Graves' ophthalmopathy (GO) is a controversial disease, with disagreement within the medical community regarding its pathogenesis, diagnosis, and treatment.
Methods
We reviewed recent literature on clinical and pathological aspects of GO from both the endocrinologist's and ophthalmologist's perspective.
Results
Investigations into the pathogenesis of GO have included possible antigenic targets, orbital cell types, and development of animal models. Diagnosis has been improved recently with new tools and grading systems, but can be complicated by conditions that may simulate one or more of the findings of GO. The new findings of clinical studies also compel practitioners to reassess commonly used GO treatments such as orbital irradiation.
Conclusions
Improved understanding of the pathogenic mechanisms of GO should hopefully lead to new diagnostic and therapeutic approaches to this problematic condition.
VanderpumpM.P., TunbridgeW.M., FrenchJ.M.The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol1995; 43: 55–68.
2.
BurchH.B., WartofskyL.Graves' ophthalmopathy: current concepts regarding pathogenesis and management. Endocrine Rev1993; 14: 747–93.
3.
CoatsD.K., PaysseE.A., PlagerD.A., WallaceD.K.Early strabismus surgery for thyroid ophthalmopathy. Ophthalmology1999; 106: 324–9.
GormanC.A., GarrityJ.A., FatourechiV.A prospective, randomized, double-blind, placebo-controlled study of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology2001; 108: 1523–34.
6.
MouritsM.P., van Kempen-HarteveldM.L., GarciaM.B., KoppeschaarH.P., TickL., TerweeC.B.Radiotherapy for Graves' orbitopathy: randomised placebo-controlled study. Lancet2000; 355: 1505–9.
7.
ChavisP.S.Thyroid and the eye. Curr Opin Ophthalmol2002; 13: 352–6.
8.
MajorB.J., BusuttilB.E., FraumanA.G.Graves' ophthalmopathy: pathogenesis and clinical implications. Aust NZ J Med1998; 28: 39–45.
9.
SimonszH.J., KommerellG.Increased muscle tension and reduced elasticity of affected muscles in recent-onset Graves' disease caused primarily by active muscle contraction. Doc Ophthalmol1989; 72: 215–24.
10.
PerrosP., CrombieA.L., MatthewsJ.N., Kendall-TaylorP.Age and gender influence the severity of thyroid-associated ophthalmopathy: a study of 101 patients attending a combined thyroid-eye clinic. Clin Endocrinol1993; 38: 367–72.
11.
NattN., BahnR.S.Cytokines in the evolution of Graves' ophthalmopathy. Autoimmunity1997; 26: 129–36.
12.
HeufelderA.E.Pathogenesis of Graves' ophthalmopathy: recent controversies and progress. Eur J Endocrinol1995; 132: 532–41.
13.
ParidaensD.A., van Den BoschW.A., van der LoosT.L., KrenningE.P., van HagenM.P.The effect of etanercept on Graves' ophthalmopathy. A pilot study. Presented at Vancouver Orbital Symposium, Vancouver, Canada; 196th annual meeting of the Dutch Ophthalmic Society, Groningen, The Netherlands; 20th annual meeting of the European Society of Ophthalmic Plastic & Reconstructive Surgery, Muenster, Germany, 2002; 221.
14.
WeightmanD.R., PerrosP., SherifI.H., Kendall-TaylorP.Autoantibodies to IGF-1 binding sites in thyroid associated ophthalmopathy. Autoimmunity1993; 16: 251–7.
15.
HanssonH.A., PetrusonB., SkottnerA.Somatomedin C in pathogenesis of malignant exophthalmos of endocrine origin. Lancet1986; 1: 218–9.
16.
BarrieW.E.Graves' ophthalmopathy [comment]. West J Med1993; 158: 591–5.
17.
OhtsukaK., HashimotoM.H-magnetic resonance spectroscopy of retrobulbar tissue in Graves ophthalmopathy. Am J Ophthalmol1999; 128: 715–9.
18.
McGregorA.M.Has the target autoantigen for Graves' ophthalmopathy been found?Lancet1998; 352: 595–6.
19.
Classification of eye changes of Graves' disease. Thyroid1992; 2: 235–6.
20.
