Toxic Nodular Goiter: Background, Pathophysiology, Epidemiology

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Sections Toxic Nodular Goiter
Overview
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Overview

Background

A toxic nodular goiter (TNG) is a thyroid gland that contains autonomously functioning thyroid nodules, with resulting hyperthyroidism. There are distinct considerations if the patient has a single solitary toxic nodule (see Solitary Thyroid Nodule). TNG, or Plummer's disease, was first described by Henry Plummer in 1913. TNG is the second most common cause of hyperthyroidism in the Western world, after Graves disease. In elderly individuals and in areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Pathophysiology

Toxic nodular goiter (TNG) represents a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of the thyrotropin, or thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and some nodules of multinodular goiters.^[1]Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG are similar to those of other types of hyperthyroidism.

Frequency

United States

Toxic nodular goiter accounts for approximately 15-30% of cases of hyperthyroidism in the United States, second only to Graves disease.

International

In areas of endemic iodine deficiency, toxic nodular goiter (TNG) accounts for approximately 58% of cases of hyperthyroidism, 10% of which are from solitary toxic nodules. Graves disease accounts for 40% of cases of hyperthyroidism. In patients with underlying nontoxic multinodular goiter, initial iodine supplementation (or iodinated contrast agents) can lead to hyperthyroidism (Jod-Basedow effect). Iodinated drugs, such as amiodarone, may also induce hyperthyroidism in patients with underlying nontoxic multinodular goiter. Roughly 3% of patients treated with amiodarone in the United States (more in areas of iodine deficiency) develop amiodarone-induced hyperthyroidism.^[2]

Mortality/Morbidity

Morbidity and mortality from toxic nodular goiter (TNG) may be divided into problems related to hyperthyroidism and problems related to growth of the nodules and gland. Local compression problems due to nodule growth, although unusual, include dyspnea, hoarseness, and dysphagia. Both TNG and Graves disease have increased mortality but for different reasons.^[3]

TNG is more common in elderly adults; therefore, complications due to comorbidities, such as coronary artery disease, are significant in the management of hyperthyroidism.

Sex

Toxic nodular goiter occurs more commonly in women than in men. In women and men older than 40 years, the prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.

Age

Most patients with toxic nodular goiter (TNG) are older than 50 years.

Thyrotoxicosis often occurs in patients with a history of longstanding goiter. Toxicity occurs in a subset of patients who develop autonomous function. This toxicity usually peaks in the sixth and seventh decades of life, especially in persons with a family history of multinodular goiter or TNG, suggesting a genetic component.

