J Endocrinol Invest (2014) 37:1233–1235 DOI 10.1007/s40618-014-0171-9
OPINION
Graves’‑like orbitopathy: do not forget IgG4‑related disease L. Bartalena · L. Chiovato
Received: 18 August 2014 / Accepted: 21 August 2014 / Published online: 7 September 2014 © Italian Society of Endocrinology (SIE) 2014
Graves’ orbitopathy (GO) affects about 25 % of patients with hyperthyroidism due to Graves’ disease [1], is usually mild and infrequently progressive [2, 3], although moderate-to-severe or (rare) sight-threatening forms do exist and require aggressive treatments [1]. In most cases, the onset of GO is temporally related to the onset of hyperthyroidism, but in some instances the orbital disease may precede or follow the onset of hyperthyroidism by months or years [1]. In addition, it is known that GO may less frequently develop in patients with euthyroid or hypothyroid Hashimoto’s thyroiditis [1]. The diagnosis of GO is simple and straightforward in the typical patient who, in addition to signs and symptoms of hyperthyroidism, has positive TSHreceptor antibody tests, bilateral eye symptoms (lacrimation, grittiness, photophobia, diplopia) and signs (exophthalmos, periorbital soft tissue swelling, ocular dysmotility, rarely visual defects). Diagnosis is confirmed by imaging studies showing enlarged extraocular muscles (with tendon sparing) and/or expansion of the orbital fibroadipose tissue [1]. Diagnostic problems arise particularly in those patients who are not hyperthyroid and have asymmetrical or unilateral orbital involvement. The presence of euthyroid/hypothyroid chronic autoimmune thyroiditis does not guarantee that orbital disease be related to GO; the absence of thyroid
L. Bartalena (*) Endocrine Unit, Department of Clinical and Experimental Medicine, University of Insubria, Ospedale di Circolo, Viale Borri, 57, Varese 21100, Italy e-mail: [email protected] L. Chiovato (*) Fondazione Salvatore Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, University of Pavia, Via S. Maugeri, 10, Pavia 27100, Italy e-mail: [email protected]
ultrasonographic and/or serological evidence of autoimmune thyroid disease makes diagnosis of GO even more uncertain. Thus, if in typical cases imaging is confirmatory, then in doubtful circumstances it is mandatory. Many conditions may cause exophthalmos and/or extraocular muscle enlargement mimicking GO. Table 1 offers a list of these conditions, for some of which etiology is uncertain. IgG4-related disease is a recently described fibroinflammatory multiorgan disorder characterized by tumefactive lesions, lymphoplasmacytic infiltration with abundant IgG4-positive plasma cells, storiform fibrosis and frequently (but not always) elevated serum IgG4 levels (see [4] for an excellent and exhaustive review of this disease). Initially described in the context of autoimmune pancreatitis, IgG4-related disease may indeed affect several extrapancreatic sites, including the thyroid and the orbit. Riedel’s (fibrosclerosing) thyroiditis has been shown immunohistochemically to be comprised within the spectrum of IgG4-related disease [5]. The fibrous variant of Hashimoto’s thyroiditis might also be closely related to IgG4-related disease [6]. Graves’-like orbitopathy was described in a patient with autoimmune pancreatitis and very high serum IgG4 concentrations, in the absence of thyroid autoimmune disease or related thyroid dysfunction [7]. Clinical features were similar to those of moderate-to-severe and active GO. Imaging was characterized by enlarged extraocular muscles (with tendon sparing) and lacrimal gland, and expansion of the adipose tissue; there was an excellent response of orbital changes to intravenous glucocorticoids and orbital radiotherapy [7]. An additional case was described at the Mayo Clinic: the patient had a longlasting diagnosis of “GO”, treated many times with oral glucocorticoids because of repeated recurrences [8]. The patient was eventually submitted to orbital
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Table 1 Main causes of enlarged extraocular muscles and/ or exophthalmos other than Graves’ orbitopathy Orbital pseudotumora Idiopathic myositisa Orbital cellulitisa Orbital lymphoma Orbital meningioma Leukemia Rhabdomyosarcoma Metastases (breast cancer, melanoma, lung cancer, pancreatic cancer, seminoma, carcinoid) Vascular causes (arteriovenous malformations, carotid-cavernous fistula, angioma) Systemic manifestations of amyloidosis, sarcoidosis, vasculitis Wegener’s granulomatosis Eosinophilic granuloma Cysts Cushing’s syndrome IgG4-related ophthalmic disease a
IgG4-related ophthalmic disease should be excluded
J Endocrinol Invest (2014) 37:1233–1235
of the lateral rectus muscle and ocular adnexa in IgG4related ophthalmic disease. Measurement of serum IgG4 concentrations may help, if they are very high as in the case described by Fonte et al. [7], but this is not always the case [4]. Biopsy and histopathological examination are the milestones for a correct diagnosis of IgG4-related ophthalmic disease. This procedure should be particularly considered in patients referred to endocrinologists, ophthalmologists, or thyroid-eye clinics if hyperthyroidism is absent or evidence of thyroid autoimmunity is lacking. In these cases, biopsy is also important to prompt a more complete search for other potential localization of this systemic disease. From a therapeutic standpoint, glucocorticoids, as for GO, are the first-line treatment, but recurrences are very frequent [7, 8]. Rituximab may be a promising treatment [8], as for GO. When fibrotic changes have occurred, responsiveness to medical treatment is obviously low. Acknowledgments This work was partially supported by grants from the Ministry of Education, University and Research (MIUR, Rome, Prin n. 2012Z3F7HE). Conflict of interest None to declare.
