eMedicine Specialties > Endocrinology > Thyroid

Graves Disease

Author: Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Coauthor(s): Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center; Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Contributor Information and Disclosures

Updated: Jun 4, 2009

Introduction

Background

Graves disease, named after Robert J. Graves, MD,1 circa 1830s, is an autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies. Thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone. Graves disease, along with Hashimoto thyroiditis, is classified as an autoimmune thyroid disorder. In some patients, Graves disease represents a part of more extensive autoimmune processes leading to dysfunction of multiple organs (eg, autoimmune polyglandular syndromes). Graves disease is associated with pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic sclerosis, myasthenia gravis, Sjögren syndrome, rheumatoid arthritis, and systemic lupus erythematosus.2

Pathophysiology

In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter, and the thyrotropin receptor. However, the thyrotropin receptor itself is the primary autoantigen of Graves disease and is responsible for the manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are well defined. Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of hyperthyroidism in healthy subjects by transferring thyrotropin receptor antibodies in serum from patients with Graves disease and the passive transfer of thyrotropin receptor antibodies to the fetus in pregnant women.

The thyroid gland is under continuous stimulation by circulating autoantibodies against the thyrotropin receptor, and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid hormones. The stimulating activity of thyrotropin receptor antibodies is found mostly in the immunoglobulin G1 subclass. These thyroid-stimulating antibodies cause release of thyroid hormone and thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP), and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth.

The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to have little role in the etiology of hyperthyroidism in Graves disease. However, they are markers of autoimmune disease against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic abnormality in persons with autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes may be the cause of CD4 lymphocyte reduction in these individuals.

Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22.3 Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. The genetic predisposition to thyroid autoimmunity may interact with environmental factors or events to precipitate the onset of Graves disease.

Frequency

United States

Graves disease is the most common cause of hyperthyroidism in the United States. A study conducted in Olmstead County, Minnesota estimated the incidence to be approximately 30 cases per 100,000 persons per year.4 The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves disease being the most common etiology. Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others.

International

Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study in the United Kingdom, the incidence is reported as 100-200 cases per 100,000 population per year.5 A recent update of the incidence in women reports a rate of 80 cases per 100,000 women per year.6

Mortality/Morbidity

If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie, thyroid storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism of bone and muscle. Cardiac complications and psychocognitive complications can cause significant morbidity. Graves disease is also associated with ophthalmopathy, dermopathy, and acropachy.

  • Thyroid storm is an exaggerated state of manifestation of thyrotoxicosis.7 It occurs in patients who have unrecognized or inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid surgery, nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute mortality rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the syndrome, the mortality rate is approximately 20%.8
  • Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be particularly devastating in women, in whom the disease may compound the bone loss secondary to chronic anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The increase in bone loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum calcium and phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than in healthy control subjects,9 suggesting that FGF-23 is physiologically related to serum phosphate homeostasis in untreated Graves disease.
  • Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves disease.
  • Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive heart failure can occur. 
  • Psychiatric manifestations such as mood and anxiety disorders are common.10 Subjective cognitive dysfunction are often reported by Graves disease patients and may be due to affective and somatic manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis.11
  • Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial area. The nearly all (>95%) patients with dermopathy had ophthalmopathy.12 Advanced forms of dermopathy are elephantiasis or thyroid acropachy.  Severe acropachy can be disabling and can lead to total loss of hand function.
  • Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal lesions or optic nerve compression can be seen in severe Graves ophthalmopathy.
  • Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroid-stimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with high TSI titer) are affected. Usually, the TSI titer falls during pregnancy.
  • Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

Race

  • In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci: AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with autoimmune thyroid diseases in persons of other races.
  • Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and in CTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to vary with ethnicity.

Sex

  • As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves disease has a female-to-male ratio of 7-8:1.
  • The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema have thyroid acropachy.
  • Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1.

Age

  • Typically, Graves disease is a disease of young women, but it may occur in persons of any age.
  • The typical age range is 20-40 years.
  • Most affected women are aged 30-60 years.