MouritsM.P., KoornneefL., WiersingaW.M., PrummelM.F., BerghoutA., van der GaagR.Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach. Br J Ophthalmol1989; 73: 639–44.
21.
El-KaissiS., FraumanA.G., WallJ.R.Thyroid-associated ophthalmopathy: a practical guide to classification, natural history and management. Intern Med J2004; 34: 482–91.
22.
SalviM., ZhangZ.G., HaegertD., WooM., LibermanA., CadarsoL., WallJ.R.Patients with endocrine ophthalmopathy not associated with overt thyroid disease have multiple thyroid immunological abnormalities. J Clin Endocrinol Metabol1990; 70: 89–94.
23.
MaugendreD., MassartC.Clinical value of a new TSH binding inhibitory activity assay using human TSH receptors in the follow-up of antithyroid drug treated Graves' disease. Comparison with thyroid stimulating antibody bioassay. Clin Endocrinol2001; 54: 89–96.
24.
RapoportB., ChazenbalkG.D., JaumeJ.C., McLachlanS.M.The thyrotropin (TSH) receptor: interaction with TSH and autoantibodies [erratum appears in Endocrine Rev 1999; 20: 100]. Endocrine Rev1998; 19: 673–716.
25.
NugentR.A., BelkinR.I., NeigelJ.M.Graves orbitopathy: correlation of CT and clinical findings. Radiology1990; 177: 675–82.
26.
PatrinellyJ.R., OsbornA.G., AndersonR.L., WhitingA.S.Computed tomography features of nonthyroid extraocular muscle enlargement. Ophthalmology1989; 96: 1038–47.
27.
ScottA.B.Botulinum toxin treatment of strabismus. In CamposE.C., ed. Strabismus and Ocular Motility Disorders. Proceedings of the sixth meeting of the International Strabismological Association; Surfer's Paradise, Australia, 1990; 401–6.
28.
BartalenaL., MarcocciC., BogazziF.Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med1998; 338: 73–8.
29.
KahalyG., SchrezenmeirJ., KrauseU.Ciclosporin and prednisone v. prednisone in treatment of Graves' ophthalmopathy: a controlled, randomized and prospective study. Eur J Clin Invest1986; 16: 415–22.
30.
GormanC.A., GarrityJ.A., FatourechiV.The aftermath of orbital radiotherapy for Graves' ophthalmopathy. Ophthalmology2002; 109: 2100–7.
31.
WilsonW.B., ProchodaM.Radiotherapy for thyroid orbitopathy. Effects on extraocular muscle balance. Arch Ophthalmol1995; 113: 1420–5.
32.
FerrisJ.D., DawsonE.L., PlowmanN., AdamsG.G., FellsP., LeeJ.P.Radiotherapy in thyroid eye disease: the effect on the field of binocular single vision. J Am Assoc Pediatr Ophthalmol Strabismus2002; 6: 71–6.
33.
GerlingJ., KommerellG., HenneK., LaubenbergerJ., Schulte-MontingJ., FellsP.Retrobulbar irradiation for thyroid-associated orbitopathy: double-blind comparison between 2.4 and 16Gy Int J Radiation Oncol Biol Physics2003; 55: 182–9.
34.
WiersingaW.M., PrummelM.F.Graves' ophthalmopathy: a rational approach to treatment. Trends Endocrinol Metab2002; 13: 280–7.
35.
FeldmanK.A., PuttermanA.M., FarberM.D.Surgical treatment of thyroid-related lower eyelid retraction: a modified approach. Ophthalmic Plast Reconstructr Surg1992; 8: 278–86.
36.
MouritsM.P., SasimI.V.A single technique to correct various degrees of upper lid retraction in patients with Graves' orbitopathy. Br J Ophthalmol1999; 83: 81–4.
37.
GayA.J., WolksteinM.A.Topical guanethidine therapy for endocrine lid retraction. Arch Ophthalmol1966; 76: 364–7.
38.
McNabA.A.Orbital decompression for thyroid orbitopathy. Aust NZ J Ophthalmol1997; 25: 55–61.
39.
LyonsC.J., RootmanJ.Orbital decompression for disfiguring exophthalmos in thyroid orbitopathy. Ophthalmology1994; 101: 223–30.
40.
LeeA.G., McKenzieB.A., MillerN.R., LouryM.G., KennedyD.W.Long term results of orbital decompression in thyroid eye disease. Orbit1995; 14: 59–70.