Clinical Presentation

Lado-Abeal J, Palos-Paz F, Perez-Guerra O, et al. Prevalence of mutations in TSHR, GNAS, PRKAR1A and RAS genes in a large series of toxic thyroid adenomas from Galicia, an iodine deficient area in NW Spain. Eur J Endocrinol. 2008 Aug 11. [Medline].
Abraham-Nordling M, Törring O, Lantz M, et al. Incidence of hyperthyroidism in Stockholm, Sweden, 2003-2005. Eur J Endocrinol. 2008 Jun. 158(6):823-7. [Medline].
Brandt F, Thvilum M, Almind D, Christensen K, Green A, Hegedüs L, et al. Graves' disease and toxic nodular goiter are both associated with increased mortality but differ with respect to the cause of death: a Danish population-based register study. Thyroid. 2013 Apr. 23(4):408-13. [Medline].
Basaria S, Salvatori R. Images in clinical medicine. Pemberton's sign. N Engl J Med. 2004 Mar 25. 350(13):1338. [Medline].
Gabriel EM, Bergert ER, Grant CS, et al. Germline polymorphism of codon 727 of human thyroid-stimulating hormone receptor is associated with toxic multinodular goiter. J Clin Endocrinol Metab. 1999 Sep. 84(9):3328-35. [Medline]. [Full Text].
Muhlberg T, Herrmann K, Joba W, et al. Lack of association of nonautoimmune hyperfunctioning thyroid disorders and a germline polymorphism of codon 727 of the human thyrotropin receptor in a European Caucasian population. J Clin Endocrinol Metab. 2000 Aug. 85(8):2640-3. [Medline]. [Full Text].
[Guideline] Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan. 26 (1):1-133. [Medline].
Cerci C, Cerci SS, Eroglu E, et al. Thyroid cancer in toxic and non-toxic multinodular goiter. J Postgrad Med. 2007 Jul-Sep. 53(3):157-60. [Medline].
van Soestbergen MJ, van der Vijver JC, Graafland AD. Recurrence of hyperthyroidism in multinodular goiter after long-term drug therapy: a comparison with Graves' disease. J Endocrinol Invest. 1992 Dec. 15(11):797-800. [Medline].
[Guideline] Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and other causes of Thyrotoxicosis. Thyroid. 2016 Aug 12. [Medline].
Grubeck-Loebenstein B, Buchan G, Sadeghi R, et al. Transforming growth factor beta regulates thyroid growth. Role in the pathogenesis of nontoxic goiter. J Clin Invest. 1989 Mar. 83(3):764-70. [Medline]. [Full Text].
Allahabadia A, Daykin J, Sheppard MC, et al. Radioiodine treatment of hyperthyroidism-prognostic factors for outcome. J Clin Endocrinol Metab. 2001 Aug. 86(8):3611-7. [Medline]. [Full Text].
Schiavo M, Bagnara MC, Camerieri L, Pomposelli E, Giusti M, Pesce G, et al. Clinical efficacy of radioiodine therapy in multinodular toxic goiter, applying an implemented dose calculation algorithm. Endocrine. 2015 Apr. 48 (3):902-8. [Medline].
Zingrillo M, Urbano N, Suriano V, et al. Radioiodine treatment of Plummer and multinodular toxic and nontoxic goiter disease by the first approximation dosimetry method. Cancer Biother Radiopharm. 2007 Apr. 22(2):256-60. [Medline].
Erkan ME, Demirin H, Asik M, Celbek G, Yildirim M, Aydin Y, et al. Efficiency of radioactive I-131 therapy in geriatric patients with toxic nodular goiter. Aging Clin Exp Res. 2012 Dec. 24(6):714-7. [Medline].
Lee YY, Tam KW, Lin YM, Leu WJ, Chang JC, Hsiao CL, et al. Recombinant human thyrotropin before (131)I therapy in patients with nodular goitre: a meta-analysis of randomized controlled trials. Clin Endocrinol (Oxf). 2015 Nov. 83 (5):702-10. [Medline].
Adamali HI, Gibney J, O'Shea D, Casey M, McKenna TJ. The occurrence of hypothyroidism following radioactive iodine treatment of toxic nodular goiter is related to the TSH level. Ir J Med Sci. 2007 Sep. 176 (3):199-203. [Medline].
Adamali HI, Gibney J, O'Shea D, et al. The occurrence of hypothyroidism following radioactive iodine treatment of toxic nodular goiter is related to the TSH level. Ir J Med Sci. 2007 Sep. 176(3):199-203. [Medline].
Bonnema SJ, Bertelsen H, Mortensen J, et al. The feasibility of high dose iodine 131 treatment as an alternative to surgery in patients with a very large goiter: effect on thyroid function and size and pulmonary function. J Clin Endocrinol Metab. 1999 Oct. 84(10):3636-41. [Medline].
FDA MedWatch Safety Alerts for Human Medical Products. Propylthiouracil (PTU). US Food and Drug Administration. Accessed: June 3, 2009. Available at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm164162.htm.
Smith JJ, Chen X, Schneider DF, Nookala R, Broome JT, Sippel RS, et al. Toxic nodular goiter and cancer: a compelling case for thyroidectomy. Ann Surg Oncol. 2013 Apr. 20(4):1336-40. [Medline].
Cirocchi R, Trastulli S, Randolph J, Guarino S, Di Rocco G, Arezzo A, et al. Total or near-total thyroidectomy versus subtotal thyroidectomy for multinodular non-toxic goitre in adults. Cochrane Database Syst Rev. 2015 Aug 7. CD010370. [Medline].
