Graves Disease Workup
- Author: Sai-Ching Jim Yeung, MD, PhD, FACP; Chief Editor: Romesh Khardori, MD, PhD, FACP more...
Ultrasensitive (third-generation) thyrotropin assays remain the best screening test for thyroid disorders.
With the exception of thyrotropin-induced hyperthyroidism, subnormal or suppressed thyrotropin levels are seen in most patients with thyrotoxicosis.
Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3 level within the reference range with suppressed thyrotropin, also can be seen.
On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3. Elevated T3 levels are often seen in early phase Graves disease as well.
Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive.
Detection of TSIs is diagnostic for Graves disease.
The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated.
Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present.
Other autoantibodies that may be present include thyrotropin receptor–blocking antibodies and anti–sodium-iodide symporter antibody.
The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.
Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications).
A CBC count with differential should be obtained at baseline and with the development of fever or symptoms of infection. Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, low-normal to slightly depressed platelet count. Thioamides may rarely cause severe hematologic side effects, but routine screening for these rare events is not cost-effective.
Investigation of gynecomastia associated with Graves disease may reveal increased sex hormone–binding globulin levels and decreased free testosterone levels.
Graves disease may worsen diabetes control and may be reflected by an increase in hemoglobin A1C in diabetic patients.
A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels.
Thyrotropin-releasing hormone testing has largely been replaced by third-generation thyrotropin assays.
A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy.
Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.
Ultrasounds with color-Doppler evaluation have been found to be cost-effective in hyperthyroid patients.[26, 39] A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome, and, in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance.
Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of orbitopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment. Careful monitoring is required after using iodinated contrast agents as they may affect ongoing treatment plans.
In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.
Ellis H. Robert Graves: 1796-1852. Br J Hosp Med (Lond). 2006 Jun. 67(6):313. [Medline].
Cruz AA, Akaishi PM, Vargas MA, de Paula SA. Association between thyroid autoimmune dysfunction and non-thyroid autoimmune diseases. Ophthal Plast Reconstr Surg. 2007 Mar-Apr. 23(2):104-8. [Medline].
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. 2007 Mar-May. 28(2-3):85-98. [Medline].
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(2):55-60. [Medline].
Chu X, Pan CM, Zhao SX, et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet. 2011 Aug 14. 43(9):897-901. [Medline].
Douglas RS, Afifiyan NF, Hwang CJ, et al. Increased generation of fibrocytes in thyroid-associated ophthalmopathy. J Clin Endocrinol Metab. 2010 Jan. 95(1):430-8. [Medline]. [Full Text].
Chu X, Pan CM, Zhao SX, Liang J, Gao GQ, Zhang XM, et al. A genome-wide association study identifies two new risk loci for Graves' disease. Nat Genet. 2011 Aug 14. 43(9):897-901. [Medline].
Furszyfer J, Kurland LT, McConahey WM, Elveback LR. Graves' disease in Olmsted County, Minnesota, 1935 through 1967. Mayo Clin Proc. 1970 Sep. 45(9):636-44. [Medline].
Tunbridge WM, Evered DC, Hall R, et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf). 1977 Dec. 7(6):481-93. [Medline].
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). 1995 Jul. 43(1):55-68. [Medline].
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 Jun. 288(6):E1067-73. [Medline].
Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am. 2006 Dec. 35(4):663-86, vii. [Medline].
Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993 Jun. 22(2):263-77. [Medline].
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). 2007 Jun. 66(6):854-8. [Medline].
Uchida T, Takeno K, Goto M, et al. Superior thyroid artery mean peak systolic velocity for the diagnosis of thyrotoxicosis in Japanese patients. Endocr J. 2010 Mar 6. [Medline]. [Full Text].
Bunevicius R, Prange AJ Jr. Psychiatric manifestations of Graves' hyperthyroidism: pathophysiology and treatment options. CNS Drugs. 2006. 20(11):897-909. [Medline].
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. 2007 Jan. 32(1):36-43. [Medline].
