Pathogenesis

Graves’ disease is an autoimmune disorder with familial predisposition. It is characterized by lymphocytic infiltration of the thyroid gland and antithyroid antibodies directed against the TSH receptor. The specific cause of Graves’ is unknown. Thyroid receptor antibodies are primarily thyroid stimulating immunoglobulins, which activate TSH receptors in the membrane of the follicular epithelial cells of the thyroid gland, resulting in excess synthesis and secretion of thyroid hormone and growth of the thyroid gland (see Chapter 5, Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease).

Historical Perspective

The syndrome known in the Western world as Graves’ disease was independently described by Dr. Caleb Hillier Parry in 1786, Sir Robert James Graves’ in 1835, and Dr. Carl A. Basedow in 1840.^2–6 Caleb Hillier Parry, an English physician and descendant from a Welsh pedigree, first described a patient with diffuse goiter and hyperthyroidism in 1786. In 1825, after Parry’s death, his report of eight patients with exophthalmic goiter and hyperthyroidism was published by his son Charles.² Sir Robert James Graves’ a physician from Dublin, Ireland, published a monograph in 1835 titled “Newly Observed Affection of the Thyroid Gland in Females,” describing six patients with thyrotoxicosis, exophthalmos, and enlargement of the thyroid gland.³ The first description of toxic goiter in Europe was in 1840 by Carl A. von Basedow, a German private practitioner.⁴ He described exophthalmos, struma (goiter) and palpitations of the heart in three women.

Graves’ disease, Parry’s disease, and Basedow’s disease have all been used to describe the syndrome of thyrotoxicosis, exophthalmos, and diffuse symmetric goiter. It was Armand Trousseau, professor of medicine at the Hotel-Dieu in Paris and author of the foreword of Robert Graves’ book of clinical lectures, who proposed that the syndrome of exophthalmic goiter be named “Maladie de Graves.”⁷ It has been suggested that the attachment of Graves’ name to the syndrome is the result of Trousseau’s influence.⁶ A strong case can be made for renaming the syndrome “Parry’s disease,” a proposal that was made by Sir William Osler.⁶

Epidemiology

The annual incidence of Graves’ disease in the United States is approximately 0.4%.⁸ It occurs four to six times more commonly in women and usually presents between the ages of 20 and 50 years.⁸ It is the most common cause of hyperthyroidism, accounting for 50% to 80% of all cases.⁹ It occurs in association with other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, chronic lymphocytic thyroiditis, Sjögren’s syndrome, vitiligo, pernicious anemia, type 1 diabetes mellitus, Addison disease, myasthenia gravis, and idiopathic thrombocytopenic purpura.¹⁰

Clinical Presentation

The clinical manifestations of Graves’ disease include symptoms and signs of thyrotoxicosis (see Boxes 9-1 and 9-2), a diffuse symmetric goiter often with a palpable thrill or an audible bruit, and a variable degree of presence of extrathyroidal manifestations including ophthalmopathy, pretibial myxedema, and acropachy. Extrathyroidal manifestations occur as a result of cellular infiltration and glycosaminoglycan deposition in the soft tissues in response to antibody reaction to tissue antigens, which cross-react with the TSH receptor in the thyroid gland.

Clinically relevant ophthalmopathy occurs in 20% to 30% of patients with Graves’ disease and is vision-threatening in 3% to 5%.¹¹ It is more common in cigarette smokers and patients with higher levels of thyrotropin receptor antibodies (Figure 9-1). It occurs as a result of antibody-mediated inflammation of the extraocular muscles, retroorbital fat and connective tissue, and the optic nerve. Stare, lid lag, and eyelid retraction are due to excess sympathetic nervous system stimulation of the levator palpebrae superioris muscles and may occur in all patients with hyperthyroidism, but only patients with Graves’ disease have ophthalmopathy. Periorbital edema, chemosis, exophthalmos, and extraocular muscle weakness are more specific manifestations of Graves’ ophthalmopathy. Patients may experience a gritty feeling in the eyes, eye pain, photophobia, tearing, diplopia, and decreased visual acuity. Patients may develop corneal ulcerations as a result of proptosis and lid retraction. Severe proptosis can cause optic neuropathy and blindness.

Figure 9-1 Graves’ ophthalmopathy.

Pretibial myxedema is an infiltrative dermopathy most often involving the skin of the legs. It occurs in 0.5% to 4% of patients with Graves’ disease. It is manifested by painful, pruritic, raised plaquelike lesions that are violaceous and hyperpigmented in appearance with a texture of an orange peel. Acropachy occurs in less than 1% of patients with Graves’ disease and is manifested by clubbing and periosteal new bone formation of the metacarpal bones and the phalanges.

Diagnosis and Evaluation

The diagnosis of Graves’ disease is established by the association of hyperthyroidism, a diffuse symmetric goiter (Figure 9-2) and increased radioiodine uptake. Iodine-123 thyroid scintigraphy demonstrates diffuse symmetric uptake in the thyroid gland (Figure 9-3); however, it is not routinely necessary to make a diagnosis of Graves’ disease. Measurement of radioiodine uptake and thyroid scintigraphy are primarily of value in helping to differentiate thyrotoxicosis caused by Graves’ disease from toxic multinodular goiter, a solitary toxic adenoma or thyroiditis. In rare circumstances, documentation of elevated thyroid stimulating immunoglobulins, because of their high sensitivity and specificity, may be helpful in establishing or excluding a diagnosis of Graves’ disease.

Figure 9-2 Marked diffuse symmetric thyroid enlargement of Graves’ disease.

Figure 9-3 Iodine-123 thyroid scan demonstrating diffuse symmetric uptake, characteristic of Graves’ disease.

Treatment

The goals of therapy for Graves’ disease are rapid amelioration of symptoms and prevention of recurrent hyperthyroidism. There are three therapeutic alternatives for Graves’ disease: antithyroid drugs, radioiodine ablation, and thyroidectomy. Each alternative has its own advantages and disadvantages. Patient, physician, institutional, or geographic preferences often influence the choice of therapy. In the United States, radioiodine ablation is most commonly used.¹² In Europe, Japan, and South America, prolonged antithyroid drug therapy is the preferred option^13,14 (see Chapter 5, Hyperthyroidism: Toxic Nodular Goiter and Graves’ Disease).