Sung JY, Baek JH, Jung SL, Kim JH, Kim KS, Lee D, et al. Radiofrequency ablation for autonomously functioning thyroid nodules: a multicenter study. Thyroid. 2015 Jan. 25 (1):112-7. [Medline].
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 Sep. 89(9):4439-44. [Medline]. [Full Text].
Azizi F, Khoshniat M, Bahrainian M, et al. Thyroid function and intellectual development of infants nursed by mothers taking methimazole. J Clin Endocrinol Metab. 2000 Sep. 85(9):3233-8. [Medline]. [Full Text].
Momotani N, Yamashita R, Makino F, et al. Thyroid function in wholly breast-feeding infants whose mothers take high doses of propylthiouracil. Clin Endocrinol (Oxf). 2000 Aug. 53(2):177-81. [Medline].
Aeschimann S, Kopp PA, Kimura ET, et al. Morphological and functional polymorphism within clonal thyroid nodules. J Clin Endocrinol Metab. 1993 Sep. 77(3):846-51. [Medline]. [Full Text].
Aghini-Lombardi F, Antonangeli L, Martino E, et al. The spectrum of thyroid disorders in an iodine-deficient community: the Pescopagano survey. J Clin Endocrinol Metab. 1999 Feb. 84(2):561-6. [Medline]. [Full Text].
Clark KJ, Cronan JJ, Scola FH. Color Doppler sonography: anatomic and physiologic assessment of the thyroid. J Clin Ultrasound. 1995 May. 23(4):215-23. [Medline].
Cooper DS. Hyperthyroidism. Lancet. 2003 Aug 9. 362(9382):459-68. [Medline].
Dumont JE, Lamy F, Roger P, et al. Physiological and pathological regulation of thyroid cell proliferation and differentiation by thyrotropin and other factors. Physiol Rev. 1992 Jul. 72(3):667-97. [Medline].
Erem C, Kandemir N, Hacihasanoglu A, et al. Radioiodine treatment of hyperthyroidism: prognostic factors affecting outcome. Endocrine. 2004 Oct. 25(1):55-60. [Medline].
Erickson D, Gharib H, Li H, et al. Treatment of patients with toxic multinodular goiter. Thyroid. 1998 Apr. 8(4):277-82. [Medline].
Feit H. Thyroid function in the elderly. Clin Geriatr Med. 1988 Feb. 4(1):151-61. [Medline].
Holzapfel HP, Fuhrer D, Wonerow P, et al. Identification of constitutively activating somatic thyrotropin receptor mutations in a subset of toxic multinodular goiters. J Clin Endocrinol Metab. 1997 Dec. 82(12):4229-33. [Medline]. [Full Text].
Kang AS, Grant CS, Thompson GB, et al. Current treatment of nodular goiter with hyperthyroidism (Plummer's disease): surgery versus radioiodine. Surgery. 2002 Dec. 132(6):916-23; discussion 923. [Medline].
Koornstra JJ, Kerstens MN, Hoving J, et al. Clinical and biochemical changes following 131I therapy for hyperthyroidism in patients not pretreated with antithyroid drugs. Neth J Med. 1999 Nov. 55(5):215-21. [Medline].
Kraiem Z, Glaser B, Yigla M, et al. Toxic multinodular goiter: a variant of autoimmune hyperthyroidism. J Clin Endocrinol Metab. 1987 Oct. 65(4):659-64. [Medline].
Krohn K, Paschke R. Clinical review 133: progress in understanding the etiology of thyroid autonomy. J Clin Endocrinol Metab. 2001 Jul. 86(7):3336-45. [Medline]. [Full Text].
Lavard L, Sehested A, Brock Jacobsen B, et al. Long-term follow-up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr). Horm Res. 1999. 51(1):43-6. [Medline].
Maussier ML, D'Errico G, Putignano P, et al. Thyrotoxicosis: clinical and laboratory assessment. Rays. 1999 Apr-Jun. 24(2):263-72. [Medline].
Pearce EN, Braverman LE. Hyperthyroidism: advantages and disadvantages of medical therapy. Surg Clin North Am. 2004 Jun. 84(3):833-47. [Medline].
Reiners C, Schneider P. Radioiodine therapy of thyroid autonomy. Eur J Nucl Med Mol Imaging. 2002 Aug. 29 Suppl 2:S471-8. [Medline].
Sato K, Miyakawa M, Eto M, et al. Clinical characteristics of amiodarone-induced thyrotoxicosis and hypothyroidism in Japan. Endocr J. 1999 Jun. 46(3):443-51. [Medline].
Siegel RD, Lee SL. Toxic nodular goiter. Toxic adenoma and toxic multinodular goiter. Endocrinol Metab Clin North Am. 1998 Mar. 27(1):151-68. [Medline].
Talbot JN, Duron F, Piketty ML, et al. Low thyrotropin (TSH) levels in goiter. Relationship with scintigraphic findings and other biological parameters. Thyroidology. 1989 Apr. 1(1):39-44. [Medline].
Tonacchera M, Chiovato L, Pinchera A, et al. Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab. 1998 Feb. 83(2):492-8. [Medline]. [Full Text].
Tonacchera M, Vitti P, Agretti P, et al. Activating thyrotropin receptor mutations in histologically heterogeneous hyperfunctioning nodules of multinodular goiter. Thyroid. 1998 Jul. 8(7):559-64. [Medline].
Rokni H, Sadeghi R, Moossavi Z, Treglia G, Zakavi SR. Efficacy of different protocols of radioiodine therapy for treatment of toxic nodular goiter: systematic review and meta-analysis of the literature. Int J Endocrinol Metab. 2014 Apr. 12 (2):e14424. [Medline].