decompression, and biopsy of the lateral rectus muscle showed a strong reactivity to IgG and IgG4 (in a ratio of 1:1, indicating a relative preponderance of IgG4); subsequently, flare of orbital disease was successfully treated by rituximab [8]. Tiegs-Heiden et al. [9] recently reviewed the imaging features of 27 patients with biopsyproven IgG4-related disease of the orbit. Extraocular muscles were enlarged in the large majority (89 %) of patients, and the lateral rectus muscle was the most enlarged muscle [9], while in GO involvement of the inferior and medial recti muscles is usually prevalent. As in GO, tendons of the extraocular muscles were spared; disease was bilateral in 88 % of cases [9]. A lacrimal gland enlargement was observed in 70 % of patients, while the orbital fat tissue was involved in 44 % of cases [9]. Most patients (89 %) had sinus disease, and 30 % had an enlargement of the infraorbital nerve [9]. Because the disease may extend beyond the orbit (e.g., involving the trigeminal nerve), recent recommendations for the nomenclature of IgG4-related disease propose the term of IgG4-related ophthalmic disease for this localization of systemic disease [10]. Endocrinologists and ophthalmologists, especially if involved in the management of GO, should be well aware of this emerging and important cause of Graves’-like orbitopathy (or ophthalmopathy), which should be included in the list of non-GO causes of extraocular muscle enlargement and exophthalmos (Table 1). Clinical signs and symptoms may be indistinguishable from those of GO. Imaging may provide some clues, because of prominent involvement
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References 1. Bartalena L, Fatourechi V (2014) Extrathyroidal manifestations of Graves’ disease: a 2014 update. J Endocrinol Invest 37:691–700 2. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L (2013) 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 98:1443–1449 3. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013) Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 36:444–449 4. Stone JH, Zen Y, Deshpande V (2012) IgG4-related disease. N Engl J Med 366:539–551 5. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V (2010) Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthr Care Res (Hoboken) 62:1312–1318 6. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K (2009) Immunohistochemistry of IgG4 can help subclassify Hashimoto’s autoimmune thyroiditis. Pathol Int 59:636–641 7. Fonte R, Pirali B, Caramia V, Dionisio R, Lodigiani S, Sibilla L, Rotondi M, Chiovato L (2011) Graves’-like orbitopathy in a patient with chronic autoimmune pancreatitis. Thyroid 21:1389–1392 8. Castillo F, Garrity JA, Kravitz DJ (2013) Intractable Graves’ ophthalmopathy? JAMA Ophthalmol 131:269–270 9. Tiegs-Heiden CA, Eckel LJ, Hunt CH, Diehn FE, Schwartz KM, Kallmes DF, Salomao DR, Witzig TE, Garrity JA (2014) Immunoglobulin G4-related disease of the orbit: imaging features in 27 patients. Am J Neuroradiol 35:1393–1397 10. Stone JH, Khosroshahi A, Deshpande V, Chan JKC, Heathcote JG, Aalberse R, Atsumi A, Bloch DB, Brugge WR, Carruthers
J Endocrinol Invest (2014) 37:1233–1235 MN, Cheuk W, Cornell L, Fernandez-Del Castillo C, Ferry JA, Forcione D, Kloppel G, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Masaki Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani D, Sato Y, Smyrk T, Stone JR, Takahira M,
1235 Umehara H, Webster G, Yamamoto M, Yi E, Yoshino T, Zamboni G, Zen Y, Chari S (2012) Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthr Rheum 64:3061–3067
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OPINION
Graves’‑like orbitopathy: do not forget IgG4‑related disease L. Bartalena · L. Chiovato
Received: 18 August 2014 / Accepted: 21 August 2014 / Published online: 7 September 2014 © Italian Society of Endocrinology (SIE) 2014
Graves’ orbitopathy (GO) affects about 25 % of patients with hyperthyroidism due to Graves’ disease [1], is usually mild and infrequently progressive [2, 3], although moderate-to-severe or (rare) sight-threatening forms do exist and require aggressive treatments [1]. In most cases, the onset of GO is temporally related to the onset of hyperthyroidism, but in some instances the orbital disease may precede or follow the onset of hyperthyroidism by months or years [1]. In addition, it is known that GO may less frequently develop in patients with euthyroid or hypothyroid Hashimoto’s thyroiditis [1]. The diagnosis of GO is simple and straightforward in the typical patient who, in addition to signs and symptoms of hyperthyroidism, has positive TSHreceptor antibody tests, bilateral eye symptoms (lacrimation, grittiness, photophobia, diplopia) and signs (exophthalmos, periorbital soft tissue swelling, ocular dysmotility, rarely visual defects). Diagnosis is confirmed by imaging studies showing enlarged extraocular muscles (with tendon sparing) and/or expansion of the orbital fibroadipose tissue [1]. Diagnostic problems arise particularly in those patients who are not hyperthyroid and have asymmetrical or unilateral orbital involvement. The presence of euthyroid/hypothyroid chronic autoimmune thyroiditis does not guarantee that orbital disease be related to GO; the absence of thyroid
