versão impressa ISSN 0871-3413
Arq Med v.22 n.4-5 Porto 2008
Doença de Graves
Celestino Neves*, Marta Alves*, José Luís Delgado††, José Luís Medina*
*Serviço de Endocrinologia, Hospital de São João, EPE, Porto e Faculdade de Medicina da Universidade do Porto; †Serviço de Imunologia, Hospital de São João, EPE, Porto
A doença de Graves é a principal causa de hipertiroidismo. É uma doença auto-imune de etiologia não esclarecida, certamente multifactorial e com evidente predisposição genética. A sua frequência, a sua natureza auto-imune e as consequências potencialmente graves da doença não tratada fazem dela objecto de intensa investigação, tendo em vista a melhor compreensão dos mecanismos patogénicos e a descoberta de novas terapêuticas, mais eﬁcazes e idealmente dirigidas contra o próprio processo auto-imune. Os autores decidiram congregar nesta revisão o conhecimento actual mais relevante sobre o tema, de modo a optimizar a qualidade da prática clínica.
Palavras-chave: doença tiroideia auto-imune; hipertiroidismo; Graves.
Graves’disease is the major cause of hyperthyroidism. It is an autoimmune disease of a certainly multifactorial unknown etiology, with genetic predisposition evidence. Its frequency, the autoimmune nature and the potentially serious consequences of the untreated disease make it an object of intense investigation, being in mind the best understanding of the pathogenic mechanisms and the discovery of new and more efficient therapeutics, ideally directed against the autoimmune process itself. The authors decided to bring together in this revision the most relevant current knowledge on this subject, in way to optimize the quality of the clinical practice.
Key-words: thyroid autoimmune disease; hyperthyroidism; Graves´ disease.
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1 -Graves RJ. Newly observed affection of the thyroid. London Medical and Surgical Journal 1835;7:515.[ Links ]
2 -Weetman AP. Graves’ Disease. N Engl J Med 2000;343: 1236-48.
3 -Vanderpump MPJ, Tunbridge WMG. The epidemiology of autoimmune thyroid disease. In: Volpé R, ed. Autoimmune endocrinopathies. Vol. 15 of Contemporary endocrinology. Totowa, N.J.: Humana Press, 1999:141-62.
4 -Davies TF. New thinking on the immunology of Graves’ disease. Thyroid Today 1992;15:1-11.
5 -Davies TF et al. Pathogenesis of Graves’disease. In Up-todate 2006.
6 -Yeung SC. Graves disease. In eMedicine 2005.
7 -Vassart G, Dumon, JE. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocrine Reviews 1992;13:596-611.
8 -Saavedra AP, Tsygankova OM, Prendergast GV, et al. Role of cAMP, PKA and Rap1A in thyroid follicular cell survival. Oncogene 2002;21:778.
9 -Saito T, Endo T, Kawaguchi A, et al. Increased expression of the Na+/I- symporter in cultured human thyroid cells exposed to thyrotropin and in Graves’ thyroid tissue. J Clin Endocrinol Metab 1997;82:3331.
10-McLachlan SM, Pegg CA, Atherton MC, et al. TSH receptor antibody synthesis by thyroid lymphocytes. Clin Endocrinol (Oxf) 1986;24:223.
11 -Tamai H, Kasagi K, Takaichi Y, et al. Development of spontaneous hypothyroidism in patients with Graves’ disease treated with antithyroidal drugs: clinical, immunological, and histological ﬁndings in 26 patients. J Clin Endocrinol Metab 1989;69:49.
12 -Kraiem Z, Baron E, Kahana L, et al. Changes in stimulating and blocking TSH receptor antibodiesin a patient undergoing three cycles of transition from hypo to hyper-thyroidism and back to hypothyroidism. Clin Endocrinol 1992;36:211.
13 -Tamai H, Ohsako N, Takeno K, et al. Changes in thyroid functionin euthyroid subjects with a family history of Graves’ disease: a follow-up study of 69 patients. J Clin Endocrinol Metab 1980;51:1123.
