Diffuse Toxic Goiter (Graves Disease)

Updated: Dec 10, 2020
  • Author: Bernard Corenblum, MD, FRCPC; Chief Editor: George T Griffing, MD  more...
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Practice Essentials

Diffuse toxic goiter is an autoimmune condition characterized by a diffusely hyperplastic thyroid gland with excessive overproduction of thyroid hormone. Graves disease, the most common cause of hyperthyroidism, is characterized by the stigmata of diffuse toxic goiter, oculopathy, and pretibial myxedema/acropachy. Diffuse toxic goiter is also present in other autoimmune thyroid conditions that cause hypothyroidism, most commonly Hashimoto thyroiditis.

Other common causes of hyperthyroidism are toxic multinodular goiter and solitary toxic adenoma. Because treatment of hyperthyroidism differs according to the etiology, the correct diagnosis must be made before therapy is instituted. Generally, a constellation of information, including the extent and duration of symptoms, past medical history, and social and family history, in addition to the information derived from physical examination, help to guide the clinician to the appropriate diagnosis. 

Diffuse toxic goiter findings on physical examination include a mildly enlarged thyroid gland (but may be normal in size, many times normal in size, or difficult to palpate) with a smooth, rubbery firm texture. It is nontender or mildly tender. Sometimes, a thyroid bruit can be heard by using the bell of the stethoscope. Toxic multinodular goiters generally occur when the thyroid gland is enlarged to at least two to three times the normal size. The gland is often soft, but individual nodules occasionally can be palpated. If the thyroid is enlarged and painful, the likely diagnosis is subacute painful or granulomatous thyroiditis. However, also consider degeneration or hemorrhage into a nodule and suppurative thyroiditis.

Acording to the American Thyroid Association guidelines for diagnosis and management of hyperthyroidism, serum thyroid-stimulating hormone (TSH) should be the initial biochemical evaluation, because it has the highest sensitivity and specificity in the diagnosis of thyroid disorders. [1]   If the diagnosis is not apparent from the clinical presentation and serum TSH measurement, further diagnostic tests should be selected based on available expertise. Thyroid ultrasonography and thyroid radioactive iodine uptake have similar sensitivity for the diagnosis of Graves disease. Advantages of ultrasonography include the absence of exposure to ionizing radiation and a higher accuracy in the detection of thyroid nodules and lower cost than with radioactive iodine uptake. [2]   

The three options for treating patients with hyperthyroidism are antithyroid drugs (ATDs), radioactive iodine ablation, and surgery. Adjunctive symptomatic therapy, such as beta blockers, may help alleviate adrenergic symptoms. Nonsurgical therapy occurs in the outpatient setting. Before surgical treatment, the hyperthyroid state must be normalized by medication.

For patient education resources, see Thyroid & Metabolism Center, as well as Thyroid Problems.



In diffuse toxic goiter, the thyroid gland is usually enlarged to a variable degree and is vascular and diffusely affected. This results in a smooth, rubbery-firm consistency, and often a bruit is heard on auscultation. Microscopically, the thyroid follicular cells are hypertrophic and hyperplastic, and they contain little colloid (stored hormone) and show evidence of hypersecretion. Lymphocytes and plasma cells infiltrate into the thyroid gland and may aggregate into lymphoid follicles.

This condition is an autoimmune disorder whereby the thyroid gland is overstimulated by antibodies directed to the thyroid-stimulating hormone (TSH) receptor on the thyroid follicular cells. This antibody stimulates iodine uptake, thyroid hormonogenesis and release, and thyroid gland growth. [3] Although mainly produced within the thyroid gland, these antibodies reach the circulation and can be measured by various assays in most, but not all, cases.

The association is high with another autoimmune thyroid disease, Hashimoto thyroiditis, and to a lesser degree with other autoimmune diseases in other endocrine glands and other systems in the same person. A strong familial association exists with the same diffuse toxic goiter or the associated disorders, especially Hashimoto thyroiditis. The presence of Hashimoto thyroiditis (which has more of a destructive effect on the thyroid gland) or the presence of another antibody (TSH-receptor blocking antibody) results in a variable natural history of the course of diffuse toxic goiter.