Clinical

History

  • Because Graves disease is an autoimmune disorder that also affects other organ systems, taking a careful patient history is essential to establishing the diagnosis.
  • In some cases, the history might suggest a triggering factor such as trauma to the thyroid, including surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma. Other factors might include interferon (eg, interferon beta-1b) or interleukin (IL-4) therapy.
  • Patients usually present with symptoms typical of thyrotoxicosis. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation.13  Tachycardia and palpitation are very common symptoms.
  • Not all patients present with such classic features. In fact, a subset of patients with euthyroid Graves disease is described.
  • In elderly individuals, fewer symptoms are apparent to the patient. Clues may include unexplained weight loss, hyperhidrosis, or rapid heart beat.
  • Young adults of Southeast Asian descent may complain of sudden paralysis thought to be related to thyrotoxic periodic paralysis. There is an association of polymorphisms of the calcium channel alpha1-subunit gene with thyrotoxic periodic paralysis.14  
  • The symptoms of Graves disease, organized by systems, are as follows:
    • General - Fatigue, general weakness 
    • Dermatologic - Warm, moist, fine skin; sweating; fine hair; onycholysis; vitiligo; alopecia; pretibial myxedema
    • Neuromuscular - Tremors, proximal muscle weakness, easy fatigability, periodic paralysis in persons of susceptible ethnic groups
    • Skeletal - Back pain, loss of stamina, history of fractures
    • Cardiovascular - Palpitations, dyspnea on exertion, chest pain, edema
    • Respiratory - Dyspnea
    • Gastrointestinal - Increased bowel motility, hyperdefecation with or without diarrhea
    • Ophthalmologic - Tearing, gritty sensation in the eye, photophobia, eye pain, protruding eye, diplopia, visual loss 
    • Renal - Polyuria, polydipsia
    • Hematologic - Easy bruising
    • Metabolic - Heat intolerance, weight loss despite increase or similar appetite, worsening diabetes control
    • Endocrine/reproductive - Irregular menstrual periods, decreased menstrual volume, gynecomastia, impotence
    • Psychiatric - Restlessness, anxiety, irritability, insomnia

Physical

  • Most of the physical findings are related to thyrotoxicosis.
  • Physical findings that are unique to Graves disease but not associated with other causes of hyperthyroidism include ophthalmopathy and dermopathy. Myxedematous changes of the skin (usually in the pretibial areas) are described as resembling an orange peel in color and texture. Onycholysis can be seen usually in the fourth and fifth fingernails.
  • The presence of a diffusely enlarged thyroid gland, thyrotoxic signs and symptoms, together with evidence of ophthalmopathy or dermopathy, can establish the diagnosis.
  • Common physical findings, organized by anatomic regions, are as follows:
    • General - Increased basal metabolic rate, weight loss despite increase or similar appetite
    • Skin - Warm, most, fine skin; increased sweating; fine hair; vitiligo; alopecia; pretibial myxedema
    • Head, eyes, ears, nose, and throat - Chemosis, conjunctival irritation, widening of the palpebral fissures, lid lag, lid retraction, proptosis, impairment of extraocular motion, visual loss in severe optic nerve involvement, periorbital edema
    • Neck - Upon careful examination, the thyroid gland generally is diffusely enlarged and smooth; a well-delineated pyramidal lobe may be appreciated upon careful palpation; thyroid bruits and, rarely, thrills may be appreciated; thyroid nodules may be palpable.
    • Chest - Gynecomastia, tachypnea, tachycardia, murmur, hyperdynamic precordium, S3, S4 heart sounds, ectopic beats, irregular heart rate and rhythm
    • Abdomen - Hyperactive bowel sound
    • Extremities - Edema, acropachy, onycholysis
    • Neurologic - Hand tremor (fine and usually bilateral), hyperactive deep tendon reflexes
    • Musculoskeletal - Kyphosis, lordosis, loss of height, proximal muscle weakness, hypokalemic periodic paralysis in persons of susceptible ethnic groups
    • Psychiatric - Restlessness, anxiety, irritability, insomnia, depression
  • Ophthalmopathy is a hallmark of Graves disease.
    • Approximately 25-30% of patients with Graves disease have clinical evidence of Graves ophthalmopathy. Thyrotropin receptor is highly expressed in the fat and connective tissue of patients with Graves ophthalmopathy.
    • Measuring diplopia fields, eyelid fissures, range of extraocular muscles, visual acuity, and proptosis provides quantitative assessment to follow the course of ophthalmopathy.
    • Signs of corneal or conjunctival irritation include conjunctival injection and chemosis.
    • A complete ophthalmologic examination, including retinal examination and slit-lamp examination by an ophthalmologist, is indicated if the patient is symptomatic.
  • Although thyroid nodule(s) may be present, excluding multinodular toxic goiter (especially in older patients) as the cause of thyrotoxicosis is essential. The approach to treatment may be different. Excluding thyroid neoplasia is also important in these patients because reports have indicated that differentiated thyroid cancer is probably more common in patients with Graves disease and may also have a more aggressive course in these patients.