Schwartz KM, Fatourechi V, Ahmed DD, Pond GR. Dermopathy of Graves' disease (pretibial myxedema): long-term outcome. J Clin Endocrinol Metab. 2002 Feb. 87(2):438-46. [Medline].
Boelaert K, Newby PR, Simmonds MJ, et al. Prevalence and relative risk of other autoimmune diseases in subjects with autoimmune thyroid disease. Am J Med. 2010 Feb. 123(2):183.e1-9. [Medline].
Tun NN, Beckett G, Zammitt NN, Strachan MW, Seckl JR, Gibb FW. Thyrotropin Receptor Antibody Levels at Diagnosis and After Thionamide Course Predict Graves' Disease Relapse. Thyroid. 2016 Jul 6. [Medline].
Rabon S, Burton AM, White PC. Graves' Disease in Children: Long Term Outcomes of Medical Therapy. Clin Endocrinol (Oxf). 2016 May 12. [Medline].
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). 2006 Jun. 64(6):611-6. [Medline].
Kung AW. Clinical review: Thyrotoxic periodic paralysis: a diagnostic challenge. J Clin Endocrinol Metab. 2006 Jul. 91(7):2490-5. [Medline].
Ryan DP, da Silva MR, Soong TW, et al. Mutations in potassium channel Kir2.6 cause susceptibility to thyrotoxic hypokalemic periodic paralysis. Cell. 2010 Jan 8. 140(1):88-98. [Medline]. [Full Text].
Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, et al. Prevalence and Natural History of Graves' Orbitopathy in a Large Series of Patients with Newly Diagnosed Graves' Hyperthyroidism Seen at a Single Center. J Clin Endocrinol Metab. 2013 Feb 13. [Medline].
Chung JO, Cho DH, Chung DJ, et al. Ultrasonographic features of papillary thyroid carcinoma in patients with Graves' disease. Korean J Intern Med. 2010 Mar. 25(1):71-6. [Medline]. [Full Text].
Pellegriti G, Mannarino C, Russo M, Terranova R, Marturano I, Vigneri R. Increased Mortality in Patients with Differentiated Thyroid Cancer Associated With Graves' Disease. J Clin Endocrinol Metab. 2013 Jan 24. [Medline].
Brandt F, Thvilum M, Almind D, Christensen K, Green A, Hegedus 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. 2012 Dec 20. [Medline].
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. 2002 May. 12(5):373-6. [Medline].
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. 2006 Apr. 33(2):87-91. [Medline].
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. 2007 Jul. 92(7):2513-8. [Medline].
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. 2006 May. 16(5):443-6. [Medline].
Heward JM, Brand OJ, Barrett JC, Carr-Smith JD, Franklyn JA, Gough SC. Association of PTPN22 haplotypes with Graves' disease. J Clin Endocrinol Metab. 2007 Feb. 92(2):685-90. [Medline].
Minich WB, Dehina N, Welsink T, Schwiebert C, Morgenthaler NG, Köhrle J. Autoantibodies to the IGF1 Receptor in Graves' Orbitopathy. J Clin Endocrinol Metab. 2013 Feb. 98(2):752-60. [Medline].
Benvenga S, Guarneri F, Vaccaro M, et al. Homologies between proteins of Borrelia burgdorferi and thyroid autoantigens. Thyroid. 2004. 14:964-6. [Medline].
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. 2004 Sep-Nov. 37(6-7):515-20. [Medline].
Al-Muqbel KM, Tashtoush RM. Patterns of thyroid radioiodine uptake: Jordanian experience. J Nucl Med Technol. 2010 Mar. 38(1):32-6. [Medline].
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 Jan. 62(1):24-9. [Medline].
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. 2007 Apr 23. [Medline].
Markovic V, Eterovic D. Thyroid echogenicity predicts outcome of radioiodine therapy in patients with graves' disease. J Clin Endocrinol Metab. 2007 Sep. 92(9):3547-52. [Medline].
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. 2006 Oct. 53(5):603-7. [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. 89:4439-44. [Medline].
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. 2004 Sep. 89(9):4229-33. [Medline].
