Does early administration of thyroxine reduce the development of Graves' ophthalmopathy after radioiodine treatment?
Abstract
Tallstedt L, Lundell G, Blomgren H, Bring J. Does early administration of thyroxine reduce the development of Graves' ophthalmopathy after radioiodine treatment? Eur J Endocrinol 1994:130: 494–7. ISSN 0804–4643 The roles of thyroid hormones and thryotropin (TSH) in the development of Graves' ophthalmopathy are not clear. Some studies suggest a protective effect of thyroid hormones on experimental exophthalmos and an adverse effect of increased TSH levels. In September 1988 we introduced early thyroxine (T 4) administration after 131 I therapy for hyperthyroidism caused by Graves' disease. We carried out a retrospective study of records from all patients with this disease treated with 131 I for 4 years. During the first 2 years 248 patients were treated (group A). They received T 4 when the serum concentration of TSH and/or T 4 indicated hypothyroidism. During the next 2 years 244 patients were treated (group B). They were all given 0.05 mg of T 4 daily, starting 2 weeks after therapy, and 0.1 mg after a further 2 weeks. With a follow-up of 18 months, 45 patients (18%) in group A and 27 patients (11%) in group B developed or deteriorated in an already present ophthalmopathy (p = 0.03, relative risk = 1.64, 95% confidence interval = 1.05–2.55). Twenty-six patients in group A required specific therapy for the ophthalmopathy (e.g. antithyroid drugs, steroids, etc.) compared to 11 patients in group B (p = 0.02, relative risk = 2.33; 95% confidence interval = 1.18–4.60). Our results suggest that early administration of T 4 after 131 I therapy reduces the occurrence of Graves' ophthalmopathy. L Tallstedt, Department of Ophthalmology, Huddinge University Hospital, S-146 81 Huddinge, Sweden
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Identified risk factors for GO include RAI therapy for hyperthyroidism, untreated hyperthyroidism, smoking, high serum pretreatment TRAb levels, and any delay in treating hypothyroidism after therapy for hyperthyroidism.
“for GO are listed in Table 15, and the most pertinent ones to this discussion are RAI therapy for hyperthyroidism (531,532), untreated hyperthyroidism, smoking, high serum pretreatment TRAb levels (normal <1.75 IU/L, high risk for progression if >8.8 IU/L) (533), and any delay in treating hypothyroidism after therapy for hyperthyroidism (106,534).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [534]
Two cohort studies in which patients received levothyroxine therapy early after RAI with the specific intent of preventing hypothyroidism noted that deterioration of GO rarely occurred (0%-2%).
“Subsequently, two cohort studies in which patients received levothyroxine therapy early after RAI with the specific intent of preventing hypothyroidism noted that deterioration of GO rarely occurred (0%-2%) (534,536).”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [534]
High pretreatment levels of T3 and T4 were each reported to have a predictive role in GO, but these conclusions were not validated by subsequent studies.
“High pretreatment levels of T 3 and T 4 were each reported to have a predictive role in GO, but these conclusions were not validated by subsequent studies (69,106,532,534), suggesting the possibility of higher TRAb values measured on less sensitive assays early-on being partly responsible for this variation.”
From 2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis (2016) · cites this paper as [534]
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“Subsequently, two cohort studies in which patients received levothyroxine therapy early after RAI with the specific intent of preventing hypothyroidism noted that deterioration of GO rarely occurred (0%–2%) (534,536).”
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“It was later demonstrated in a retrospective analysis that early administration of L-thyroxine reduced the occurrence of TAO (8).”
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“One group studied the early initiation of levothyroxine (at 2 week after the treatment) to avoid hypothyroidism, comparing GO outcome in that group with their historical cohort of patients who did not receive levothroxine until they were documented to be hypothyroid (permissive hypothyroidism) (38).”
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“…therapy has been identified as a potential contributor to GO, it has been suggested that the initiation of levothyroxine (LT4) replacement therapy should begin at a low dose as early as 2 weeks after RAI treatment, with frequent monitoring and dose adjustment as needed to maintain euthyroidism (5).”
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“Of course, this treatment has a long history, and there are both positive and negative data already published on the utility of thyroid ablation (12-14).”
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BackgroundThyroid-associated ophthalmopathy: pathogenesis and clinical management
Perros, P., & Kendall‐Taylor, P. (1995) · Baillière s Clinical Endocrinology and Metabolism · doi:10.1016/s0950-351x(95)80867-1 · Cited by 50 · see citing works
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“Early administration of levothyroxine after RAI therapy reduces the occurrence of GO [20].”