Causes

  • Graves disease is autoimmune in etiology, and the immune mechanisms involved may be one of the following:
    • Expression of a viral antigen (self-antigen) or a previously hidden antigen
    • The specificity crossover between different cell antigens with an infectious agent or a superantigen
    • Alteration of the T cell repertoire, idiotypic antibodies becoming pathogenic antibodies
    • New expression of HLA class II antigens on thyroid epithelial cells (eg, HLA-DR antigen)
  • The autoimmune process in Graves disease is influenced by a combination of environmental and genetic factors.
    • Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22.3 Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility.
      • Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene,15,16 and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease.15  This SNP of the CTLA4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment.17  
      • There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease.18,3  
      • The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases.19
      • Alleles of intron 7 of the thyrotropin receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease.
    • Environmental factors associated with susceptibility are largely unproven. Other factors include infection, iodide intake, stress, female sex, steroids, and toxins. Smoking has been implicated in the worsening of Graves ophthalmopathy.
      • Graves disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens.20,21
      • Stress can be a factor for thyroid autoimmunity. Acute stress-induced immunosuppression may be followed by immune system hyperactivity, which could precipitate autoimmune thyroid disease.
        • This may occur during the postpartum period, in which Graves disease may occur 3-9 months after delivery.
        • Estrogen may influence the immune system, particularly the B-cell repertoire.
        • Both T- and B-cell function are diminished during pregnancy, and the rebound from this immunosuppression is thought to contribute to the development of postpartum thyroid syndrome.
        • Experimental evidence suggests that androgen protects against, and estrogen enhances, thyroiditis after thyroglobulin immunization. The experimental results provide evidence for a major influence of sex steroids on the development of Graves disease.
      • Interferon beta-1b and interleukin-4, when used therapeutically, may cause Graves disease.
      • Trauma to the thyroid has also been reported to be associated with Graves disease. This may include surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma.

More on Graves Disease

Overview: Graves Disease
Differential Diagnoses & Workup: Graves Disease
Treatment & Medication: Graves Disease
Follow-up: Graves Disease
Multimedia: Graves Disease
References
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References

  1. Ellis H. Robert Graves: 1796-1852. Br J Hosp Med (Lond). Jun 2006;67(6):313. [Medline].

  2. Cruz AA, Akaishi PM, Vargas MA, de Paula SA. Association between thyroid autoimmune dysfunction and non-thyroid autoimmune diseases. Ophthal Plast Reconstr Surg. Mar-Apr 2007;23(2):104-8. [Medline].

  3. Jacobson EM, Tomer Y. The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future. J Autoimmun. Mar-May 2007;28(2-3):85-98. [Medline].

  4. Furszyfer J, Kurland LT, McConahey WM, Elveback LR. Graves' disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clin Proc. Sep 1970;45(9):636-44. [Medline].

  5. Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). Dec 1977;7(6):481-93. [Medline].

  6. Vanderpump MP, Tunbridge WM, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf). Jul 1995;43(1):55-68. [Medline].

  7. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. Dec 2006;35(4):663-86, vii. [Medline].

