THYROTOXICOSIS (HYPERTHYROIDISM) - Graves Disease



This complex autoimmune disorder consists of toxic goiter, ophthalmopathy, and not infre­quently dermopathy, which may occur together or separately. The abnormal immunoglobulin(s) responsible for the hyperthyroidism can now be measured by bioassay. Thyroid-stimulating im­munoglobulins (TSI) are antibodies to the normal thyroid gland TSH receptor site. They have pow­erful agonist action and consequently induce hy­perthyroidism. The initiating factors in the de­velopment of TSI and the role of TSI in the development of the ophthalmopathy or dermo­pathy have not been elucidated.

Clinical Features. The clinical presentation of the thyrotoxic patient is extremely variable. The actual features relate to the age at onset, the duration of the condition, and the de­gree of hormone excess. The patient most fre­quently presents with a history of nervousness, heat intolerance, sweating, palpitations, tremor, and weight loss. In addition a change in collar size (goiter formation) and eye discomfort (Graves’ ophthalmopathy) may be noted.

More prolonged disease is associated with features of chronic catabolism. Skeletal muscle wasting, especially of the limb girdles, induces a proximal myopathy. Patients may experience difficulty in climbing stairs or getting up from the sitting position. Although dyspnea in the absence of cardiac failure is common, more severe disease can be manifested by a severe cardiomyopathy and congestive failure, especially in the elderly.

The mental changes are characterized by anx­iety, irritability, poor concentration, restlessness, and emotional lability. In addition, insomnia and forgetfulness may be disturbing features.

Physical Findings . The majority of young patients with hyperthyroidism have’ an enlarged thyroid (goiter). Diffuse symmetrical en­largement of the thyroid is characteristic of Graves’ disease, whereas asymmetric changes occur in toxic nodular goiter. A bruit over the thy­roid indicates extreme vascularity and is gener­ally found only in Graves’ disease. In addition, the finding of a palpable pyramidal lobe in a hy-perthyroid patient is suggestive of Graves’ dis­ease.

The eye changes may be due to excess thyroid hormone or to the ophthalmopathy of Graves’ dis­ease. Enhanced sympathetip tone due to excess thyroid hormone causes the characteristic wid­ening of the palpebral fissure (stare) and failure of the upper lid to closely follow globe movement(lag). Proptosis (exophthalmos), forward protru­sion of the globe due to retro-orbital deposition of fat,mucopolysaccharides, and lymphocytes, is the cardinal feature of Graves’ ophthalmopathy. In addition, extraocular muscle weakness may limit eye movement and result in diplopia.

Smooth, shiny, silky, warm skin is frequently noted in hyperthyroidism. Thinning and loss of hair may be particularly worrisome for women. Hyperpigmentation over extensor surfaces and clubbing (thyroid acropachy) are rare features. Onycholysis, separation of the distal portion of the nail from the nailbed (Plummer’s nails), fine tremor of the outstretched hands, and brisk re­flexes are commonly noted. Pretibial myxedema may occasionally be seen in Graves’ disease.

A spectrum of cardiovascular abnormalities may be detected on physical examination. Sinus tachycardia with a wide pulse pressure may progress to atrial fibrillation and congestive heart failure. Systolic flow murmurs and a forceful ap­ical pulse are common features.

Diagnosis. A typical case of Graves’ disease is easily diagnosed. In many instances, however, the typical eye features are minimal, goiter may be moderate (especially in the elderly), and systemic features may be few. Thus the condition may go unrecognized for years. In the majority of cases serum total and free T4 levels will be high. If nor­mal, a serum total T3 must be performed as T3 toxicosis occurs in 5 to 10 per cent of cases. If all other tests are equivocal, the TSH response to TRH should be flat if the patient is indeed hyperthyroid.

The recognition of hyperthyroidism in the el­derly is frequently delayed owing to the insidious nature of the disease. These patients have been classically described as “apathetic” owing to the paucity of features of sympathetic overactivity. The dominant features may be reflected in other systems such as the cardiovascular system. Pa­tients present with atrial fibrillation and conges­tive failure. In the absence of ophthalmopathy and goiter the hyperthyroid state is generally missed. All elderly patients presenting with new-onset cardiovascular disorders should be screened for hyperthyroidism. Beware, however, that patients with nonthyroidal systemic disorders may have a transient rise in serum total and free T4 values asa byproduct of their disease and require close monitoring with serial thyroid function tests in order to elucidate their thyroid status.

Anxiety neurosis may be difficult to differen­tiate clinically from hyperthyroidism. These pa­tients may present with tremor, tachycardia, ir­ritability, and fatigue. Typical anxiety neurosis is generally associated with depression, weight loss accompanied by anorexia, cold moist hands, and a normal resting (sleeping) pulse. If the clinical suspicion for hyperthyroidism remains, a baseline screening test with total and free T4 should clarify the diagnosis. Some patients with psychiatric dis­orders (10 per cent) have a transient elevation in serum total and free T4 levels, such that serial analyses may be needed or further detailed testing may be indicated to exclude hyperthyroidism.
Graves’ ophthalmopathy may occur in a euthy­roid or even a hypothyroid patient. Other diseases of the orbit or retro-orbital space must be consid­ered as a cause of exophthalmos. Orbital pseu­dotumor may display similar extraocular muscle swelling on CT scan or sonogram. When the ophthalmopathy is bilateral and the TRH test and TSI analysis are positive, the diagnosis of Graves’ disease can generally be made. Other features of the disease eventually become evident in most cases.