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Wiersinga, W. M., & Prummel, M. F. (2000) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/s0889-8529(05)70133-x · Cited by 49 · see citing works
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“Factors that have been known to confer risk for GO activation are elevated serum TRAb levels (12,21,22), cigarette smoking (23), severe hypothyroidism after RAI (4), the degree of T3 levels at diagnosis (24), and pre-existing active GO (25).”
Relationship between management of hyperthyroidism and course of the ophthalmopathy
Bartalena, L., Tanda, M. L., Piantanida, E., Lai, A., & Pinchera, A. (2004) · Journal of Endocrinological Investigation · doi:10.1007/bf03345279 · Cited by 41 · see citing works
Total thyroid ablation in Graves’ orbitopathy
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“Thus, they concluded that worsening of GO after radioiodine was due to hypothyroidism [54].”
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“Sub-sequently, Tallstedt et al. (25), in a retrospective analysis, have shown that administration of levothyroxine early after 131I therapy may protect against exacerbation of oph-thalmopathy, because levothyroxine will decrease any rise in serum TSH, restraining a possible worsening of oph-thalmopathy associated with…”
Smoking Induces Overexpression of Immediate Early Genes in Active Graves' Ophthalmopathy
Planck, T., Shahida, B., Parikh, H. M., Ström, K., Åsman, P., Brorson, H., Hallengren, B., & Lantz, M. (2014) · Thyroid · doi:10.1089/thy.2014.0153 · Cited by 37 · see citing works
“Other GO-associated risk factors include iatrogenic hypothyroidism (7), treatment with radioiodine (6,8,9), and treatment with thiazolidinediones (10,11), among others.”
Treating the thyroid in the presence of Graves’ ophthalmopathy
Hegedűs, L. D., Bonnema, S. J., Smith, T. J., & Brix, T. H. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.09.005 · Cited by 37 · see citing works
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The relation of Graves' ophthalmopathy to circulating thyroid hormone status
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“28 29 Thus, strict normalisation of thyroid function may be beneficial in lessening the severity of ophthalmopathy.”
BackgroundRadioiodine Therapy and Graves' Ophthalmopathy
Sisson, J. C., Schipper, M. J., Nelson, C. C., Freitas, J. E., & Frueh, B. R. (2008) · Journal of Nuclear Medicine · doi:10.2967/jnumed.107.049437 · Cited by 33 · see citing works
“In a retrospective evaluation (20) and a prospective study (3), prolonged hypothyroidism was significantly associated with progressive ocular changes; these reports led to preventive or prompt treatment of hypothyroidism by others (2,4,6).”
BackgroundGraves Orbitopathy: Update on Diagnosis and Therapy
Melcescu, E., Horton, W. B., Kim, D., Vijayakumar, V., Corbett, J. J., Crowder, K. W., Pitman, K. T., Uwaifo, G. I., & Koch, C. A. (2014) · Southern Medical Journal · doi:10.1097/smj.0000000000000038 · Cited by 32 · see citing works
“Patients with euthyroid function seem to have a mild disease course.(16,20,22,23) IncreasedTSH-R activation (by thyroidstimulating immunoglobulin [TSI] in hyperthyroidism and TSH in hypothyroidism) leads to an increased expression and release of antigens, followedby an autoimmune reaction directed against them in the…”
BackgroundAblative or non-ablative therapy for Graves’ hyperthyroidism in patients with ophthalmopathy?
Marcocci, C., Bartalena, L., & Pinchera, A. (1998) · Journal of Endocrinological Investigation · doi:10.1007/bf03347329 · Cited by 31 · see citing works
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“The course of GO after RIT remains controversial.[3,13,24-28] The initial prevalence of GO was low in our population (16.”
BackgroundRadioiodine treatment of hyperthyroidism. Success rate and influence of thyrostatic medication
Ghadban, W. K., Zirie, M. A., Al-Khateeb, D. A., Jayyousi, A., Mobayed, H., & El-Aloosy, A. S. (2003) · Saudi Medical Journal · doi:10.15537/1658-3175.2007 · Cited by 21 · see citing works
(131)I and thyroid-associated ophthalmopathy
ÅK, R., Nygaard, B., & Feldt‐Rasmussen, U. (2000) · European Journal of Endocrinology · doi:10.1530/eje.0.1430155 · Cited by 21 · see citing works
“However, in a retrospective analysis early administration of thyroxine was shown to reduce the frequency of development or deterioration of TAO ( 13 ).”
