eMedicine Specialties > Endocrinology > Thyroid

Goiter, Diffuse Toxic

Author: Bernard Corenblum, MD, FRCP(C), Professor of Medicine, Director, Endocrine-Metabolic Testing and Treatment Unit, Ovulation Induction Program, Department of Internal Medicine, Division of Endocrinology, University of Calgary, Canada
Coauthor(s): Oluyinka S Adediji, MD, Consulting Staff, Department of Adult and General Medicine, Health Services Incorporated, Montgomery, Alabama; Paul Killian, MD, Former Chief of Endocrine Service, Former Associate Professor, Department of Internal Medicine, Harlem Hospital, Harlem Hospital Center
Contributor Information and Disclosures

Updated: Jun 4, 2009

Introduction

Background

This condition was first described by the English physician Caleb H. Parry (1755-1822). The disorder is known as Graves disease (after Robert J. Graves) in the English-speaking world and as Basedow disease (after Karl A. von Basedow) in the rest of Europe. 

In diffuse toxic goiter, the thyroid gland is diffusely hyperplastic and excessively overproduces thyroid hormone. This results in accelerated metabolism in most body organs. The clinical response and its manifestations are variable in intensity, distribution, and are modified by age, gender, and associated premorbid medical problems. When the diffuse toxic goiter is associated with clinical evidence of oculopathy, or rarely with dermopathy/acropachy, the term Graves’ disease is often applied. Awareness is needed regarding the atypical clinical presentations.

Pathophysiology

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. 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 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 is high. 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.

Frequency

United States

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

Prewar Copenhagen found 0.2 new cases per 1000 per year.

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

Mortality/Morbidity

The natural history is usually of a benign course, which may vary in intensity of the symptoms and 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 gender.

Mortality is rare but is due to cardiovascular problems such as heart failure, arrhythmias, or myocardial infarction. Debility and infection may occur. Thyroid storm is rare but may be fatal from dehydration, hyperthermia, and organ failure.

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 quality of life changes. Associated oculopathy may be symptomatic, especially with double vision. Rarely it may progress to affect the integrity of the cornea and 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, such as adrenal insufficiency, each has their own associated morbidity and mortality, especially if undiagnosed.

Race

No racial predilection exists.

Sex

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

Age

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

Incidence is increased in postpartum women, often the first presentation of disease.

Clinical

History

Symptoms of the hyperthyroidism, the goiter itself, and of comorbid conditions are present. The symptoms may be present for weeks, months, or even years before diagnosis.

The hyperthyroid symptoms may be multisystemic or predominate in a single organ system and mask the correct diagnosis in this manner. Many symptoms are adrenergic in origin and may be misdiagnosed as an anxiety disorder.

Elderly patients may have no adrenergic symptoms and present as weight loss (malignancy), atrial fibrillation (cardiac), or apathy (depression), and this presentation is referred to as apathetic thyrotoxicosis.

The presenting symptoms may be modified by preexisting medical or psychiatric disorders, which may be modified or worsened. Symptoms are described below.

• Hypermetabolism with heat generation and protein catabolism - Weight loss with good appetite, heat intolerance, sweating, muscle weakness (proximal more than distal), osteoporosis
• Adrenergic - Palpitations, tremor, emotional lability, insomnia, restlessness, hyperdefecation
• Other - Gynecomastia, lighter menses, insomnia, decreased concentration, fatigue, shortness of breath on exertion, and decreased exercise tolerance
• Goiter - May be mildly tender, may have difficulty swallowing if large
• Associated oculopathy (clinically present in about 25% of cases) - Tearing, pain, puffiness, grittiness, double vision, prominent appearance, rarely visual loss

Physical

General physical examination findings may include restless appearance, evidence of weight loss, pruritus, palmar erythema, and onycholysis of the finger nails.

• Hypermetabolism with protein catabolism - Warm hands, often with heat radiation, velvety skin, proximal muscle weakness in the arms and legs compared with distal muscle strength  
• Hyperadrenergic - Bounding and fast pulse, wide pulse pressure with higher systolic and lower diastolic blood pressure, active precordium and abdominal aorta to palpation; lid retraction (upper eyelid more than halfway from pupil to top of iris) and lid lag or globe lag, tremor of fingers, brisk reflexes  
• Organ decompensation - Atrial fibrillation, congestive heart failure, jaundice  
• Oculopathy - Periorbital puffiness, chemosis, conjunctival redness, proptosis (sclera visible below iris), double vision with eye movements, loss of color vision (rare), or papilledema (rare)  
• Thyroid gland - Mildly enlarged (but may be normal in size, many times normal in size, or difficult to palpate); smooth, rubbery firm in texture; nontender or mildly tender; systolic bruit on auscultation  
• Miscellaneous - Pretibial myxedema (uncommon), rare may be finger clubbing, diffuse lymphadenopathy, and splenomegaly

Causes

Diffuse toxic goiter and its hyperthyroidism are caused by 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 familial association indicates a strong genetic factor. Predisposing factors include genetic susceptibility (including HLA factors); female gender; mental stress; viral infection; surgery; postpartum state; iodine administration; drugs such as lithium and iodine-containing agents, such as amiodarone, interferons and interleukins, and antiretroviral agents.

Associated ophthalmopathy is not well understood, but it is a related but separate autoimmune disorder directed toward the extraocular muscles. It may run a course similar to or different from the hyperthyroidism. Smoking is an environmental aggravating factor. The presence and degree of clinical ophthalmopathy does correlate with the degree of elevation of the anti-TSH receptor antibodies.

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

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