eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Graves Disease

Author: Robert J Ferry Jr, MD, Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children's Medical Center, University of Tennessee Health Science Center at Memphis, and St Jude Children's Research Hospital; Field Surgeon (Medical Corps), 162nd Area Support Medical Company, Army National Guard
Coauthor(s): Lynne Lipton Levitsky, MD, Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; Associate Professor, Department of Pediatrics, Harvard University Medical School
Contributor Information and Disclosures

Updated: Jun 4, 2009

Introduction

Background

Graves disease is the most common cause of hyperthyroidism in children. It is an immune-mediated disorder that results from the production of thyroid-stimulating immunoglobulins (TSI) by stimulated B lymphocytes. These immunoglobulins bind to the thyroid-stimulating hormone (TSH) receptor to mimic the action of TSH and stimulate thyroid growth and thyroid hormone overproduction.

Signs and symptoms of thyrotoxic Graves disease include an enlarged thyroid, rapid heart rate, widened pulse pressure, a hyperthyroid stare (infrequent blinking) or frank exophthalmos, tremor, sweating, palpitations, smooth moist skin, frequent bowel movements or diarrhea, sleeplessness, attention problems in school, irritability, and weight loss.

Diagnosis requires identification of suppressed TSH (thyrotropin) levels and elevated levels of free thyroxine (FT4) and/or triiodothyronine (T3). Measurement of TSI is of interest but is not required for therapeutic evaluation. Treatment is directed at alleviating symptoms and reducing thyroid hormone production. Symptoms may be improved by treatment with beta-blocking drugs. Reduction of thyroid hormone is accomplished by use of drug therapy, surgical subtotal thyroidectomy, or treatment with radioactive iodine (RAI). Because circulating TSI can cross the placenta, infants born to women with a history of Graves disease may have transient neonatal Graves thyrotoxicosis and also require treatment.

Although Perry was first to report hyperthyroidism in English, the classic description in 1835 by Graves became most widely accepted. Europeans often prefer to recognize the description by Basedow.

Pathophysiology

The reasons for the development of Graves disease are presently unknown. Patients likely have defective immune tolerance, leading to the development of specific autoantibodies directed against various thyroid antigens and against proteins with putatively similar antigenic sites in other tissues, notably the subcutaneous tissues and extraocular muscles. The TSH receptor is the most significant thyroid autoantigen in this disorder. However, children with Graves disease also produce immunoglobulins directed against thyroperoxidase (anti-TPO) and thyroglobulin, as well as TSH receptor–blocking antibodies, as may be found in chronic lymphocytic thyroiditis (Hashimoto thyroiditis).

Because other antibodies can coexist with TSI, not all children with Graves disease are thyrotoxic. However, thyrotoxicosis is the hallmark of most cases of Graves disease. In general, thyrotoxic Graves disease is considered in this article. Onset of Graves disease in susceptible individuals has variously been attributed to acute infections and to both physical and emotional stress.

The thyroid is enlarged because of constant TSH receptor stimulation and the presence of activated T lymphocytes and plasma cells in pseudofollicular patterns. The thyroid often has a firm rubbery consistency when palpated, and the pyramidal lobe may be prominent. When overstimulated by TSI, the thyroid becomes quite vascular, and an audible bruit is not uncommon. If the thyroid becomes very large, it may cause pressure symptoms and signs, including difficulty swallowing and hoarseness. Rarely, children may report associated pain.

Thyroid hormone excess, as a result of thyroid hyperstimulation, affects all organ systems. Patients with thyroid hyperstimulation are irritable and restless, have poor sleep habits, and often report daytime tiredness associated with nocturnal insomnia. Inability to concentrate and tremor translate in children into scholastic inattention, poor handwriting, and deteriorating school performance. Neuropsychiatric symptoms can mimic attention deficit hyperactivity disorder (ADHD), yet few children with ADHD are actually discovered to be thyrotoxic. ADHD and thyrotoxicosis are usually easily distinguished by thyroid examination and measurement of pulse and blood pressure (BP).