  8. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. Jun 1993;22(2):263-77. [Medline].

  9. Park SE, Cho MA, Kim SH, Rhee Y, Kang ES, Ahn CW. The adaptation and relationship of FGF-23 to changes in mineral metabolism in Graves' disease. Clin Endocrinol (Oxf). Jun 2007;66(6):854-8. [Medline].

  10. Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves' hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006;20(11):897-909. [Medline].

  11. Vogel A, Elberling TV, Hørding M, Dock J, Rasmussen AK, Feldt-Rasmussen U. Affective symptoms and cognitive functions in the acute phase of Graves' thyrotoxicosis. Psychoneuroendocrinology. Jan 2007;32(1):36-43. [Medline].

  12. Schwartz KM, Fatourechi V, Ahmed DD, Pond GR. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab. Feb 2002;87(2):438-46. [Medline].

  13. Chen JL, Chiu HW, Tseng YJ, Chu WC. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation of heart rate: evidence from spectral analysis of heart rate variability. Clin Endocrinol (Oxf). Jun 2006;64(6):611-6. [Medline].

  14. Kung AW. Clinical review: Thyrotoxic periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab. Jul 2006;91(7):2490-5. [Medline].

  15. Zaletel K, Krhin B, Gaberscek S, Pirnat E, Hojker S. The influence of the exon 1 polymorphism of the cytotoxic T lymphocyte antigen 4 gene on thyroid antibody production in patients with newly diagnosed Graves' disease. Thyroid. May 2002;12(5):373-6. [Medline].

  16. Zaletel K, Krhin B, Gaberscek S, Hojker S. Thyroid autoantibody production is influenced by exon 1 and promoter CTLA-4 polymorphisms in patients with Hashimoto's thyroiditis. Int J Immunogenet. Apr 2006;33(2):87-91. [Medline].

  17. Wang PW, Chen IY, Liu RT, Hsieh CJ, Hsi E, Juo SH. Cytotoxic T lymphocyte-associated molecule-4 gene polymorphism and hyperthyroid Graves' disease relapse after antithyroid drug withdrawal: a follow-up study. J Clin Endocrinol Metab. Jul 2007;92(7):2513-8. [Medline].

  18. Ban Y, Tozaki T, Taniyama M, Tomita M, Ban Y. Association of a C/T single-nucleotide polymorphism in the 5' untranslated region of the CD40 gene with Graves' disease in Japanese. Thyroid. May 2006;16(5):443-6. [Medline].

  19. Heward JM, Brand OJ, Barrett JC, Carr-Smith JD, Franklyn JA, Gough SC. Association of PTPN22 haplotypes with Graves' disease. J Clin Endocrinol Metab. Feb 2007;92(2):685-90. [Medline].

  20. Benvenga S, Guarneri F, Vaccaro M, et al. Homologies between proteins of Borrelia burgdorferi and thyroid autoantigens. Thyroid. 2004;14:964-6. [Medline].

  21. Gangi E, Kapatral V, El-Azami El-Idrissi M, et al. Characterization of a recombinant Yersinia enterocolitica lipoprotein; implications for its role in autoimmune response against thyrotropin receptor. Autoimmunity. Sep-Nov 2004;37(6-7):515-20. [Medline].

  22. Cappelli C, Pirola I, De Martino E, Agosti B, Delbarba A, Castellano M. The role of imaging in Graves' disease: A cost-effectiveness analysis. Eur J Radiol. Apr 23 2007;[Medline].

  23. Markovic V, Eterovic D. Thyroid echogenicity predicts outcome of radioiodine therapy in patients with graves' disease. J Clin Endocrinol Metab. Sep 2007;92(9):3547-52. [Medline].

  24. Kubota S, Ohye H, Yano G, Nishihara E, Kudo T, Ito M. Two-day thionamide withdrawal prior to radioiodine uptake sufficiently increases uptake and does not exacerbate hyperthyroidism compared to 7-day withdrawal in Graves' disease. Endocr J. Oct 2006;53(5):603-7. [Medline].