41.
GairE.J., LeeJR, KhooB.K., MaurinoV.What is the role of botulinum toxin in the treatment of dysthyroid strabismus?J Am Assoc Pediatr Ophthalmol Strabismus1999; 3: 272–4.
42.
BiglanA.W.Control of eyelid retraction associated with Graves' disease with botulinum A toxin. Ophthalmic Surgery1994; 25: 186–8.
43.
SimonszH.J., VingerlingJ.R.Botulinum toxin as adjunct for refractory compressive optic neuropathy in Graves' disease. Orbit1998; 17: 173–8.
44.
KrassasG.E., DumasA., PontikidesN., KaltsasT.Somatostatin receptor scintigraphy and octreotide treatment in patients with thyroid eye disease. Clin Endocrinol1995; 42: 571–80.
45.
KrassasG.E., KaltsasT., DumasA., PontikidesN., TolisG.Lanreotide in the treatment of patients with thyroid eye disease. Eur J Endocrinol1997; 136: 416–22.
46.
ProphetH., MaticG.B., WinklerR.E.Two cases of refractory endocrine ophthalmopathy successfully treated with extracorporeal immunoadsorption. Ther Apher2001; 5: 142–6.
47.
PrummelM.F., WiersingaW.M.Immunomodulatory treatment of Graves' ophthalmopathy. Thyroid1998; 8: 545–8.
48.
CockerhamK.P., PalC., JaniB., WolterA., KennerdellJ.S.The prevalence and implications of ocular hypertension and glaucoma in thyroid-associated orbitopathy [comment]. Ophthalmology1997; 104: 914–7.
49.
PrummelM.F., WiersingaW.M.Medical management of Graves' ophthalmopathy. Thyroid1995; 5: 231–4.
WeetmanA.P., PooleJ.Failure to find an association of blood group P1 with thyroid-associated ophthalmopathy. Clin Endocrinol1992; 37: 423–5.
52.
VillanuevaR., InzerilloA.M., TomerY.Limited genetic susceptibility to severe Graves' ophthalmopathy: no role for CTLA-4 but evidence for an environmental etiology. Thyroid2000; 10: 791–8.
PrummelM.F., WiersingaW.M.Smoking and risk of Graves' disease [comment]. JAMA1993; 269: 479–82.
59.
KaradimasP., BouzasE.A., MastorakosG.Advice against smoking is not effective in patients with Graves' ophthalmopathy. Acta Medica Austriaca2003; 30: 59–60.
60.
KubotaS., GunjiK., AckrellB.A.The 64-kilodalton eye muscle protein is the flavoprotein subunit of mitochondrial succinate dehydrogenase: the corresponding serum antibodies are good markers of an immune-mediated damage to the eye muscle in patients with Graves' hyperthyroidism. J Clin Endocrinol Metab1998; 83: 443–7.
61.
ZhangZ.G., WallJ.R., BernardN.F.Tissue distribution and quantitation of a gene expressing a 64-kDa antigen associated with thyroid-associated ophthalmopathy. Clin Immunol Immunopathol1996; 80: 236–44.
62.
RossP.V., KoenigR.J., ArscottP.Tissue specificity and serologic reactivity of an autoantigen associated with autoimmune thyroid disease. J Clin Endocrinol Metab1993; 77: 433–8.
63.
GunjiK., SkolnickC., BednarczukT.Eye muscle antibodies in patients with ocular myasthenia gravis: possible mechanism for eye muscle inflammation in acetylcholine-receptor antibody-negative patients. Clin Immunol Immunopathol1998; 87: 276–81.
64.
KhooD.H., HoS.C., SeahL.L.The combination of absent thyroid peroxidase antibodies and high thyroid-stimulating immunoglobulin levels in Graves' disease identifies a group at markedly increased risk of ophthalmopathy. Thyroid1999; 9: 1175–80.
65.
KurokiT., RufJ., WhelanL., MillerA., WallJ.R.Antithyroglobulin monoclonal and autoantibodies cross-react with an orbital connective tissue membrane antigen: a possible mechanism for the association of ophthalmopathy with autoimmune thyroid disorders. Clin Exp Immunol1985; 62: 361–70.
66.