Cardiovascular stimulation by thyroid hormone leads to a rapid pulse rate and a dynamic precordium. Patients sometimes subjectively report palpitations. The patient typically shows a widened pulse pressure. Hypermetabolism usually leads to weight loss with increased appetite. Heat intolerance is often subtle. Muscle wasting is present with decreased muscle strength. Typically, atrophy of the thenar and hypothenar eminences may be observed. The hair becomes fine, and temporal hair loss often occurs. Rare genetically determined individuals may develop thyrotoxic periodic paralysis. Darkening of the skin may occur, most noticeably in darker-skinned individuals, and intense pruritus may also occur. The skin is typically very fine and moist. Sweating is increased. Thickening of the skin (localized myxedema) is almost never observed in childhood Graves disease.

In individuals with severe hypermetabolism, abnormal liver function may be observed with elevations of serum glutamic-oxaloacetic transaminase (SGOT) and serum glutamic-pyruvic transaminase (SGPT). Increases in gut motility result in diarrhea and frequent bowel movements. Graves disease with thyrotoxicosis leads to loss of bone mineral, decreased bone density, and resultant hypercalcuria. Hypercalcuria, as well as hyposthenuria, as a direct effect of thyroid hormone on the renal tubule, leads to nocturia, and in some susceptible children, it leads to nocturnal enuresis. Nocturnal enuresis occasionally is the first finding noted in children with Graves disease.

Growth in height may be enhanced by hypermetabolism, and bone age may be advanced. Puberty may be affected. Girls with Graves disease may have irregular sparse menses, and boys may have excess estrogen effect because of increased metabolism of steroids to estrogen. Symptoms of gynecomastia and decreased libido in older adolescents are not uncommon.

Frequency

United States

The prevalence of Graves disease in childhood in the United States has not been quantitated. One speculation has been an incidence of 0.2-0.4%, which is probably an overestimation. Approximately 10% of infants born to women with Graves disease have elevations of thyroid hormone levels, but only 1-2% have clinical symptoms of thyrotoxicosis. The most common association with childhood Graves disease is a history of other family members with thyroid disease. On the other hand, concordance for Graves disease in identical twins is only 30-50%, indicating that both genetic and environmental factors play a role in this disease.

International

A Danish study identified a national incidence density for thyrotoxicosis of 0.79 cases per 100,000 person-years in children aged 0-14 years.¹ Incidence density increases during childhood, with a peak incidence of 0.48 cases per 100,000 persons for boys and 3.01 cases per 100,000 persons for girls aged 10-14 years.

Mortality/Morbidity

Graves disease is potentially life threatening. The most severe manifestation of Graves disease is thyroid storm, which carries a mortality risk approaching 100% in untreated adults. Recent series with newer treatments, including the use of beta-adrenergic blocking agents, show a reduced risk of death near 20%. This is such a rare disorder in children that no comparable figures are available. Even children and adolescents with less severe manifestations of Graves disease can display long-term consequences of this disorder, including problems with schooling and chronic loss of bone mineral.

Race

No racial predilection for Graves disease is apparent. It has been reported in every population studied. In whites, Graves disease is associated with certain histocompatibility antigens (ie, DR3, DR1) that have previously been linked to other autoimmune disorders. The link between histocompatibility antigen subtypes and Graves disease identified in whites is weaker in blacks.

Sex

Graves disease is much more common at any age in girls than in boys. The female preponderance has been estimated to be 4-7 girls for every boy affected.

Age

Incidence increases with age, reaching a childhood peak during adolescence. Graves disease is a very rare cause of thyrotoxicosis in children younger than 5 years.

Clinical

History

Children with Graves disease are usually initially identified because of an enlarged thyroid, weight loss, or behavioral changes. Exophthalmos, which is common in adults with Graves disease, is less common in children. The reason for this difference is not clear; however, smoking is a well-recognized risk factor for exophthalmos.