  25. Bonnema SJ, Bennedbaek FN, Veje A, et al. Propylthiouracil before 131I therapy of hyperthyroid diseases: effect on cure rate evaluated by a randomized clinical trial. J Clin Endocrinol Metab. 2004;89:4439-44. [Medline].

  26. Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and safety of radioactive iodine in treating young Graves' patients. J Clin Endocrinol Metab. Sep 2004;89(9):4229-33. [Medline].

  27. Ceccarelli C, Canale D, Battisti P, Caglieresi C, Moschini C, Fiore E. Testicular function after 131I therapy for hyperthyroidism. Clin Endocrinol (Oxf). Oct 2006;65(4):446-52. [Medline].

  28. Rivkees SA, Dinauer C. An optimal treatment for pediatric Graves' disease is radioiodine. J Clin Endocrinol Metab. Mar 2007;92(3):797-800. [Medline].

  29. Macchia PE, Bagattini M, Lupoli G, et al. High-dose intravenous corticosteroid therapy for Graves' ophthalmopathy. J Endocrinol Invest. 2001;24:152-8. [Medline].

  30. Dickinson AJ, Vaidya B, Miller M, Coulthard A, Perros P, Baister E. Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. Dec 2004;89(12):5910-5. [Medline].

  31. Wemeau JL, Caron P, Beckers A, et al. Octreotide (long-acting release formulation) treatment in patients with graves' orbitopathy: clinical results of a four-month, randomized, placebo-controlled, double-blind study. J Clin Endocrinol Metab. 2005;90:841-8. [Medline].

  32. Stan MN, Garrity JA, Bradley EA, Woog JJ, Bahn MM, Brennan MD. Randomized, double-blind, placebo-controlled trial of long-acting release octreotide for treatment of Graves' ophthalmopathy. J Clin Endocrinol Metab. Dec 2006;91(12):4817-24. [Medline].

  33. Durrani OM, Reuser TQ, Murray PI. Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit. Jun 2005;24(2):117-9. [Medline].

  34. Salvi M, Vannucchi G, Campi I, Currò N, Dazzi D, Simonetta S. Treatment of Graves' disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study. Eur J Endocrinol. Jan 2007;156(1):33-40. [Medline].

  35. Grodski S, Stalberg P, Robinson BG, Delbridge LW. Surgery versus Radioiodine Therapy as Definitive Management for Graves' Disease: The Role of Patient Preference. Thyroid. Feb 2007;17(2):157-60. [Medline].

  36. Pradeep PV, Agarwal A, Baxi M, Agarwal G, Gupta SK, Mishra SK. Safety and efficacy of surgical management of hyperthyroidism: 15-year experience from a tertiary care center in a developing country. World J Surg. Feb 2007;31(2):306-12; discussion 313. [Medline].

  37. Panzer C, Beazley R, Braverman L. Rapid preoperative preparation for severe hyperthyroid Graves' disease. J Clin Endocrinol Metab. May 2004;89(5):2142-4. [Medline].

  38. Erbil Y, Ozluk Y, Giris M, Salmaslioglu A, Issever H, Barbaros U. Effect of lugol solution on thyroid gland blood flow and microvessel density in the patients with Graves' disease. J Clin Endocrinol Metab. Jun 2007;92(6):2182-9. [Medline].

  39. FDA MedWatch Safety Alerts for Human Medical Products. Propylthiouracil (PTU). US Food and Drug Administration. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm164162.htm. Accessed June 3, 2009.

  40. Aktaran S, Akarsu E, Erbagci I, Araz M, Okumus S, Kartal M. Comparison of intravenous methylprednisolone therapy vs. oral methylprednisolone therapy in patients with Graves' ophthalmopathy. Int J Clin Pract. Jan 2007;61(1):45-51. [Medline].

  41. Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. Jan 8 1998;338(2):73-8. [Medline].

  42. Bartalena L, Marcocci C, Bogazzi F, et al. Use of corticosteroids to prevent progression of Graves'' ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med. Nov 16 1989;321(20):1349-52. [Medline].