BackgroundAcute pre‐tibial myxoedema following radioiodine therapy for thyrotoxic Graves' disease
Harvey, R., Metcalfe, R. A., Morteo, C., Furmaniak, W., Weetman, A. P., & Bevan, J. S. (1995) · Clinical Endocrinology · doi:10.1111/j.1365-2265.1995.tb02695.x · Cited by 20 · see citing works
Treatment strategies for Graves’ ophthalmopathy: a network meta-analysis
Zhou, X., Zhou, D., Wang, J., & Chen, G. (2019) · British Journal of Ophthalmology · doi:10.1136/bjophthalmol-2018-313697 · Cited by 20 · see citing works
Razvi, S., Basu, A., McIntyre, E. A., Wahid, S. T., Bartholomew, P. H., & Weaver, J. U. (2004) · Nuclear Medicine Communications · doi:10.1097/01.mnm.0000130242.29692.b2 · Cited by 19 · see citing works
Lazarus, J. H., & Marinò, M. (2010) · KARGER eBooks · doi:10.1159/000320425 · Cited by 19 · see citing works
Eckstein, A. K., & Esser, J. (2003) · Der Ophthalmologe · doi:10.1007/s00347-003-0873-4 · Cited by 18 · see citing works
Postradioiodine Graves' management: The PRAGMA study
Perros, P., Basu, A., Boelaert, K., Dayan, C., Vaidya, B., Williams, G. R., Lazarus, J. H., Hickey, J., Drake, W. M., Crown, A., et al. (2022) · Clinical Endocrinology · doi:10.1111/cen.14719 · Cited by 16 · see citing works
“Strategies used by clinicians to bridge the transition from hyperthyroidism to euthyroidism on stable L‐T4 therapy following RI include a short course of antithyroid drugs (ATDs) alone, the combination of ATDs with L‐T4 known as “block and replace” (B&R), or watchful monitoring with the introduction of L‐T4 when neede…”
MethodInfluentialTreatment options for Graves' orbitopathy
Marcocci, C., Altea, M. A., & Leo, M. (2012) · Expert Opinion on Pharmacotherapy · doi:10.1517/14656566.2012.668529 · Cited by 16 · see citing works
Treatment of Hyperthyroidism in Graves' Disease Complicated by Thyroid Eye Disease
Bartalena, L., & Smith, T. J. (2025) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaf009 · Cited by 21 · see citing works
Determinants of Extraocular Muscle Volume in Patients with Graves' Disease
El-Kaissi, S., & Wall, J. R. (2012) · Journal of Thyroid Research · doi:10.1155/2012/368536 · Cited by 15 · see citing works
Tay, W. L., Chng, C. L., Tien, C. S., Loke, K., Lam, W. W.-C., Fook-Chong, S. M. C., & Tong, A. K. T. (2019) · Annals of the Academy of Medicine Singapore · doi:10.47102/annals-acadmedsg.v48n6p181 · Cited by 14 · see citing works
Thyroid eye disease: current and potential medical management
Pouso-Diz, J. M., Abalo-Lojo, J. M., & González, F. (2020) · International Ophthalmology · doi:10.1007/s10792-019-01258-7 · Cited by 13 · see citing works
Gupta, M. K., Perl, J., Beham, R., Sheeler, L. R., Foster, J. A., Gliga, M., McBride, N., Faiman, M. R., MEHTA, A., Dattatreya, R., et al. (2001) · Thyroid · doi:10.1089/105072501753211037 · Cited by 13 · see citing works
“The other factor appearing to influence the outcome of GO relates to the promptness of correction of hypothyroidism resulting from 131 I therapy (19,35).”
Leray, B., Imbert, P., Thouvenin, D., Boutault, F., & Caron, P. J. (2013) · Journal Français d Ophtalmologie · doi:10.1016/j.jfo.2013.07.004 · Cited by 9 · see citing works
Galofré, J. C., Duntas, L. H., Premawardhana, L. D. K. E., & Davies, T. F. (2012) · Journal of Thyroid Research · doi:10.1155/2012/809231 · Cited by 12 · see citing works
El-Kaissi, S., Bowden, J., Henry, M. J., Yeo, M., Champion, B. L., Brotchie, P., Nicholson, G. C., & Wall, J. R. (2010) · International Ophthalmology · doi:10.1007/s10792-010-9368-x · Cited by 12 · see citing works
“The development or exacerbation of TAO postRAI may be related to the presence of other risk factors such as pre-existing eye disease [3], tobacco smoking [18], high pre-treatment serum T3 [2] and TSH-R antibody levels [19, 20], multiple doses of RAI [21], and high serum TSH or hypothyroidism post-RAI [15, 19, 22].”