The enlarged thyroid may be big enough to cause dysphagia, with reports of difficulty swallowing. Usually, the enlarged thyroid is identified by a parent or physician and is not overtly symptomatic. Weight loss accompanied by a voracious appetite and excessive growth in height can lead to initial evaluation. Often, children begin to have distractibility in the classroom, trouble sleeping, and mood changes, resulting in the identification of thyroid enlargement and elevated levels of circulating thyroid hormone.

The astute clinician may identify these children when they are referred for evaluation of symptoms of attention deficit disorder (ADD). Adolescents with this disorder may also report pruritus, temporal hair loss, thinning of the hair, darkening of the skin, palpitations, and, in girls, amenorrhea or infrequent or light menses. Frequent stools or frank diarrhea and symptoms of heat intolerance are common. A strong family history of Graves disease or other autoimmune thyroid disease may be noted.

Symptoms include the following:

• Dysphagia
• Irritability and emotional lability
• Sleeplessness and restlessness
• Inability to concentrate
• Deterioration of handwriting and school performance
• Frequent stools or diarrhea
• Palpitations
• Pruritus
• Weight loss
• Increased appetite
• Nocturia, increase in urination and thirst
• Infrequent or light menses
• Weakness and tiredness
• Exercise intolerance
• Heat intolerance

Physical

• General manifestations
  • Upon initial inspection, children and adolescents with thyrotoxicosis are usually tall and thin, with a fixed staring gaze and fidgety behavior.
  • Children with thyrotoxicosis may sit on their hands or clasp their hands to control fidgeting.
  • A widened pulse pressure and a rapid heart rate are typically found.
• Ocular findings
  • Ocular findings are often independent of the degree of thyrotoxicosis and may appear before the onset of hyperthyroidism.
  • Exophthalmos may be present and is usually mild. Weakness of the extraocular muscles is rare, but may be elicited by checking the capacity for convergence and looking for lid lag. Some adolescents may have true inability to close the eyelids because of more severe exophthalmos. Severe exophthalmos can be associated with a sandy gritty feeling in the eyes upon awakening or with corneal irritation or ulceration (exceedingly rare). Exophthalmos may be unilateral.
  • Nonspecific signs include lid reaction, wide palpebral aperture (ie, Dalrymple sign, confirmed when the sclera is visible above the superior limbal margin), lid lag (von Graefe sign), stare or appearance of fright, infrequent blinking (Stellwag sign), and absent wrinkling of forehead skin on upward gaze (Joffroy sign).  Signs unique to orbitopathy in Graves disease include the following:
    • Inability to keep the eyeballs converged (Mobius sign)
    • Limited extraocular gaze (especially upward)
    • Diplopia
    • Blurred vision due to inadequate convergence and accommodation
    • Swollen orbital contents and puffy lids
    • Chemosis
    • Corneal injection or ulceration
    • Irritated eye
    • Globe pain
    • Exophthalmos
    • Enlarged lacrimal glands (visible on inspection and palpable)
    • Visible swelling of lateral rectus muscles at insertion sites into the globe and injection of overlying vessels
    • Decreased visual acuity due to papilledema, retinal edema, retinal hemorrhages, or optic nerve damage
  • Always perform thyroid function tests (TFTs) in addition to local imaging studies in children with unilateral exophthalmos or proptosis to rule out orbital tumor.
  • Exophthalmos can be quantitated using an exophthalmometer, which measures the extension of the eye beyond the bony socket. This measurement is standardized for adults. Values for young children are not readily available, but these findings may still be useful to measure progression of the eye disease.
• Thyroidal findings
  • The thyroid is firm and usually smooth and rubbery.
  • A bosselated gland may suggest the thyrotoxic phase of chronic lymphocytic thyroiditis.
  • A gland with a single nodule suggests an autonomously functioning nodule inducing thyrotoxicosis, whereas a multinodular gland indicates a multinodular goiter, a reasonably rare finding in children living in an iodine-replete environment. Malignancy is rarely associated with such hyperfunctioning lesions.
  • The finding of hyperthyroidism without a goiter suggests the possibility of exogenous administration of thyroid hormone.
• Cardiopulmonary manifestations
  • Cardiac examination may reveal the murmur of mitral valve prolapse.
  • A rapid heart rate and prominent precordium are noted.
  • In the most severe form of thyrotoxicosis associated with Graves disease, thyroid storm, high-output heart failure is observed.
  • Atrial fibrillation may rarely be induced by thyrotoxicosis in children.
• Neuromuscular findings
  • Deep tendon reflexes are exaggerated.
  • Thenar and hypothenar wasting may be noted.
  • Muscle weakness can be profound.
  • In some genetically prone individuals, periodic paralysis associated with hypokalemia may be induced by thyrotoxicosis. Although thyrotoxic periodic paralysis is described as an adult disorder, it has been observed in adolescents.
• Dermal manifestations
  • The skin is usually fine and moist.
  • Excoriations may be present because of pruritus.
  • Skin darkening may be observed in some darker-skinned individuals.
  • Thyrotoxicosis may intensify the lesions of acanthosis nigricans.
  • The presence of irregular café au lait spots may suggest the diagnosis of thyrotoxicosis associated with McCune-Albright syndrome rather than Graves disease.