KodamaK., SikorskaH., BaylyR., Bandy-DafoeP., WallJ.R.Use of monoclonal antibodies to investigate a possible role of thyroglobulin in the pathogenesis of Graves' ophthalmopathy. J Clin Endocrinol Metab1984; 59: 67–73.
67.
GunjiK., De BellisA., LiA.W.Cloning and characterization of the novel thyroid and eye muscle shared protein G2s: autoantibodies against G2s are closely associated with ophthalmopathy in patients with Graves' hyperthyroidism. J Clin Endocrinol Metab2000; 85: 1641–7.
68.
De BellisA., BizzarroA., ConteM.Relationship between longitudinal behaviour of some markers of eye autoimmunity and changes in ocular findings in patients with Graves' ophthalmopathy receiving corticosteroid therapy. Clin Endocrinol2003; 59: 388–95.
69.
GerdingM.N., van der MeerJ.W., BroeninkM., BakkerO., WiersingaW.M., PrummelM.F.Association of thyrotrophin receptor antibodies with the clinical features of Graves' ophthalmopathy. Clin Endocrinol2000; 52: 267–71.
70.
CostagliolaS., ManyM.C., DenefJ.F., PohlenzJ., RefetoffS., VassartG.Genetic immunization of outbred mice with thyrotropin receptor cDNA provides a model of Graves' disease. J Clin Invest2000; 105: 803–11.
71.
EliseiR., WeightmanD., Kendall-TaylorP., VassartG., LudgateM.Muscle autoantigens in thyroid associated ophthalmopathy: the limits of molecular genetics. J Endocrinol Invest1993; 16: 533–40.
72.
KosugiS., SugawaH., MoriT.Epitope analysis of the thyrotropin receptor, 1997. Mol Cell Endocrinol1997; 128: 11–8.
73.
CundiffJ.G., KaithamanaS., SeetharamaiahG.S., BakerJ.R.Jr., PrabhakarB.S.Studies using recombinant fragments of human TSH receptor reveal apparent diversity in the binding specificities of antibodies that block TSH binding to its receptor or stimulate thyroid hormone production. J Clin Endocrinol Metab2001; 86: 4254–60.
74.
FelicielloA., PorcelliniA., CiulloI., BonavolontaG., AvvedimentoE.V., FenziG.Expression of thyrotropin-receptor mRNA in healthy and Graves' disease retro-orbital tissue [comment]. Lancet1993; 342: 337–8.
75.
MajorB.J., CuresA., FraumanA.G.The full length and splice variant thyrotropin receptor is expressed exclusively in skeletal muscle of extraocular origin: a link to the pathogenesis of Graves' ophthalmopathy. Biochem Biophys Res Commun1997; 230: 493–6.
76.
LuoG., FanJ.L., SeetharamaiahG.S.Immunization of mice with Yersinia enterocolitica leads to the induction of antithyrotropin receptor antibodies. J Immunol1993; 151: 922–8.
77.
WangP.W., HiromatsuY., LaryeaE., WosuL., HowJ., WallJ.R.Immunologically mediated cytotoxicity against human eye muscle cells in Graves' ophthalmopathy. J Clin Endocrinol Metab1986; 63: 316–22.
78.
KazuoK., FujikadoT., OhmiG., HosohataJ., TanoY.Value of thyroid stimulating antibody in the diagnosis of thyroid associated ophthalmopathy of euthyroid patients. Br J Ophthalmol1997; 81: 1080–3.
79.
BahnR.S.The fibroblast is the target cell in the connective tissue manifestations of Graves' disease. Int Arch Allergy Immunol1995; 106: 213–8.
PaschkeR., MetcalfeA., AlcaldeL., VassartG., WeetmanA., LudgateM.Presence of nonfunctional thyrotropin receptor variant transcripts in retroocular and other tissues [comment]. J Clin Endocrinol Metab1994; 79: 1234–8.
84.
WuS.L., YangC.S., WangH.J., LiaoC.L., ChangT.J., ChangT.C.Demonstration of thyrotropin receptor mRNA in orbital fat and eye muscle tissues from patients with Graves' ophthalmopathy by in situ hybridization. J Endocrinol Invest1999; 22: 289–95.
85.