L. Bartalena (*) Endocrine Unit, Department of Clinical and Experimental Medicine, University of Insubria, Ospedale di Circolo, Viale Borri, 57, Varese 21100, Italy e-mail: [email protected] L. Chiovato (*) Fondazione Salvatore Maugeri IRCCS, Unit of Internal Medicine and Endocrinology, University of Pavia, Via S. Maugeri, 10, Pavia 27100, Italy e-mail: [email protected]
ultrasonographic and/or serological evidence of autoimmune thyroid disease makes diagnosis of GO even more uncertain. Thus, if in typical cases imaging is confirmatory, then in doubtful circumstances it is mandatory. Many conditions may cause exophthalmos and/or extraocular muscle enlargement mimicking GO. Table 1 offers a list of these conditions, for some of which etiology is uncertain. IgG4-related disease is a recently described fibroinflammatory multiorgan disorder characterized by tumefactive lesions, lymphoplasmacytic infiltration with abundant IgG4-positive plasma cells, storiform fibrosis and frequently (but not always) elevated serum IgG4 levels (see [4] for an excellent and exhaustive review of this disease). Initially described in the context of autoimmune pancreatitis, IgG4-related disease may indeed affect several extrapancreatic sites, including the thyroid and the orbit. Riedel’s (fibrosclerosing) thyroiditis has been shown immunohistochemically to be comprised within the spectrum of IgG4-related disease [5]. The fibrous variant of Hashimoto’s thyroiditis might also be closely related to IgG4-related disease [6]. Graves’-like orbitopathy was described in a patient with autoimmune pancreatitis and very high serum IgG4 concentrations, in the absence of thyroid autoimmune disease or related thyroid dysfunction [7]. Clinical features were similar to those of moderate-to-severe and active GO. Imaging was characterized by enlarged extraocular muscles (with tendon sparing) and lacrimal gland, and expansion of the adipose tissue; there was an excellent response of orbital changes to intravenous glucocorticoids and orbital radiotherapy [7]. An additional case was described at the Mayo Clinic: the patient had a longlasting diagnosis of “GO”, treated many times with oral glucocorticoids because of repeated recurrences [8]. The patient was eventually submitted to orbital
13
1234
Table 1 Main causes of enlarged extraocular muscles and/ or exophthalmos other than Graves’ orbitopathy Orbital pseudotumora Idiopathic myositisa Orbital cellulitisa Orbital lymphoma Orbital meningioma Leukemia Rhabdomyosarcoma Metastases (breast cancer, melanoma, lung cancer, pancreatic cancer, seminoma, carcinoid) Vascular causes (arteriovenous malformations, carotid-cavernous fistula, angioma) Systemic manifestations of amyloidosis, sarcoidosis, vasculitis Wegener’s granulomatosis Eosinophilic granuloma Cysts Cushing’s syndrome IgG4-related ophthalmic disease a
IgG4-related ophthalmic disease should be excluded
J Endocrinol Invest (2014) 37:1233–1235
of the lateral rectus muscle and ocular adnexa in IgG4related ophthalmic disease. Measurement of serum IgG4 concentrations may help, if they are very high as in the case described by Fonte et al. [7], but this is not always the case [4]. Biopsy and histopathological examination are the milestones for a correct diagnosis of IgG4-related ophthalmic disease. This procedure should be particularly considered in patients referred to endocrinologists, ophthalmologists, or thyroid-eye clinics if hyperthyroidism is absent or evidence of thyroid autoimmunity is lacking. In these cases, biopsy is also important to prompt a more complete search for other potential localization of this systemic disease. From a therapeutic standpoint, glucocorticoids, as for GO, are the first-line treatment, but recurrences are very frequent [7, 8]. Rituximab may be a promising treatment [8], as for GO. When fibrotic changes have occurred, responsiveness to medical treatment is obviously low. Acknowledgments This work was partially supported by grants from the Ministry of Education, University and Research (MIUR, Rome, Prin n. 2012Z3F7HE). Conflict of interest None to declare.