BackgroundMEDICAL TREATMENT OF GRAVES' OPHTHALMOPATHY
Fatourechi, V. (2000) · Ophthalmology Clinics of North America · doi:10.1016/s0896-1549(05)70225-x · Cited by 12 · see citing works
Antithyroid Drugs: Their Mechanism of Action and Clinical Use
Sheikh, M. E., & McGregor, A. (1997) · Handbook of experimental pharmacology · doi:10.1007/978-3-642-60709-7_8 · Cited by 11 · see citing works
Eckstein, A. K., & Esser, J. (2010) · Der Internist · doi:10.1007/s00108-009-2497-5 · Cited by 11 · see citing works
Gibb, F. W., Zammitt, N. N., Beckett, G. J., & Strachan, M. W. J. (2013) · PubMed · doi:10.3275/8949 · Cited by 12 · see citing works
Orbital inflammatory disorders: new knowledge, future challenges
Kahana, A. (2021) · Current Opinion in Ophthalmology · doi:10.1097/icu.0000000000000743 · Cited by 10 · see citing works
“Smokers with TED are at higher risk of developing moderate-to-severe orbitopathy, may be less responsive to treatment, have higher risk for reactivation after the quiescent phase, and have more aggressive disease progression following RAI [58,103–106].”
BackgroundInfluentialEffect of Addition of Thyroxine in the Treatment of Graves’ Disease: A Systematic Review
Li, J., Bai, L., Wei, F., Wei, M., Xiao, Y., Yan, W., & Wei, J. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.560157 · Cited by 11 · see citing works
“retrospectively analyzed the clinical data of 492 patients who received RAI treatment, divided in 2 groups (41).”
MethodLane, C. (2006) · Eye · doi:10.1038/sj.eye.6702386 · Cited by 10 · see citing works
Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy
(1998) · American Journal of Ophthalmology · doi:10.1016/s0002-9394(99)80222-0 · Cited by 10 · see citing works
“At base line Hyperthyroid Euthyroid Hypothyroid 21 (14) 128 (85) 1 (1) — — — 14 (10) 130 (90) 1 (1) — — — 22 (15) 125 (84) 1 (1) — — — Months 1–3 Hyperthyroid Euthyroid Hypothyroid 12 (8) 115 (77) 23 (15) 1 (8) 13 (11) 2 (9) 10 (7) 109 (75) 26 (18) 0 0 0 9 (6) 132 (89) 7 (5) 0 1 (1) 0 Months 4–6 Hyperthyroid Euthyroid…”
Ladsous, M., Marks, C., Smirnov, V. M., & Guerreschi, P. (2022) · Elsevier eBooks · doi:10.1016/b978-2-294-77583-3.00014-9 · Cited by 9 · see citing works
- Authors
- Tallstedt, L., Lundell, G., Blomgren, H., & Bring, J.
- Affiliations
- Karolinska University Hospital (SE)
- Uppsala University (SE)
- Corresponding author
- Tallstedt, Leif
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 1994-05
- Volume
- 130
- Issue
- 5
- Pages
- 494-497
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2153640804
- Cited by
- 171
- References
- 0
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 5 · 2021: 3 · 2020: 5 · 2019: 8 · 2018: 4 · 2017: 1 · 2016: 11 · 2015: 7 · 2014: 6 · 2013: 8 · 2012: 13
- FWCI
- 2.44
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Ophthalmology and Eye Disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
- Keywords
- Graves' ophthalmopathy, thyroxine, radioiodine therapy, iodine-131, Graves' disease, hyperthyroidism, thyroid hormones, proptosis, prophylaxis, hypothyroidism
- MeSH terms
- Drug Administration Schedule, Exophthalmos, Female, Graves Disease, Humans, Hyperthyroidism, Iodine Radioisotopes, Male, Middle Aged, Prognosis, Retrospective Studies, Risk Factors, Thyroxine, Time Factors, Confidence Intervals
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