever, extreme weakness and muscle atrophy, restlessness, mood changes, confusion, coma, cardiovascular collapse, shock and hepatomegaly with mild jaundice.1 Treatment should be instituted immediately.

Medical Management
The medical management of thyrotoxicosis makes use of agents that block the synthesis of thyroid hormone, like propylthiouracil (PTU) and methimazole (Tapazole). These medications are generally recommended for children or young adults demonstrating minimal goiter and only mild symptoms. Propranolol (Inderal) is often used adjunctively to control symptoms such as tachycardia.

Other medical treatment modalities, based on the presumption that the disorder is a consequence of an autoimmune process, attempt to alter the autoimmune response via systemic corticosteroids, retrobulbar steroids, supervoltage orbital radiation, azathioprine, cyclophosphamide cyclosporine, plasmapheresis and thyroid ablation.15,16

The effectiveness of combination treatment involving corticosteroids and orbital irradiation cannot be denied. Failure with this potent combination therapy usually results from poorly tolerated and unacceptable side effects.

Clinicians often recommend radioactive iodine therapy in patients over 40 with well-documented hyperthyroidism. With this approach, careful monitoring of thyroid status is critical as patients may develop hypothyroidism, necessitating permanent thyroid replacement.

Recent research suggests that all treatment for hyperthyroidism should be surgical. Surgeons performed near total or total thyroidectomies on 400 patients with hyperthyroidism and closely followed them postoperatively with serum thyroid hormone testing. None had recurrent hyperthyroidism postoperatively and surgical complications were rare, avoiding the known risk of cancer associated with radioactive iodine treatment.17

Another study of 1,178 patients in the Philippines over a 12.5 year period also concluded that thyroidectomy is a safe and effective, and should be considered as first-line therapy in all cases of thyroid disease.18

Neoplastic Thyroid Disease
Thyroid cancer remains a controversial topic because there is no clear consensus on the proper approach to the problem. Two facts remain: Death from thyroid cancer is rare (about 1,100 such deaths per year)1 and, clinically, single thyroid nodules are common. Statistics from the National Cancer Institute indicate that the death rate from thyroid cancer in the United States has remained stable at 0.6 per 100,000.12

Few patients with thyroid nodules will die from malignancy. The prevalence of malignancy increases in some ethnic groups: Occult thyroid carcinomas are found in approximately 25 percent of the Japanese. Yet the death rate of Japanese from thyroid cancer is no higher than that of non-Japanese.

Auscultation, along with percussion and 
palpation, is part of the exam technique for
thyroid disorders.

Since treatments for thyroid carcinoma are associated with high morbidity, in many cases the risk of therapy may be higher than the risk of leaving the disease untreated. Although they are rare, these processes can produce ocular signs and symptoms that result from secondary hypothyroidism or hyperthyroidism.5
Thyroid malignancies have a broad spectrum of behavior, from clinically insignificant papillary carcinomas to relentlessly progressive anaplastic cancers. Thyroid cancers may be caused by low-dose irradiation of the gland (usually for enlarged thymus or tonsils), or may be familial as in the case of medullary carcinoma or idiopathic. Thyroid cancer typically first presents as a thyroid nodule, which may or may not produce local symptoms. Even though the diagnosis of a malignancy can be difficult, the earlier the lesion is identified, the better the prognosis.12,13

Non-invasive techniques, such as ultrasonography, may help differentiate some benign masses (such as a hemorrhagic nodule) from malignant tumors. While ultrasound imaging lacks resolution to differentiate between malignant tumor types, it serves as a useful diagnostic weapon, as it may indicate if more invasive procedures are needed.19

When the diagnosis of a thyroid mass remains unclear, invasive procedures are required. With both the sensitivity and specificity above 95 percent, fine-needle aspiration biopsy is a powerful and highly reliable diagnostic test, whose results help guide the practitioner toward the most effective treatment modalities.20 These are the primary forms of thyroid cancers.