It is believed that 75-80% of the heritability of Graves disease is caused by likely associated genes, variants, and polymorphisms. [4] Environmental and epigenetic factors may play a role in the pathogenesis of this disease (eg, initiation, progression, development), but the interaction among genetic, epigenetic, and immunologic factors remains unclear. [4]



Diffuse toxic goiter and its hyperthyroidism are caused by thyroid-stimulating hormone (TSH)-receptor stimulating antibodies. Although the exact cause is not understood, it has been suggested that there is a genetic lack of suppressor T cells that results in the unregulated production of the antibody, resulting in the autoimmune disease. The antibody may pass the placenta and result in fetal and neonatal hyperthyroidism.

As with most such disorders, usually a combination of genetic and environmental factors is present. The genes involved in Graves’ disease are immune-regulatory genes (HLA region, CD40CTLA4PTPN22, and FCRL3) and thyroid autoantigens such as the thyroglobulin and TSH-receptor genes. [2, 5]  Non-genetic risk factors include the following [6] :

  • Female sex 
  • Pregnancy
  • Mental stress
  • Smoking and alcohol
  • Infectious diseases
  • Iodine administration
  • Drugs such as lithium and iodine-containing agents, as well as agents, including amiodarone, interferons and interleukins, and antiretroviral agents

Given that the prevalence of Graves disease is 10 times greater in women compared to men, [7]  sex hormones and chromosomal factors, such as the skewed inactivation of the X chromosome, are suspected to be triggers. Other factors are also suspected, such as infection (especially with Yersinia enterocolitica, due to a mechanism of molecular mimicry with the TSH receptor), vitamin D and selenium deficiency, thyroid damage, and immunomodulating drugs. 

Associated ophthalmopathy occurs in approximately 20% of individuals with Graves disease, and it is not well understood. It is thought to be a related but separate autoimmune disorder directed toward the extraocular muscles. The condition may run a course similar to or different from the hyperthyroidism. The presence and degree of clinical ophthalmopathy correlates with the degree of elevation of the anti-TSH receptor antibodies. [6]

Dermopathy (pretibial myxedema) may be brought on or aggravated by local trauma.



United States data

Diffuse toxic goiter is the most common cause of spontaneous hyperthyroidism. A Minnesota study found 0.3 new cases per 1000 per year.

In late childhood, the incidence rate is 3 per 100,000 in girls and 0.5 per 100,000 in boys. Prevalence studies show a rate of 2.7% in women and 0.23% in men.

A marked increase in familial incidence is noted.

International data

Prewar Copenhagen found 0.2 new cases per 1000 per year.

British studies found 0.08-0.2 new cases per 1000 per year.

Race-, sex-, and age-related demographics

No racial predilection exists.

Diffuse toxic goiter is 7-10 times more common in women than in men. It is often associated with or following pregnancy.

Diffuse toxic goiter can occur in persons of all ages, but it is rare in children younger than 10 years and is unusual in elderly persons. The peak incidence is in third and fourth decades of life.

There is an increased incidence in postpartum women, when the first presentation of the disease often occurs.



The natural history of diffuse toxic goiter is usually a benign course and may even spontaneously remit. The intensity of the symptoms and effect on quality of life are variable from person to person and are affected by age and sex.

Mortality is rare, but when it occurs, it is due to cardiovascular problems such as heart failure, arrhythmias, or myocardial infarction. [8, 9] Thyroid storm is rare but may be fatal from dehydration, hyperthermia, and organ failure.

Therapy may be needed for myocardial ischemia, congestive failure, or atrial arrhythmias, which may require anticoagulation. Debility and infection may occur.

Morbidity may result from increased bone turnover and osteoporosis, especially in postmenopausal women, or from atrial fibrillation and its sequelae, such as thromboembolism, especially in older men. Personality changes and psychopathology, muscular weakness, and systemic symptoms all lead to changes in quality of life. Associated oculopathy may be symptomatic, especially with double vision. Rarely, it may progress to affect the integrity of the cornea, and it may even endanger vision.

Associated dermopathy is uncommon and is usually minimally symptomatic, but it may be symptomatic to become debilitating.

Associated hypokalemic periodic paralysis, most commonly seen in Asian males, may be sudden, dramatic, and concerning but usually runs a benign course of recovery after a few hours of skeletal muscle paralysis.

A higher risk of associated immunologic diseases exists, such as adrenal insufficiency; each disease has its own associated morbidity and mortality, especially if it remains undiagnosed.