Ceccarelli C, Canale D, Battisti P, Caglieresi C, Moschini C, Fiore E. Testicular function after 131I therapy for hyperthyroidism. Clin Endocrinol (Oxf). 2006 Oct. 65(4):446-52. [Medline].
Rivkees SA, Dinauer C. An optimal treatment for pediatric Graves' disease is radioiodine. J Clin Endocrinol Metab. 2007 Mar. 92(3):797-800. [Medline].
Chen YK, Lin CL, Chang YJ, Cheng FT, Peng CL, Sung FC. Cancer risk in patients with Graves' disease: A nationwide cohort study. Thyroid. 2013 Feb 19. [Medline].
Ye X, Liu J, Wang Y, Bin L, Wang J. Increased serum VEGF and b-FGF in Graves' ophthalmopathy. Graefes Arch Clin Exp Ophthalmol. 2014 Oct. 252 (10):1639-44. [Medline].
Stein JD, Childers D, Gupta S, Talwar N, Nan B, Lee BJ, et al. Risk factors for developing thyroid-associated ophthalmopathy among individuals with Graves disease. JAMA Ophthalmol. 2015 Mar. 133 (3):290-6. [Medline].
Watanabe N, Noh JY, Kozaki A, Iwaku K, Sekiya K, Kosuga Y, et al. Radioiodine-Associated Exacerbation of Graves' Orbitopathy in the Japanese Population: Randomized Prospective Study. J Clin Endocrinol Metab. 2015 Jul. 100 (7):2700-8. [Medline].
Shiber S, Stiebel-Kalish H, Shimon I, Grossman A, Robenshtok E. Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Thyroid. 2014 Oct. 24 (10):1515-23. [Medline].
Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. 1998 Jan 8. 338(2):73-8. [Medline].
Bartalena L, Marcocci C, Bogazzi F, Panicucci M, Lepri A, Pinchera A. Use of corticosteroids to prevent progression of Graves' ophthalmopathy after radioiodine therapy for hyperthyroidism. N Engl J Med. 1989 Nov 16. 321(20):1349-52. [Medline].
Bartalena L, Tanda ML, Piantanida E, Lai A, Pinchera A. Relationship between management of hyperthyroidism and course of the ophthalmopathy. J Endocrinol Invest. 2004 Mar. 27(3):288-94. [Medline].
Macchia PE, Bagattini M, Lupoli G, et al. High-dose intravenous corticosteroid therapy for Graves' ophthalmopathy. J Endocrinol Invest. 2001. 24:152-8. [Medline].
Sisti E, Coco B, Menconi F, Leo M, Rocchi R, Latrofa F, et al. Intravenous glucocorticoid therapy for Graves' ophthalmopathy and acute liver damage: an epidemiological study. Eur J Endocrinol. 2015 Mar. 172 (3):269-76. [Medline].
Liao SL, Huang SW. Correlation of retrobulbar volume change with resected orbital fat volume and proptosis reduction after fatty decompression for Graves ophthalmopathy. Am J Ophthalmol. 2011 Mar. 151(3):465-9.e1. [Medline].
Wakelkamp IM, Tan H, Saeed P, et al. Orbital irradiation for Graves' ophthalmopathy: Is it safe? A long-term follow-up study. Ophthalmology. 2004 Aug. 111(8):1557-62. [Medline].
Seals KF, Lee EW, Cagnon CH, Al-Hakim RA, Kee ST. Radiation-Induced Cataractogenesis: A Critical Literature Review for the Interventional Radiologist. Cardiovasc Intervent Radiol. 2015 Sep 24. [Medline].
Rajendram R, Bunce C, Lee RW, Morley AM. Orbital radiotherapy for adult thyroid eye disease. Cochrane Database Syst Rev. 2012 Jul 11. 7:CD007114. [Medline].
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. 2004 Dec. 89(12):5910-5. [Medline].
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].
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. 2006 Dec. 91(12):4817-24. [Medline].
Durrani OM, Reuser TQ, Murray PI. Infliximab: a novel treatment for sight-threatening thyroid associated ophthalmopathy. Orbit. 2005 Jun. 24(2):117-9. [Medline].
