Hyperthyroidism : Graves' disease ?
Introduction
Graves' disease accounts for 60–80% of thyrotoxicosis.
More common in females.
Rarely begins before adolescence.
Typically occurs between 20 and 50 years of age.
Indirect evidence suggests that stress is an important environmental factor.
Smoking is a minor risk factor for Graves' disease.
Sudden increases in iodine intake may precipitate Graves' disease.
There is a threefold increase in the occurrence of Graves' disease in the postpartum period.
Pathophysiology
Production of IgG antibodies (thyroid-stimulating immunoglobulins or TSH receptor antibodies TRAb) directed against the TSH receptor.
This stimulate hormone production and goitre formation.
Utimate thyroid failure is seen in some patients is thought to result from the presence of blocking antibodies against the TSH receptor, and
From tissue distruction by cytotoxic antibodies and cell-mediated immunity.
Cytokines appear to play a major role in thyroid-associated ophthalmopathy.
Infiltration of the extraocular muscles by activated T cells; the release of cytokines results in fibroblast activation and increased synthesis of glycosaminoglycans that trap water, thereby leading to characteristic muscle swelling.
Late in the disease, there is irreversible fibrosis of the muscles.
Increased fat is an additional cause of retrobulbar tissue expansion.
The increase in intraorbital pressure can lead to proptosis, diplopia, and optic neuropathy.
Smoking is strongly linked with the development of ophthalmopathy.
Trigger for the development of thyrotoxicosis in genetically susceptible individuals may be infection with viruses or bacteria.
Escherichia coli and Yersinia enterocolitica possess cell membrane TSH receptors; antibodies to these microbial agents may cross react with the TSH receptors.
Clinical features
Signs and symptoms include features that are common to any cause of thyrotoxicosis as well as those specific for Graves' disease.
The clinical presentation depends on the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient's age.
In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis.
Symptoms
Hyperactivity, irritability, dysphoria
Heat intolerance and sweating
Palpitations
Fatigue and weakness
Weight loss with increased appetite
Diarrhea
Polyuria
Oligomenorrhea, loss of libido
Signs
Tachycardia; atrial fibrillation in the elderly
Fine Tremor
Goiter
Warm, moist skin
Muscle weakness, proximal myopathy
Lid retraction or lag
Gynecomastia
aExcludes the signs of ophthalmopathy and dermopathy (The typical lesion is a noninflamed, indurated plaque with a deep pink or purple color and an "orange-skin" appearance.) specific for Graves' disease.
The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur and can lead to worsening of angina or heart failure.
Investigations
Thyroid function test:
Serum T3 and T4- elevated, T4 at upper normal range.
T3 is raised in only in 5% of the patients.
Serum TSH is undetected and less then 0.05mU/L.
Further investigation:
TSH receptor antibody (TRAb elevated)
Factitious thyrotoxicosis: by consuming excess amount of thyroid hormone preparation, esp. thyroxine which supress TSH and the release of endogenous thyroid hormone.
T4:T3 ratio in conventional thyrotoxicosis 30:1 is increased to 70:1 due to exogenous T4.
Management
The hyperthyroidism of Graves' disease is treated by reducing thyroid hormone synthesis, using antithyroid drugs, or reducing the amount of thyroid tissue with radioiodine (131I) treatment or by thyroidectomy.
The main antithyroid drugs are the thionamides, such as propylthiouracil, carbimazole, and the active metabolite of the latter, methimazole.
All inhibit the function of TPO, reducing oxidation and organification of iodide.
Propylthiouracil inhibits deiodination of T4 T3.
The initial dose of carbimazole or methimazole is usually 10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored.
Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, and divided doses are usually given throughout the course.
Thyroid function tests and clinical manifestations are reviewed 3–4 weeks after starting treatment, and the dose is titrated based on unbound T4 levels.
Most patients do not achieve euthyroidism until 6–8 weeks after treatment is initiated. TSH levels often remain suppressed for several months and therefore do not provide a sensitive index of treatment response.
All patients should be followed closely for relapse during the first year after treatment and at least annually thereafter.
The common side effects of antithyroid drugs are rash, urticaria, fever, and arthralgia (1–5% of patients).
Rare but major side effects include hepatitis, an SLE-like syndrome, and, most importantly, agranulocytosis (<1%).
Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol, may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid drugs take effect.
Radioiodine causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs.
Pregnancy and breast feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely 6 months after treatment.
Subtotal or near-total thyroidectomy is an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine.
The titration regimen of antithyroid drugs should be used to manage Graves' disease in pregnancy, as blocking doses of these drugs produce fetal hypothyroidism. Propylthiouracil is usually used because of relatively low transplacental transfer and its ability to block T4 T3 conversion.