Hyperthyroidism in the absence of goiter sug­gests factitious thyrotoxicosis or thyroiditis (or very rarely struma ovarii). In both conditions the RAIU test is suppressed. Serum thyroglobulin is high in thyroiditis but reduced in subjects taking exogenous thyroid hormone.

Therapy. Graves’ disease is a self-limiting dis­ease; 30 per cent of cases will go into spontaneous remission within one to two years. Antithyroid drugs can be used for the temporary control of symptoms, or the gland can be ablated with 131I or surgery. The choice of therapy is usually dic­tated by the patient’s age, the size of gland, and the severity of the disease.

Drugs. The thionamides propylthiouracil (PTU) and methimazole (Tapazole) will control the fea­tures of hyperthyroidism in almost all cases. These drugs inhibit the synthesis of thyroid hor­mone and will restore a euthyroid state in four to eight weeks. The initial dose recommended is 150 to 300 mg every 8 hours for PTU or 20 to 30 mg every 12 hours for methimazole. Once achieved, euthyroidism can generally be maintained by smaller doses of PTU (50 to 100 mg twice daily) or methimazole (5 to 10 mg once daily). Antithy­roid drugs are preferred for children, young adults, and the pregnant patient. They are also used in the adult and elderly patient to induce euthyroidism prior to definitive therapy with 131I or surgery. Antithyroid drugs will induce a per­manent remission in about 30 per cent of patients with Graves’ disease, usually within three to six mouths of therapy. A reduction in TSI during therapy generally indicates that a remission has occurred and consequently is a good guide for the discontinuation of therapy.

Transient dermatitis, the most common side effect of antithyroid drugs, is not dose-related and generally disappears despite continued therapy. Urticaria and pruritus may also occur. Dose-re­lated leukopenia, myalgia, arthralgia, and ele­vated serum alkaline phosphatase occur com­monly in patients during therapy with PTU. Generally these abnormalities can be controlled by dose adjustment. The most serious side effect (agranulocytosis) is not dose-related. A routine blood count is of no value as a predictor, since this complication occurs acutely. Thus patients shcnild be advised to watch for fever and sore throats and to report such developments imme­diately to their physician. Fortunately the major­ity of patients recover from agranulocytosis once the drug is stopped.

Sympathetic overactivity can be controlled with beta-adrenergic blockade. Such therapy with propranolol (40 mg every 6 hours) is indicated for severe agitation, tremor, sweating, and tachycar­dia. Beta-blockers should not be used in the pa­tient with severe thyrotoxic heart disease.

Radioactive iodine therapy with 131I is the pre­ferred form of therapy for the majority of patients with Graves’ disease. An appropriate dose (7 to 12 mCi 131I) will induce euthyroidism in most pa­tients. This form of therapy is inexpensive and easy to administer. Since the gonadal exposure is extremely low (less than a diagnostic radiograph), genetic effects are unlikely. Thus 131I can be used in all adult patients. 131I is contraindicated during pregnancy; thus a pregnancy test should be per­formed prior to therapy, or the dose should be given during the first half of the menstrual cycle. Long-term hypothyroidism (70 per cent at 10 years) is the major disadvantage of 131I therapy. In addition, dose-related hypothyroidism occurs acutely after therapy (in six months) in a number of subjects. These complications are currently un­avoidable, since lower doses may fail to induce euthyroidism.
Surgery. Surgical ablation is still preferred for children who cannot be controlled with antithy­roid drugs and possibly for young adults with ex­tremely large glands. The procedure, subtotal thy­roidectomy, should be performed only by an experienced surgeon. In the proper hands it is very effective therapy associated with minimal morbidity. Recurrent laryngeal nerve damage with vocal cord paralysis, permanent hypopara­thyroidism, and hypothyroidism may be signifi­cant postoperative problems. Long-term hypothy­roidism (40 per cent at 10 years) occurs despite the best of surgery, and immediate postoperative hypothyroidism may occur in 5 to 10 per cent of patients. Furthermore,recurrent hyperthyroidism also occurs in about 5 to 10 per cent of cases and should always be treated with 131I therapy, since. reoperation is-more frequently accompanied by, major complications.

Hyperthyroidism During Pregnaruy. Graves’; disease is responsible for the majority of cases of j thyrotoxicosis associated with pregnancy. It’ should always be treated with antithyroid drugs. Surgery is rarely indicated and l31I therapy should.

never be used. The dose of antithyroid drug used should be the minimum needed to restore euthy-roidism. These drugs freely cross the placenta; thus hypothyroidism and goiter can be induced in the fetus with inappropriate high dosage. In general propylthiouracil is the drug of choice in the pregnant patient needing thionamide therapy, since aplasia cutis has been described in fetuses following methimazole therapy. The maternal thyroid status should be monitored with free T4 determinations, since the total T4 concentration is normally elevated during pregnancy because of the’ estrogen-induced high serum TBG level. The physician caring for the newborn infant of a Graves’ mother should carefully monitor for neo­natal Graves’ disease. Passive transfer of TSI oc­curs and may produce transient neonatal hyper­thyroidism. The cord blood TSI level may predict the infant at risk.





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