Graves disease is an autoimmune disorder that is a form of hyperthyroidism characterized by goiter

Graves Disease

The natural course of hyperthyroidism due to Graves disease in pregnancy is characterized by an exacerbation of symptoms in the first trimester and during the postpartum period, and an amelioration of symptoms in the second half of pregnancy. Stimulation of the thyroid gland by hCG in the first trimester and an elevation in TRAb values have been suggested as the cause of the exacerbation. Immunologic responses caused by changes in lymphocyte subsets could explain spontaneous improvement in the second half of pregnancy and recurrences in the postpartum period. In a study that compared Graves disease in pregnant and nonpregnant women, Kung and Jones postulated that the amelioration of symptoms seen with progression of pregnancy was due to a decrease in the titers of TRAbs with stimulating activity and an increase in TRAbs with thyroid-blocking activity.60 The reverse was true in the postpartum period, when aggravation of Graves hyperthyroidism usually occurs. Another theory suggests that the amelioration of Graves disease in the last half of pregnancy is induced by a decrease of thyroid receptor antibodies (TRAbs, TSIs).

When hyperthyroidism is properly managed throughout pregnancy, the outcome for mother and fetus is good; however, maternal and neonatal complications for mothers with untreated or poorly controlled hyperthyroidism are significantly increased (Box 47.3).61

In most patients in whom the diagnosis is made for the first time during pregnancy, hyperthyroid symptoms antedate conception. The clinical diagnosis of thyrotoxicosis may present difficulties during gestation because many symptoms and signs are commonly seen in normal pregnancy, such as mild palpitations, heart rate between 90 and 100 beats/min, mild heat intolerance, shortness of breath on exercise, and warm skin. However, some clinical clues increase the likelihood of the diagnosis of hyperthyroidism including presence of goiter, ophthalmopathy, proximal muscle weakness, tachycardia with a pulse rate of more than 100 beats/min, and weight loss or inability to gain weight despite a good appetite. Occasionally, the patient may be seen for the first time in congestive heart failure, and the etiologic diagnosis is difficult because many of the physical findings are suggestive of cardiac valvular disease, particularly mitral insufficiency or stenosis. Hyperthyroidism under poor control is frequently complicated by preeclampsia, small-for-gestational-age (SGA) infants, and preterm delivery. The physician should suspect hyperthyroidism in the presence of systolic hypertension with an inappropriately low diastolic blood pressure and a wide pulse pressure, which is also seen in other conditions such as aortic insufficiency.

On physical examination, the thyroid gland is enlarged frequently in pregnant woman with Graves disease. Indeed, the absence of a goiter makes the diagnosis of Graves disease unlikely in young people. The gland is diffusely enlarged, between two and six times the normal size, and varies from soft to firm; sometimes it is irregular to palpation, with one lobe being more prominent than the other. A thrill may be felt or a bruit may be heard, indications of a hyperdynamic circulation. Examination of the eyes may reveal obvious ophthalmopathy, but in most cases, exophthalmos is absent or mild, with one eye slightly more prominent than the other with retraction of the upper lid. Extraocular movements may be impaired on careful eye examination. Stare is common, as is injection or edema of the conjunctiva. Severe ophthalmopathy is rare in pregnancy; glucocorticoid therapy and surgical orbital wall decompression may be required to restore visual acuity. Pretibial myxedema is rare, seen in less than 10% of women. A hyperdynamic heart with a loud systolic murmur is a common finding. Proximal muscle weakness, fine tremor of the outstretched fingers, and hyperkinetic symptoms are seen frequently. The skin is warm and moist, and palmar erythema is accentuated.

1 Western medical aetiology and pathology

Graves' disease is an autoimmune disease in which T lymphocytes become sensitized to antigens within the thyroid gland and stimulate B lymphocytes to synthesize antibodies, specifically thyrotropin receptor antibody (TRAb). These bind to the surface of thyroid cells. They do not destroy the thyroid cells, but stimulate them to produce excessive amounts of thyroid hormone, while feedback leads to a decline in thyroid-stimulating hormone (TSH), causing hyperthyroidism. The patient's catabolic processes exceed the anabolic processes. The resulting inflammation of the thyroid gland is responsible for its growth and protrusion of the eyes, two classical signs of Graves' disease. The causes of Graves' disease may be a combination of factors, including heredity, gender, age and stress.

Graves Disease

Graves disease, named after Dr. Robert J. Graves from the 1830s, is an autoimmune disease characterized by the constitutive activation of the TSH receptor by TRAb, which results in increased synthesis and secretion of thyroid hormone. Graves disease is the most common cause of hyperthyroidism in the United States, with an estimated incidence of 30 cases per 100,000 persons per year. The disease has a female predominance, with an 8:1 female-to-maleratio, and typically presents during younger adult life, with a typical patient age range of between 20 and 40 years.