• Papillary carcinoma. This the most common primary thyroid cancer, comprising 60-70 percent of all such cancers in adults.1,13 It is more common in females by about 2:1 and occurs around the third or fourth decade.1

The histopathology of these lesions includes papilliform arrangement of cells, atypical nuclei with cytoplasmic inclusions and psammona bodies (deposits of calcium), which can be detected upon biopsy. Often these masses are a mixture of papillary and follicular components.1,13 This distinction is important as a mass containing follicular elements responds well to radioiodine (131I), while lesions composed solely of papillary components tend to respond poorly to radioiodine therapy.1,13 
The disease is multifocal in 20 percent of cases and typically spreads into adjacent structures by extension or regional lymphatics.13 The lungs are considered a distant site of metastases for progressive malignant disease, and no cases of metastases to the choroid of the eye have been reported.12,13 These tumors are typically treated with hemithyroidectomy of the lobe containing the nodule or in certain cases, a total thyroidectomy.13

• Follicular carcinoma. One-fourth of thyroid cancers have what is known as follicular appearance.15 Follicular carcinoma occurs most commonly in the middle-aged and elderly, accounts for approximately 15 percent of thyroid cancers, and is found more in females by a ratio of 2:1.5,16 This type of carcinoma usually spreads by vascular invasion and commonly invades lung, liver, and bone.5,16

The prognosis of this slow-growing tumor is based on the age of the patient, the size of the mass, the amount of encapsulation and the degree of metastasis.5 There are no reported cases of metastases to the choroid.16

• Anaplastic carcinomas. This form of cancer comprises approximately 5 percent of all thyroid cancers and carries a grave prognosis.1 Histologically, specimens show hoards of anaplastic spindle and multinucleated giant cells. These masses tend to be rock-hard and fixed on palpation.

Few patients survive more than a year, with most perishing within months of diagnosis.1,12 Treatment with chemotherapy and radioiodine has produced dismal results. These techniques serve only to slow the disease process without rendering a cure. Surgery may be considered when the mass becomes large enough that it compresses the trachea or esophagus, causing obstruction and subsequent hoarseness, dysphagia, hemoptysis and respiratory distress.1 

• Medullary carcinoma. This cancer takes its derivation from calcitonin-secreting parafollicular C cells and constitutes approximately 5-10 percent of thyroid malignancies.1 Medullary carcinomas may develop from an inherited, autosomal dominant trait, and may be associated with functional tumors of the adrenal medulla and hyperparathyroidism. Patients will often complain of symptoms of sweating and flushing.
Calcitonin radioimmunoassay is the primary test to evaluate these patients. In questionable cases, a thyroid radioisotope scan and fine needle biopsy may be considered. Patients at high risk should be reevaluated every 1-2 years, with total thyroidectomy being the standard treatment in confirmed cases.12,20,21
• Lymphoma and other thyroid malignancy. This firm, rapidly growing tumor is typically associated with pain and tenderness of the neck and throat. Histopathologic studies reveal diffuse histiocytic lymphoma. These patients routinely demonstrate elevated levels of thyroid antimicrosomal antibodies upon laboratory testing.

This phenomenon may be associated with Hashimoto’s thyroiditis (autoimmune thyroiditis), as Hashimoto’s and lymphoma seem to occur together too often to be sheer coincidence.1,19 The lymphoma has the potential to be limited to the thyroid gland or spread to involve several organ systems. When this malignancy is confined to the thyroid gland, patients can expect a five-year survival rate in approximately 75-85 percent.1 Early diagnosis is a critical factor for improving the overall prognosis. The diagnosis is confirmed by fine needle biopsy.13,20 Treatment consists of a combination of radiotherapy and chemotherapy.1 

The process that the human body has developed to regulate metabolism is complex, and our understanding of that system’s effects on the body and the eye continues to evolve. In fulfilling our role as primary care eye doctors, optometrists need both solid diagnostic skills and an understanding of the testing and treatment options available to our patients who have, or may have, thyroid diseases.

Dr. Gurwood is an associate professor of clinical sciences and senior attending optometric physician at The Eye Institute of the Pennsylvania College of Optometry. Dr. Dente is a clinical instructor and attending optometric physician at the same institution.

REFERENCES
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15. Antonelli A, et al. High-Dose Intravenous Immunoglobulin Treatment in Graves’ Ophthalmopathy. Acta Endocrinologica 1992;126(1):13-23.
16. Perros P, Kendall-Taylor P. Biological Activity of Antibodies from Patients with Thyroid-Associated Ophthalmopathy: In Vitro Effects on Porcine Extraocular Myoblasts. Quarterly J of Medicine 1992;84(305):691-706.
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