BellA., GagnonA., GrunderL., ParikhS.J., SmithT.J., SoriskyA.Functional TSH receptor in human abdominal preadipocytes and orbital fibroblasts. Am J Physiol Cell Physiol2000; 279: C335–40.
86.
MurakamiM., KamiyaY., MorimuraT.Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes. Endocrinology2001; 142: 1195–201.
87.
PerrosP., Kendall-TaylorP.Pathogenesis of thyroid-associated ophthalmopathy. Trends Endocrinol Metab1993; 4: 270–5.
88.
WeetmanAR, CohenS., GatterK.C., FellsP., ShineB.Immunohistochemical analysis of the retrobulbar tissues in Graves' ophthalmopathy. Clin Exp Immunol1989; 75: 222–7.
89.
PappaA., CalderV., AjjanR.Analysis of extraocular muscle-infiltrating T cells in thyroid-associated ophthalmopathy (TAO). Clin Exp Immunol1997; 109: 362–9.
90.
PerrosP., Kendall-TaylorP.Biological activity of autoantibodies from patients with thyroid-associated ophthalmopathy: in vitro effects on porcine extraocular myoblasts. Q J Med1992; 84: 691–706.
91.
FarynaM., NaumanJ., GardasA.Measurement of autoantibodies against human eye muscle plasma membranes in Graves' ophthalmopathy. Br Med J Clin Res Ed1985; 290: 191–2.
92.
HiromatsuY., FukazawaH., HowJ., WallJ.R.Antibody-dependent cell-mediated cytotoxicity against human eye muscle cells and orbital fibroblasts in Graves' ophthalmopathy - roles of class II MHC antigen expression and gamma-interferon action of effector and target cells. Clin Exp Immunol1987; 70: 593–603.
93.
BlumerR., LukasJ.R., AignerM., BittnerR., BaumgartnerI., MayrR.Fine structural analysis of extraocular muscle spindles of a two-year-old human infant. Invest Ophthalmol Vis Sci1999; 40: 55–64.
94.
GormanC.Ophthalmopathy of Graves' disease. N Engl J Med1983; 308: 453–4.
95.
PorterJ.D., KhannaS., KaminskiH.J.Extraocular muscle is defined by a fundamentally distinct gene expression profile. Proc Nat Acad Sci USA2001; 98: 12062–7.
96.
WallJ.R., BernardN., BoucherA.Pathogenesis of thyroid-associated ophthalmopathy: an autoimmune disorder of the eye muscle associated with Graves' hyperthyroidism and Hashimoto's thyroiditis [comment]. Clin Immunol Immunopathol1993; 68: 1–8.
97.
BusuttilB.E., FraumanA.G.Extrathyroidal manifestations of Graves' disease: the thyrotropin receptor is expressed in extraocular, but not cardiac, muscle tissues. J Clin Endocrinol Metab2001; 86: 2315–9.
98.
KloproggeS.J., KapsaR., FraumanA.G.The extraocular muscle thyroid stimulating hormone receptor (TSHR) and its relevance to Graves' ophthalmopathy. Proceedings of the Endocrine Society of Australia; Adelaide, Australia, 2002; 62.
99.
AirdR.B.Experimental exophthalmos and associated myopathy induced by the thyrotropic extract. Arch Ophthalmopathy1940; 24: 1167–78.
100.
SmelserG.K.The histology of orbital and other fat tissue deposits in animals with experimentally produced exophthalmos. Am J Pathol1939; 15: 341–55.
101.
DobynsB.M.Studies on exophthalmos produced by thyrotropic hormone II. Changes induced in various tissues and organs (including the orbit) by thyrotropic hormone and their relationship to exophthalmos. Surg Gynecol Obstetrics1946; 82: 609–10.
SmelserG.K.Water and fat content of orbital tissues of guinea pigs with experimental exophthalmos produced by extracts of the anterior pituitary gland. Am J Physiol1943; 140: 308–15.
104.
YamadaM., LiA.W., WestK.A., ChangC.H., WallJ.R.Experimental model for ophthalmopathy in BALB/c and outbred (CD-1) mice genetically immunized with G2s and the thyrotropin receptor. Autoimmunity2002; 35: 403–13.
105.
KrollA.J., KuwabaraT.Dysthyroid ocular myopathy. Anatomy, histology, and electron microscopy. Arch Ophthalmol1966; 76: 244–7.