Because of its autoimmune etiology, Graves disease can have other manifestations in addition to the classic symptoms and signs of hyperthyroidism. The most common is Graves orbitopathy, which occurs in up to 25% to 30% of patients. In this process, autoimmune reactions at the orbital and periorbital soft tissues lead to proptosis, eyelid retraction, chemosis, periorbital edema, and diminished ocular muscle motility (Fig. 37.12); if left untreated, the orbitopathy can lead to vision loss from corneal lesions or optic nerve compression. Skin manifestations also can occur, including pretibial myxedema and acropachy (edema at the digits). Other autoimmune conditions that have been associated with Graves disease include Hashimoto thyroiditis, lupus, rheumatoid arthritis, pernicious anemia, and Addison disease, among others.

The biochemical workup for Graves disease typically includes thyroid function tests, including TSH, free T4 and T3, as well as measurement for TRAb (typically with TSI but also with TSH receptor-binding inhibitory immunoglobulin in selected scenarios). The presence of TRAb is diagnostic for Graves disease. Imaging may consist of neck ultrasound and/or nuclear medicine thyroid uptake scan, depending on the indications. Sonographic features may include a diffusely hypervascular gland, often with heterogeneous echogenicity; thyroid nodular disease may also be identified. Nuclear scintigraphy using either99mtechnetium pertechnetate or123I may help differentiate TSI-negative Graves disease from toxic nodular disease based on diffuse versus nodular uptake pattern. Cross-sectional imaging of the head may be useful for the evaluation of orbitopathy.

The three management options for Graves hyperthyroidism include antithyroid medications, RAI ablation, and thyroidectomy. In the United States, RAI is the most common employed treatment option, although antithyroid medication is being used more frequently as a first option; nearly one-third of patients may be able to achieve long-term remission with medication alone. In truth, each of the three treatment options comes with its own unique set of advantages and disadvantages, as well as indications and contraindications, which must be tailored according to individual patient values and preferences. The 2016 American Thyroid Association (ATA) guidelines on the management of hyperthyroidism provide a helpful evidence-based summary of the clinical scenarios that would most favor a particular option for treatment (Table 37.1).4

Pathogenesis

Although the cause of Graves' disease is unknown, autoimmunity directed against the TSH receptor is the hallmark of Graves' thyroid disease. Autoantibodies against this receptor mimic the action of its natural ligand, TSH, inducing hyperthyroidism and goiter. Whether these antibodies also are responsible for the other, extra-thyroidal manifestations of Graves' disease is uncertain, although the TSH receptor has been found in fibroblasts residing in the retrobulbar tissues and in the pretibial skin. The pathogenetic importance of TSH receptor autoantibodies as the cause of Graves' hyperthyroidism is, however, without doubt. Transfer of human immunoglobulin (IgG) samples containing these antibodies to rodents causes a prolonged release of previously radiolabeled thyroid hormone from mouse or guinea pig thyroids. This bioassay was used to make the diagnosis of Graves' disease in the past, and the transferred antibodies were named “long-acting thyroid stimulator” (LATS). Nowadays, different tests are applied. Patient IgGs can be incubated with cells transfected with the human TSH receptor, and the response of these cells in terms of the release of cyclic AMP (cAMP) can be measured in a TSH receptor-stimulating immunoglobulin (TSI) bioassay. Another widely used and less cumbersome assay measures the inhibition of binding of 125I-labeled TSH to TSH receptor containing preparations by patient IgGs in the so-called TSH-binding inhibitory immunoglobulins (TBII) assay.

In the majority of patients, other antithyroidal autoantibodies are also present. In approximately 70% of patients, antibodies against thyroid peroxidase (TPO) can be detected. TPO antibodies are the hallmark of Hashimoto's hypothyroidism, and their titers are related to the degree of lymfocytic infiltration of the thyroid gland. The importance of these antibodies in Graves' hyperthyroidism is unclear, but they might be related to the fact that some patients with Graves' hyperthyroidism become hypothyroid in the long run.

Acute General Rx

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Advantages and disadvantages of treatment options for Graves hyperthyroidism are summarized inTable 3.

Antithyroid drugs (thionamides, ATDs) to inhibit thyroid hormone synthesis or peripheral conversion of T4 to T3:

Methimazole or propylthiouracil (PTU) are available. Methimazole is generally preferred because it has a longer half-life, allowing for once-daily dosing. PTU is preferred during pregnancy.

Side effects: Skin rash (3% to 5%), arthralgias, myalgias, granulocytopenia (0.5%); rare side effects: Aplastic anemia, hepatic necrosis (PTU), cholestatic jaundice.

Thionamide antithyroid drug therapy results in a remission in 40% to 50% of patients treated for 12 to 18 mo.

Radioactive iodine (RAI):

Treatment of choice for patients >21 yr and younger patients who have not achieved remission after 1 yr of ATD therapy

Contraindicated during pregnancy and lactation

After radioactive therapy there may be an acute elevation of thyroid antibody titers and exacerbation of ocular symptoms in 15% to 20% of patients

Surgery: Near-total thyroidectomy. Indications: Obstructing goiters despite RAI and ATD therapy, patients who refuse RAI and cannot be adequately managed with ATDs, and pregnant women inadequately managed with ATDs. Complications of surgery include hypoparathyroidism (4%) and vocal cord paralysis (1%).