decompression, and biopsy of the lateral rectus muscle showed a strong reactivity to IgG and IgG4 (in a ratio of 1:1, indicating a relative preponderance of IgG4); subsequently, flare of orbital disease was successfully treated by rituximab [8]. Tiegs-Heiden et al. [9] recently reviewed the imaging features of 27 patients with biopsyproven IgG4-related disease of the orbit. Extraocular muscles were enlarged in the large majority (89 %) of patients, and the lateral rectus muscle was the most enlarged muscle [9], while in GO involvement of the inferior and medial recti muscles is usually prevalent. As in GO, tendons of the extraocular muscles were spared; disease was bilateral in 88 % of cases [9]. A lacrimal gland enlargement was observed in 70 % of patients, while the orbital fat tissue was involved in 44 % of cases [9]. Most patients (89 %) had sinus disease, and 30 % had an enlargement of the infraorbital nerve [9]. Because the disease may extend beyond the orbit (e.g., involving the trigeminal nerve), recent recommendations for the nomenclature of IgG4-related disease propose the term of IgG4-related ophthalmic disease for this localization of systemic disease [10]. Endocrinologists and ophthalmologists, especially if involved in the management of GO, should be well aware of this emerging and important cause of Graves’-like orbitopathy (or ophthalmopathy), which should be included in the list of non-GO causes of extraocular muscle enlargement and exophthalmos (Table 1). Clinical signs and symptoms may be indistinguishable from those of GO. Imaging may provide some clues, because of prominent involvement
13
References 1. Bartalena L, Fatourechi V (2014) Extrathyroidal manifestations of Graves’ disease: a 2014 update. J Endocrinol Invest 37:691–700 2. Tanda ML, Piantanida E, Liparulo L, Veronesi G, Lai A, Sassi L, Pariani N, Gallo D, Azzolini C, Ferrario M, Bartalena L (2013) 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 98:1443–1449 3. Piantanida E, Tanda ML, Lai A, Sassi L, Bartalena L (2013) Prevalence and natural history of Graves’ orbitopathy in the XXI century. J Endocrinol Invest 36:444–449 4. Stone JH, Zen Y, Deshpande V (2012) IgG4-related disease. N Engl J Med 366:539–551 5. Dahlgren M, Khosroshahi A, Nielsen GP, Deshpande V (2010) Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthr Care Res (Hoboken) 62:1312–1318 6. Li Y, Bai Y, Liu Z, Ozaki T, Taniguchi E, Mori I, Nagayama K, Nakamura H, Kakudo K (2009) Immunohistochemistry of IgG4 can help subclassify Hashimoto’s autoimmune thyroiditis. Pathol Int 59:636–641 7. Fonte R, Pirali B, Caramia V, Dionisio R, Lodigiani S, Sibilla L, Rotondi M, Chiovato L (2011) Graves’-like orbitopathy in a patient with chronic autoimmune pancreatitis. Thyroid 21:1389–1392 8. Castillo F, Garrity JA, Kravitz DJ (2013) Intractable Graves’ ophthalmopathy? JAMA Ophthalmol 131:269–270 9. Tiegs-Heiden CA, Eckel LJ, Hunt CH, Diehn FE, Schwartz KM, Kallmes DF, Salomao DR, Witzig TE, Garrity JA (2014) Immunoglobulin G4-related disease of the orbit: imaging features in 27 patients. Am J Neuroradiol 35:1393–1397 10. Stone JH, Khosroshahi A, Deshpande V, Chan JKC, Heathcote JG, Aalberse R, Atsumi A, Bloch DB, Brugge WR, Carruthers
J Endocrinol Invest (2014) 37:1233–1235 MN, Cheuk W, Cornell L, Fernandez-Del Castillo C, Ferry JA, Forcione D, Kloppel G, Hamilos DL, Kamisawa T, Kasashima S, Kawa S, Kawano M, Masaki Y, Notohara K, Okazaki K, Ryu JK, Saeki T, Sahani D, Sato Y, Smyrk T, Stone JR, Takahira M,
1235 Umehara H, Webster G, Yamamoto M, Yi E, Yoshino T, Zamboni G, Zen Y, Chari S (2012) Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthr Rheum 64:3061–3067
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