Media Gallery

Patchy uptake of iodine (123I) in a toxic multinodular goiter.

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Author

Philip R Orlander, MD Director and Professor, Division of Endocrinology, Associate Dean for Educational Programs, Vice-Chair of Medicine for Education, Program Director, Internal Medicine Residency Program, University of Texas Health Science Center at Houston

Philip R Orlander, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, Endocrine Society, Texas Medical Association

Disclosure: Nothing to disclose.

Coauthor(s)

Caroline B Chiu, MD Fellow, Department of Endocrinology, University of Texas Health Science Center at Houston

Caroline B Chiu, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Thyroid Association, Endocrine Society

Disclosure: Nothing to disclose.

Anu Bhalla Davis, MD Assistant Professor, Department of Internal Medicine, Division of Diabetes, Endocrinology, and Metabolism, University of Texas Medical School at Houston

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

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, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD Professor Emeritus 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, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Acknowledgements

Robert A Gabbay, MD, PhD Associate Professor of Medicine, Division of Endocrinology, Diabetes and Metabolism, Laurence M Demers Career Development Professor, Penn State College of Medicine; Director, Diabetes Program, Penn State Milton S Hershey Medical Center; Executive Director, Penn State Institute for Diabetes and Obesity

Robert A Gabbay, MD, PhD is a member of the following medical societies: American Association of Clinical Endocrinologists, American Diabetes Association, and Endocrine Society

Disclosure: Novo Nordisk Honoraria Speaking and teaching; Merck Honoraria Speaking and teaching

Asra Kermani, MBBS Postdoctoral Fellow, Center for Human Nutrition, University of Texas Southwestern Medical School

Asra Kermani, MBBS is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine

Disclosure: Nothing to disclose.

Sections Toxic Nodular Goiter
Overview
Presentation
- History
- Physical
- Causes
- Show All
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Toxic Nodular Goiter

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