14 -Bahn RS, Heufelder AE. Pathogenesis of Graves’ ophthalmopathy. N Engl J Med 1993;329:1468-75.
15 -Bahn RS, Dutton CM, Natt N, Joba W, Spitzweg C, Heufelder AE. Thyrotropin receptor expression in Graves’ orbital adipose/connective tissues: potential autoantigen in Graves’ ophthalmopathy. J Clin Endocrinol Metab 1998;83: 998-1002.
16 -Heufelder AE. Pathogenesis of Graves‘ ophthalmopathy: recent controversies and progress. Eur J Endocrinol 1995;132:532-41.
17 -McGregor AM, Petersen MM, Capiferri R, et al. Effects of radioiodine on thyrotrophin bindinginhibitingimmunoglobulins in Graves’ disease. Clin Endocrinol 1979;11:437.
18 -Aizawa Y, Yoshida K, Kaise N, et al. Long-term effects of radioiodine on thyrotrophin receptor antibodies in Graves’ disease. Clin Endocrinol (Oxf) 1995;42:517.
19 -Bull RH, Coburn PR, Mortimer PS. Pretibial myxedema: a manifestation of lymphoedema? Lancet 1993;341:403.
20 -Davies TF. Inﬁltrative dermopathy (pretibial myxedema) in thyroid disease. In Uptodate 2006.
21 -Ajjan RA, Watson PF, Weetman AP. Cytokines and thyroid function. Adv Neuroimmunol 1996;6:359.
22 -Kahaly G, Forster G, Hansen C. Glycosaminoglycans in thyroid eye disease. Thyroid 1998;8:429.
23 -Tomer Y, Barbesino G, Greenberg DA, et al. Mapping the major susceptibilitylocifor familialGraves’and Hashimoto’s diseases: evidence for genetic heterogeneity and gene interactions. J Clin Endocrinol Metab 1999;84:4656.
24 -Stenszky V, Kozma L, Balazs C, et al. The genetics of Graves’ disease: HLA and disease susceptibility. J Clin Endocrinol Metab 1985;61:735.
25 -Tomer Y, Davies T. In: Wass, J, Shalet, S (eds), Oxford Textbook of Endocrinology, Oxford University Press, Oxford, UK, 2000.
26 -Heward JM, Allahabadia A, Armitage M, et al. The development of Graves’ disease and the CTLA-4 gene on chromosome 2q33. J Clin Endocrinol Metab 1999;84:2398.
27 -Heward JM, Allahabadia A, Daykin J, et al. Linkage disequilibrium between the humanleukocyte antigen class II region of the major histocompatibility complex and Graves’disease: replication using a population case controland family-based study. J Clin Endocrinol Metab 1998;83:3394-7.
28 -Chen QY, Huang W, She JX, et al. HLA-DRB108, DRB103/ DRB30101, and DRB30202 are susceptibility genes for Graves’ disease in North American Caucasians, whereas DRB107 is protective. J Clin Endocrinol Metab 1999; 84:3182-6.
29 -Ban Y, Greenberg DA, Concepcion E, et al. Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease. Proc Natl Acad Sci USA 2003;100:15119.
30 -Tomer Y, Davies TF. Infection, thyroid disease and autoimmunity. Endocr Rev 1993;14:107.
31 -Radosavljevic VR, Jankovic SM, Marinkovic JM. Stressful life events in the pathogenesis of Graves’ disease. Eur J Endocrinol 1996;134:6.
32 -Paavonen T. Hormonal regulation of immune responses. Ann Med 1994;26:255.
33 -Da Silva JAP. Sex hormones, glucocorticoids, and autoimmunity: facts and hypotheses. Ann Rheum Dis 1995; 54:6.
34 -Holm IA, Manson JE, Michels KB, et al. Smoking and other lifestyle factors and the risk of Graves’ hyperthyroidism. Arch Intern Med 2005;165:1606.
35 -Jansson R, Dahlberg PA, Winsa B, et al. The postpartum period constitutes an important risk for the development of clinical Graves’ disease in young women. Acta Endocrinol (Copenh) 1987;116:321.