Adjunctive therapy: Beta-adrenergic receptor blockers (e.g., atenolol 50 to 100 mg/day) to alleviate the beta-adrenergic symptoms of hyperthyroidism (tachycardia, tremor); contraindicated in patients with bronchospasm.

Graves ophthalmopathy: Methylcellulose eye drops to protect against excessive dryness, sunglasses to decrease photophobia, intraocular and systemic high-dose corticosteroids for severe exophthalmos. Worsening of ophthalmopathy after RAI therapy is often transient and can be prevented by the administration of prednisone. Other treatment options include antiinflammatory and immunosuppressive agents, radiation, and corrective surgical procedures. The administration of the antioxidant selenium (100 μg PO bid) has been recently reported as effective in improving quality of life, reducing ocular involvement, and slowing progression of the disease in patients with mild Graves orbitopathy. Its mechanism of action is believed to be an effect on the oxygen free radicals and cytokines that play a pathogenic role in Graves orbitopathy. Inhibition of the insulin-like growth factor I receptor (IGF-IR)is a new therapeutic strategy to combat the underlying autoimmune etiology of ophthalmopathy. Trials with teprotumumab, a human monoclonal antibody inhibitor of IGF-IR, in patients with active, moderate-to-severe ophthalmopathy have shown effectiveness in reducing proptosis.1

Dermopathy and acropachy: Topical corticosteroids are often used but are generally ineffective. Trials using rituximab infusion for dermopathy have shown striking improvement.

Complications

Graves' disease is associated with a variety of complications during pregnancy (Table III). There can also be significant fetal complications as a consequence of antithyroid drug treatment. Preterm labor and infants small for gestational age are associated with Graves' disease. Approximately 1 in 100 infants from mothers with Graves' disease will have neonatal Graves' disease. Since this results from maternal thyroid-stimulating immunoglobulin (TSI) crossing the placenta, the fetus is at risk even if the mother has been definitively treated with radioiodine or surgery. Some advocate measuring maternal TSI levels in the serum to determine the risk of neonatal Graves' disease, although the predictive value of this measurement is not known.

Table III. Hyperthyroidism and Pregnancy

Complications

Graves׳ disease is associated with a variety of complications during pregnancy (Table 3). There can also be significant fetal complications as a consequence of antithyroid drug treatment. Preterm labor and infants small for gestational age are associated with Graves׳ disease. Approximately 1 in 100 infants from mothers with Graves׳ disease will have neonatal Graves׳ disease. Since this results from maternal thyroid-stimulating immunoglobulin (TSI) crossing the placenta, the fetus is at risk even if the mother has been definitively treated with radioiodine or surgery. Some advocate measuring maternal TSI levels in the serum at 26–28 weeks gestation to determine the risk of neonatal Graves׳ disease, although the predictive value of this measurement is uncertain.

Table 3. Hyperthyroidism and pregnancy

Abstract

Graves’ disease (GD) is an autoimmune disorder in which autoantibodies against the TSH receptor (TRAbs) cause hyperthyroidism, and characterized by goiter and manifestations such as orbitopathy and more rarely pretibial myxedema. The etiology of GD is probably multifactorial, resulting from a combination of genetic and environmental factors. Smoking has been identified as a risk factor for developing GD. Familiar clustering and disease occurrence in twins suggest genetic factors in the pathogenesis of the disease. Elevated circulating free thyroid hormones are measured in patients with GD and, although not essential TRAb may also be measured to support the diagnosis of GD The therapy of GD aims at achieving stable restoration of euthyroidism with different therapeutic strategy including antithyroid drugs, radioiodine and total thyroidectomy. Restoration of permanent euthyroidism is attained in only about 30%–50% of patients after antithyroid therapy and therefore thyroid ablation with radioiodine (RAI) or surgery may be required.

Graves Disease

Graves disease, an autoimmune disorder, is the most common cause of childhood hyperthyroidism. The pathophysiology of Graves disease involves thyroid-stimulating immunoglobulins that bind to the TSH receptor, causing hyperstimulation of the thyroid gland. Most children with Graves disease have a diffuse goiter, and some develop autoimmune ophthalmopathy and myxedema. Because few children with Graves disease enter spontaneous remission, treatment of hyperthyroidism is required. Current treatment options include antithyroid medications (methimazole or propylthiouracil), surgical removal of the thyroid gland, or radioactive iodine.147,148 Although virtually all children go into remission during therapy with antithyroid drugs, side effects are common (see later) and the majority of children treated for 2 to 3 years relapse shortly after discontinuation of therapy.149,150 Radioactive ablation is usually definitive and carries less risk than surgery.151

Clinical Presentation

Hyperthyroid GD can present with manifestations affecting almost any organ system in the body, and as with many endocrine conditions, affected individuals may report a gradual onset of nonspecific symptoms, typically over a period of months. This often leads to a delay in seeking medical attention and in the initial diagnosis being made. The signs and symptoms of GD can be divided into those associated with hyperthyroidism in general and those specific to GD. These are summarized in Table 70.1.

Clinical Pearls

Clinical Signs Specific to Graves Disease

Graves orbitopathy

Thyroid bruit

Thyroid acropachy

Pretibial myxedema