  43. Bartalena L, Tanda M L, Piantanida E, et al. Relationship between management of hyperthyroidism and course of the ophthalmopathy. J Endocrinol Invest. 2004;27:288-94. [Medline].

  44. Brusco F, Gonzalez G, Soto N, Arteaga E. Successful treatment of hyperthyroidism with amiodarone in a patient with propylthiouracil-induced acute hepatic failure. Thyroid. 2004;14:862-5. [Medline].

  45. Bunevicius R, Velickiene D, Prange AJ, Jr. Mood and anxiety disorders in women with treated hyperthyroidism and ophthalmopathy caused by Graves' disease. Gen Hosp Psychiatry. 2005;27:133-9. [Medline].

  46. Chattaway JM, Klepser TB. Propylthiouracil versus methimazole in treatment of Graves' disease during pregnancy. Ann Pharmacother. Jun 2007;41(6):1018-22. [Medline].

  47. De Bellis A, Sansone D, Coronella C, et al. Serum antibodies to collagen XIII: a further good marker of active Graves' ophthalmopathy. Clin Endocrinol (Oxf). 2005;62:24-9. [Medline].

  48. Dickinson A J, Vaidya B, Miller M, et al. Double-blind, placebo-controlled trial of octreotide long-acting repeatable (LAR) in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2005;89:5910-5. [Medline].

  49. Ebner R, Devoto MH, Weil D, Bordaberry M, Mir C, Martinez H. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. Nov 2004;88(11):1380-6. [Medline].

  50. Finamor F E, Martins J R, Nakanami D, et al. Pentoxifylline (PTX)--an alternative treatment in Graves' ophthalmopathy (inactive phase): assessment by a disease specific quality of life questionnaire and by exophthalmometry in a prospective randomized trial. Eur J Ophthalmol. 2004;14:277-83. [Medline].

  51. Franklyn JA. The management of hyperthyroidism [published erratum appears in N Engl J Med 1994 Aug 25;331(8):559]. N Engl J Med. Jun 16 1994;330(24):1731-8. [Medline].

  52. Gungor K, Gonen S, Kisakol G, Dikbas O, Kaya A. ANCA positive propylthiouracil induced pyoderma gangrenosum. J Endocrinol Invest. Jun 2006;29(6):575-6. [Medline].

  53. Hiraiwa T, Ito M, Imagawa A, et al. High diagnostic value of a radioiodine uptake test with and without iodine restriction in Graves' disease and silent thyroiditis. thyroid. 2004;14:531-5. [Medline].

  54. Iwama S, Ikezaki A, Kikuoka N, et al. Association of HLA-DR, -DQ Genotype and CTLA-4 Gene Polymorphism with Graves' Disease in Japanese Children. Horm Res. 2005;63:55-60. [Medline].

  55. Karincaoglu Y, Esrefoglu M, Aki T, Mizrak B. Propylthiouracil-induced vasculitic oral ulcers with anti-neutrophil cytoplasmic antibody. J Eur Acad Dermatol Venereol. Jan 2006;20(1):120-2. [Medline].

  56. Klein I, Becker DV, Levey GS. Treatment of hyperthyroid disease. Ann Intern Med. Aug 15 1994;121(4):281-8. [Medline].

  57. Marcocci C, Bartalena L, Tanda ML, et al. Comparison of the effectiveness and tolerability of intravenous or oral glucocorticoids associated with orbital radiotherapy in the management of severe Graves' ophthalmopathy: results of a prospective, single-blind, randomized study. J Clin Endocrinol Metab. 2001;86:3562-7. [Medline].

  58. Metso S, Jaatinen P, Huhtala H, et al. Long-term follow-up study of radioiodine treatment of hyperthyroidism. Clin Endocrinol (Oxf). Nov 2004;61(5):641-8. [Medline].

  59. Prummel MF, Terwee CB, Gerding MN, et al. A randomized controlled trial of orbital radiotherapy versus sham irradiation in patients with mild Graves' ophthalmopathy. J Clin Endocrinol Metab. 2004;89:15-20. [Medline].