36 -Laurberg P, Pedersen KM, Vestergaard H, et al. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland Denmark and Iceland. J Intern Med 1991;229:415.
37 -Bartalena L, Bogazzi F, Martino E. Amiodarone-induced thyrotoxicosis: a difﬁcult diagnostic and therapeutic challenge. Clin Endocrinol (Oxf) 2002;56:23.
38 -Burikhanov RB, Matsuzaki S. Excess iodine induces apoptosis in the thyroid of goitrogen-pretreated rats in vivo. Thyroid 2000;10:123.
39 -Barclay ML et al. Lithium associated thyrotoxicosis: a re-porto f 14 cases, with statistical analysis of incidence. Clin Endocrinol (Oxf) 1994;40:759-64.
40 -Gilquin J, Viard J-P, Jubault V, Sert C, Kazatchkine MD. Delayed occurrence of Graves’ disease after immune restoration with HAART: highly active antiretroviral therapy. Lancet 1998;352:1907-8.
41 -Kendall-Taylor P. Thyrotoxicosis. In: Grossman A, ed. Clinical endocrinology. Oxford, England: Blackwell Science, 1998:328-58.
42 -Nordyke RA, Gilbert FI Jr, Harada ASM. Graves’ disease: inﬂuence of age on clinical ﬁndings. Arch Intern Med 1988;148:626-31.
43 -Ross DS. Overview of the clinical manifestations of hyperthyroidism in adults. In Uptodate 2006.
44 -Fuster V, Ryden LE, Cannom DS, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation A Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation). J Am Coll Cardiol 2006;48:e149.
45 -Iglesias P, Acosta M, Sanchez R, et al. Ambulatory blood pressure monitoringin patients with hyperthyroidism before and after control of thyroid function. Clin Endocrinol (Oxf) 2005;63:66.
46 -Kirkeby K, Hangaard G, Lingjaerde P. The pigmentation of thyrotoxic patients. Acta Med Scand 1963;174:257.
47 -O’Brien T, Katz K, Hodge D, et al. The effect of the treatment of hypothyroidism and hyperthyroidism on plasmalipids and apoproteins AI, AII and E. Clin Endocrinol 1997;46:17.
48 -Villadolid MC, Yokoyama N, Izumi M, et al. Untreated Graves’ disease patients without clinical ophthalmopathy demonstrate a high frequency of extraocular muscle (EOM) enlargement by magnetic resonance. J Clin Endocrinol Metab 1995;80:2830-3.
49 -Perros P, Crombie AL, Matthews JNS, Kendall-Taylor P. Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol (Oxf) 1993;38:367-372.
50 -Fatourechi V, Pajouhi M, Fransway AF. Dermopathy of Graves’ disease (pretibial myxedema): review of 150 cases. Medicine (Baltimore) 1994;73:1-7.
51 -Carnell NE, Valent WA. Thyroid nodules in Graves’ disease: classification, characterization, and response to treatment. Thyroid 1998;8:647-52. (Erratum, Thyroid 1998;8:1079.)
52 -Alves M, Neves C, Delgado JL, Medina JL. Disfunção tiroideia na gravidez. Rev Port End Diab Metab2007;2:47- 56.
53 -Singer PA, Cooper DS, Levy EG, et al. Treatment guidelines for patients with hyperthyroidism and hypothyroidism. JAMA 1995;273:808.
54 -Torring O, Tallstedt L, Wallin G, et al. Graves’ hyperthyroidism: treatment with antithyroid drugs, surgery, or radioiodine - a prospective, randomized study. J Clin Endocrinol Metab 1996;81:2986.
55 -Ross D. Beta blockers in the treatment of hyperthyroidism. In Uptodate 2006.
56 -Ross DS. Treatment of Graves’ hyperthyroidism. In Uptodate 2006.
57 -Lavin N. Manual of Endocrinology and Metabolism. Lippincott Williams and Wilkins. 3ª edição, 2002.