Causes

Graves disease is a humorally mediated autoimmune disorder in which hyperthyroidism is induced by TSH receptor–stimulating antibodies.

• In most children and adults, these antibodies are endogenous; however, transplacental passage of immunoglobulin G (IgG) antibodies from women with Graves disease to their infants may lead to the development of neonatal Graves disease. This is a self-limited disorder that resolves when the immunoglobulins are cleared by the neonate and may be followed by transient hypothyroidism if fetal pituitary TSH remains suppressed.
• The presence of a long-acting thyroid stimulator (LATS) was postulated by Adams and Purves in 1956 and was confirmed by the identification of the stimulatory immunoglobulins some years later. These immunoglobulins bind to the TSH receptor and mimic TSH action.
• Almost all patients producing TSI also produce other immunoglobulins more commonly associated with chronic lymphocytic thyroiditis, such as antibodies directed against thyroperoxidase and thyroglobulin. This suggests a close relation between Graves disease and chronic lymphocytic thyroiditis. Indeed, many individuals have thyrotoxic components to their chronic lymphocytic thyroiditis, and the natural history of untreated Graves disease is that a percentage of individuals with Graves eventually become hypothyroid. Moreover, lymphocytic infiltrates similar to those of chronic lymphocytic thyroiditis are found in the thyroids of patients with Graves disease.
  • Immunoglobulins produced in this disorder may be measured by numerous in vitro assays. Because these assays may measure different aspects of immunoglobulin function, results in different assays may be discrepant. For instance, TSH-receptor binding is measured in assays of thyroid-binding immunoglobulins (TBI), whereas TSH-receptor activation (eg, increased activation of adenyl cyclase) is measured by TSI or thyroid-stimulating antibodies (TSAb).
  • Some immunoglobulins may bind to the TSH receptor without stimulating it and may actually block the action of TSH (so-called blocking antibodies). These may be produced in individuals with Graves disease or chronic lymphocytic thyroiditis, further complicating the picture in occasional individuals with these disorders.
• The mechanism of the failure of immune tolerance that leads to the development of Graves disease is not entirely understood, and competing hypotheses have not yet been definitively evaluated.
  • Nonetheless, histocompatibility antigen haplotypes commonly associated with other autoimmune disorders (B8, DR3) have also been linked to Graves disease.
  • An infectious etiology of thyrotoxicosis has been postulated based on occurrence frequency in unrelated family members. An association with Yersinia enterocolitica infection has been described but has not been fully confirmed.
  • Case-controlled studies have suggested an association with recent life stress. The familial occurrence of thyrotoxicosis as well as other autoimmune thyroid disorders suggests a genetic link that may be more powerful than that of the histocompatibility antigen association.

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