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. 2007 Jan. 156(1):33-40. [Medline].
Stan MN, Garrity JA, Carranza Leon BG, Prabin T, Bradley EA, Bahn RS. Randomized controlled trial of rituximab in patients with Graves' orbitopathy. J Clin Endocrinol Metab. 2015 Feb. 100 (2):432-41. [Medline].
Salvi M, Vannucchi G, Currò N, Campi I, Covelli D, Dazzi D, et al. Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study. J Clin Endocrinol Metab. 2015 Feb. 100 (2):422-31. [Medline].
Ebner R, Devoto MH, Weil D, et al. Treatment of thyroid associated ophthalmopathy with periocular injections of triamcinolone. Br J Ophthalmol. 2004 Nov. 88(11):1380-6. [Medline]. [Full Text].
Finamor FE, Martins JR, Nakanami D, Paiva ER, Manso PG, Furlanetto RP. 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 Jul-Aug. 14(4):277-83. [Medline].
Grodski S, Stalberg P, Robinson BG, Delbridge LW. Surgery versus Radioiodine Therapy as Definitive Management for Graves' Disease: The Role of Patient Preference. Thyroid. 2007 Feb. 17(2):157-60. [Medline].
Genovese BM, Noureldine SI, Gleeson EM, Tufano RP, Kandil E. What is the best definitive treatment for graves' disease? A systematic review of the existing literature. Ann Surg Oncol. 2013 Feb. 20(2):660-7. [Medline].
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. 2007 Feb. 31(2):306-12; discussion 313. [Medline].
Panzer C, Beazley R, Braverman L. Rapid preoperative preparation for severe hyperthyroid Graves' disease. J Clin Endocrinol Metab. 2004 May. 89(5):2142-4. [Medline].
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. 2007 Jun. 92(6):2182-9. [Medline].
Alsuhaibani AH, Carter KD, Policeni B, Nerad JA. Effect of orbital bony decompression for Graves' orbitopathy on the volume of extraocular muscles. Br J Ophthalmol. 2011 Sep. 95(9):1255-8. [Medline].
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 Jul. 14(7):531-5. [Medline].
Anagnostis P, Adamidou F, Polyzos SA, Katergari S, Karathanasi E, Zouli C, et al. Predictors of long-term remission in patients with Graves' disease: a single center experience. Endocrine. 2013 Feb 11. [Medline].
Sato H, Sasaki N, Minamitani K, Minagawa M, Kazukawa I, Sugihara S, et al. Higher dose of methimazole causes frequent adverse effects in the management of Graves' disease in children and adolescents. J Pediatr Endocrinol Metab. 2012. 25(9-10):863-7. [Medline].
Rivkees SA, Stephenson K, Dinauer C. Adverse events associated with methimazole therapy of Graves' disease in children. Int J Pediatr Endocrinol. 2010. 2010:176970. [Medline]. [Full Text].
Mohlin E, Filipsson Nyström H, Eliasson M. Long-term prognosis after medical treatment of Graves' disease in a northern Swedish population 2000-2010. Eur J Endocrinol. 2014 Mar. 170 (3):419-27. [Medline].
Liu X, Shi B, Li H. Valuable predictive features of relapse of Graves' disease after antithyroid drug treatment. Ann Endocrinol (Paris). 2015 Oct 26. [Medline].
Villagelin D, Romaldini JH, Santos RB, Milkos AB, Ward LS. Outcomes in Relapsed Graves' Disease Patients Following Radioiodine or Prolonged Low Dose of Methimazole Treatment. Thyroid. 2015 Oct 20. [Medline].
Salvi M, Campi I. Medical Treatment of Graves' Orbitopathy. Horm Metab Res. 2015 Sep. 47 (10):779-88. [Medline].
Prasek K, Płazińska MT, Krolicki L. Diagnosis and treatment of Graves' disease with particular emphasis on appropriate techniques in nuclear medicine. General state of knowledge. Nucl Med Rev Cent East Eur. 2015. 18 (2):110-6. [Medline].