  60. Riis AL, Jørgensen JO, Gjedde S, et al. Whole body and forearm substrate metabolism in hyperthyroidism: evidence of increased basal muscle protein breakdown. Am J Physiol Endocrinol Metab. 2005/06;288(6):E1067-E1073.

  61. Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology. 2004;111:1557-62. [Medline].

  62. Williams DE, Chopra IJ, Orgiazzi J, Solomon DH. Acute effects of corticosteroids on thyroid activity in Graves' disease. J Clin Endocrinol Metab. Aug 1975;41(2):354-61. [Medline].

  63. Yeung SC, Go R, Balasubramanyam A. Rectal administration of iodide and propylthiouracil in the treatment of thyroid storm. Thyroid. Oct 1995;5(5):403-5. [Medline].

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Further Reading

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Keywords

Graves' disease, diffuse toxic goiter, thyrotoxicosis, hyperthyroidism, Basedow's disease, Basedow disease, autoimmune thyroid disorder, autoimmune polyglandular syndrome, pernicious anemia, vitiligo, diabetes mellitus type 1, autoimmune adrenal insufficiency, systemic lupus erythematosus, thyroid antigens, thyroglobulin, thyroperoxidase, sodium-iodide symporter, TSH receptor, life-threatening thyrotoxic crisis, thyroid storm, Graves ophthalmopathy, thyroid acropachy, severe weight loss, osteoporosis, apathetic hyperthyroidism, cardiac hypertrophy, CTLA-4, pretibial myxedema, palpitation, nervousness, tremor, heat intolerance, hyperdefecation, inability to concentrate, proximal muscle weakness, easy fatigability with physical activity, proptosis, lid retraction, lacrimation, gritty sensation in the eye, photophobia, eye pain, diplopia, hyperhidrosis, increased sweating, restlessness, anxiety, irritability, insomnia, thyrotoxic periodic paralysis, onycholysis, alopecia, hyperactive deep-tendon reflexes, brisk deep-tendon reflexes, hypokalemic periodic paralysis, atrial fibrillation, cardiomyopathy, elevated transaminases, lid lag, irregular menstrual periods, gynecomastia, impotence, increased sex hormone–binding globulin levels, decreased free testosterone levels, decreased parathyroid hormone levels, decreased total cholesterol, decreased triglycerides, hand tremor, thyroid bruits, conjunctival injection, conjunctival chemosis, Yersinia enterocolitica, postpartum thyroid syndrome, use of interferons, use of interleukins, injection of percutaneous ethanol

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Contributor Information and Disclosures

Author

Sai-Ching Jim Yeung, MD, PhD, FACP, Deputy Section Chief of Emergency Care, Assistant Professor, Department of General Internal Medicine, Ambulatory Treatment and Emergency Care, University of Texas MD Anderson Cancer Center
Sai-Ching Jim Yeung, MD, PhD, FACP is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Medical Association, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Coauthor(s)

Mouhammed Amir Habra, MD, Endocrine Fellow, Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center
Mouhammed Amir Habra, MD is a member of the following medical societies: American College of Physicians, American Thyroid Association, and Endocrine Society
Disclosure: Nothing to disclose.

Alice Cua Chiu, MD, Consulting Staff, Department of Internal Medicine, Division of Endocrinology, Columbia Bayshore Medical Center
Alice Cua Chiu, MD is a member of the following medical societies: American Medical Association and Endocrine Society
Disclosure: Nothing to disclose.

Medical Editor

Steven R Gambert, MD, MACP, Chairman, Department of Medicine, Physician-in-Chief, Sinai Hospital of Baltimore; Professor of Medicine, Program Director, Internal Medicine Program, Johns Hopkins University School of Medicine
Steven R Gambert, MD, MACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physician Executives, American College of Physicians, American Geriatrics Society, Association of Professors of Medicine, Endocrine Society, and Gerontological Society of America
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Kent Wehmeier, MD, Professor, Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, St Louis University School of Medicine
Kent Wehmeier, MD is a member of the following medical societies: American Society of Hypertension, Endocrine Society, and International Society for Clinical Densitometry
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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