58 -Cooper DS. Antithyroid drugs. N Engl J Med 2005;352;9: 905-17.
59 -Ross D. Surgery in the treatment of hyperthyroidism. In Uptodate 2006.
60 -Davies TF. Tretment of Graves’ ophthalmopathy. In Uptodate 2006.
61 -Eastell R, Devogelaer JP, Peel NF, et al. Prevention of bone loss with risedronate in glucocorticoid-treated rheumatoid arthritis patients. Osteoporos Int 2000;11:331.
62 -Kahaly GJ, Pitz S, Hommel G, Dittmar M. Randomized, single blind trial of intravenous versus oral steroid monotherapy in Graves’ orbitopathy. J Clin Endocrinol Metab 2005;90:5234.
63 -Nygaard B, Specht L. Transitory blindness after retrobulbar irradiation of Graves’ ophthalmopathy. Lancet 1998; 351:725.
64 -Lyons CJ, Rootman J. Orbital decompression for disfiguring exophthalmos in thyroid orbitopathy. Ophthalmology 1994;101:223.
65 -Braley-Mullen H, Yu S. Early requirement for B cells for development of spontaneous autoimmune thyroiditis in NOD.H-2h4 mice. J Immunol 2000,,165:7262-9.
66 -Segundo C, Rodriguez C, Aguilar M, Garcia-Poley A, Gavilan Bellas CI, Brieva JA. Differences in thyroid-infiltrating B lymphocytes in patients with Graves’ disease: relationship to autoanti-body detection. Thyroid 2004;14:337-44.
67 -Armengol MP, Juan M, Lucas-Martin A, Fernandez-Figueras Jaraquemada DMT, Gallart T, Pujol-Borrell R. Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 2001;159:861-73.
68 -Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710-8.
69 -Pichurin P, Aliesky H, Chen CR, Nagayama Y, Rapoport B, McLachlan SM. Thyrotrophin receptor-specific memory T cell responses require normal B cells in a murine model of Graves’ disease. Clin Exp Immunol 2003;134:396-402.
70 -Boye J, Elter T & Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Annals of Oncology 2003;14:520-35.
71 -Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R, Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994;83:435-45.
72 -Kneitz C, Wilhelm M, Tony HP. Effective B cell depletion with rituximab in the treatment of autoimmune diseases. Immunobiology 2002;206:519-27.
73 -Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its potential as a target for mAb therapy. Curr Dir Autoimmun 2005;8:140-74.
74 -Smith MR. Rituximab (monoclonal anti-CD20 antibody): mechanisms of action and resistance. Oncogene 2003; 22:7359-68.
75 -Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology 1999;97:188-96.
76 -El Fassi D, Nielsen CH, Hasselbalch HC, Hegedus L. Successful B lymphocyte depletion with Rituximab in a patient with recurrent Graves’ disease and severe ophthalmopathy. Thyroid 2005;15:S28.
77 -Smith TJ. Insights into the role of fibroblasts in human autoimmune diseases. Clin Exp Immunol. 2005;141: 388-97.
78 -Pritchard J, Tsui S, Horst N, Cruikshank WW, Smith TJ. Synovial fibroblasts from patients with rheumatoid arthritis, like fibroblasts from Graves’ disease, express high levels of IL-16 when treated with Igs against insulin-like growth factor-1 receptor. J Immunol 2004;173:3564-9.
79 -Nielse CH, El Fassi D, Hasselbach HC, Bendtzen K, Hegedüs L. B-cell depletion with rituximab in the treatment of autoimmune diseases. Graves’ ophthalmopathy the latest addition to an expanding family. Expert Opin Biol Ther 2007;7:1061-78.
80 -Fassi ED, Nielsen CH, Hasselbalch HC, Hegedüs L. The rationale for B lymphocyte depletion in Graves' disease. Monoclonal anti-CD20 antibody therapy as a novel treatment option 2006. Eur J Endocrinol 2006;154:623-32.
Dr. Celestino Neves
Serviço de Endocrinologia
Hospital de São João
Alameda Prof. Hernâni Monteiro