Purpose
Serum thyroglobulin levels are often elevated in Graves’ disease (GD) and in most cases decrease during treatment. Its relation to Graves’ orbitopathy (GO) has not been clarified. Previously, ...a risk of GO has been linked to smoking, TSH receptor stimulation, high TSH-receptor antibodies (TRAb), low thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb).
Methods
We examined Tg levels in 30 consecutive patients with GD were given drug therapy (methimazole + thyroxine) for up to 24 months. GO was identified by clinical signs and symptoms. 17 patients had GO, 11 of whom had it at diagnosis while 6 developed GO during treatment. During the study, 5 subjects were referred to radioiodine treatment, 3 to surgery. The remaining 22 subjects (GO
n
= 12, non-GO
n
= 10) completed the drug regimen.
Results
At diagnosis, Tg levels in GO patients (
n
= 11) were higher (84, 30–555 µg/L, median, range) than in non-GO patients (
n
= 19) (38, 3.5–287 µg/L),
p
= 0.042. Adding the 6 subjects who developed eye symptoms during treatment to the GO group (
n
= 17), yielded
p
= 0.001 vs. non-GO (
n
= 13). TRAb tended to be higher, while TPOAb and TgAb tended to be lower in the GO group. For the 22 patients who completed the drug regimen, Tg levels were higher in GO (
n
= 12) vs. non-GO (
n
= 10),
p
= 0.004, whereas TRAb levels did not differ.
Conclusion
The data may suggest that evaluation of thyroglobulin levels in GD could contribute to identify patients at increased risk of developing GO. Possibly, thyroidal release of Tg in GD reflects a disturbance that also impacts retroorbital tissues.
Abstract
Context
Invited update on the management of systemic autoimmune Graves disease (GD) and associated Graves orbitopathy (GO).
Evidence acquisition
Guidelines, pertinent original articles, ...systemic reviews, and meta-analyses.
Evidence synthesis
Thyrotropin receptor antibodies (TSH-R-Abs), foremost the stimulatory TSH-R-Abs, are a specific biomarker for GD. Their measurement assists in the differential diagnosis of hyperthyroidism and offers accurate and rapid diagnosis of GD. Thyroid ultrasound is a sensitive imaging tool for GD. Worldwide, thionamides are the favored treatment (12-18 months) of newly diagnosed GD, with methimazole (MMI) as the preferred drug. Patients with persistently high TSH-R-Abs and/or persistent hyperthyroidism at 18 months, or with a relapse after completing a course of MMI, can opt for a definitive therapy with radioactive iodine (RAI) or total thyroidectomy (TX). Continued long-term, low-dose MMI administration is a valuable and safe alternative. Patient choice, both at initial presentation of GD and at recurrence, should be emphasized. Propylthiouracil is preferred to MMI during the first trimester of pregnancy. TX is best performed by a high-volume thyroid surgeon. RAI should be avoided in GD patients with active GO, especially in smokers. Recently, a promising therapy with an anti-insulin-like growth factor-1 monoclonal antibody for patients with active/severe GO was approved by the Food and Drug Administration. COVID-19 infection is a risk factor for poorly controlled hyperthyroidism, which contributes to the infection–related mortality risk. If GO is not severe, systemic steroid treatment should be postponed during COVID-19 while local treatment and preventive measures are offered.
Conclusions
A clear trend towards serological diagnosis and medical treatment of GD has emerged.
Graves’ Disease Smith, Terry J; Hegedüs, Laszlo
New England journal of medicine/The New England journal of medicine,
10/2016, Letnik:
375, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Graves' disease is an autoimmune disorder in which the thyroid is activated by antibodies to the thyrotropin receptor. The hyperthyroidism that develops is one of many somatic and psychiatric ...manifestations of the disease that can affect the quality and length of life.
Graves’ disease was first recognized in the 19th century as a syndrome comprising an enlarged and overactive thyroid gland, an accelerated heart rate, and ocular abnormalities (Figure 1). Critical for our current understanding of this disease was the discovery of its autoimmune basis, which results from complex interactions between genetic and environmental factors.
1
,
2
Graves’ disease has adverse effects on quality of life,
3
as a consequence of somatic
4
and psychiatric
5
symptoms and an inability to work,
6
and is associated with an increased risk of death.
7
Activating thyrotropin-receptor antibodies induce thyroid hormone overproduction. Many characteristic signs and symptoms of Graves’ disease . . .
Abstract
Context
Serum TSH receptor autoantibody (TSH-R-Ab) is a biomarker of Graves disease (GD). Studies have shown that the levels of this TSH-R-Ab have clinical significance.
Objective
To ...differentiate between thyroidal GD only and Graves orbitopathy (GD + GO).
Design
Controlled, follow-up study.
Setting
Academic tertiary referral center for GD + GO.
Subjects
Sixty patients with GD, GD + GO, and controls.
Intervention
Serial serum dilution analyses with six automated, ELISA, and cell-based assays for TSH-R-Ab.
Main Outcome Measure
Differentiation among GD phenotypes.
Results
All undiluted samples of hyperthyroid-untreated GD patients were positive with the six assays but became negative at dilution 1:9 in four of six assays. In contrast, all undiluted samples of hyperthyroid-untreated GD + GO patients remained positive up to dilution 1:81, P < 0.001. At high dilutions 1:243, 1:729, 1:2187, and 1:6561, the rate of stimulating TSH-R-Ab positivity in the bioassay for GD + GO patients was 75%, 35%, 5%, and 0%, respectively (all P < 0.001). The five ELISA and/or automated assays confirmed this marked difference of anti-TSH-R-Ab detection between GD-only and GD + GO. In comparison, the baseline-undiluted samples of GD vs GD + GO showed an overlap in the ranges of TSH-R-Ab levels. Subsequent to 12-month methimazole treatment, samples from euthyroid GD + GO patients were still TSH-R-Ab positive at the high dilution of 1:243. In contrast, all GD samples were negative already at dilution 1:3. A GD patient with TSH-R-Ab positivity at dilution 1:729 developed de novo GO.
Conclusions
TSH-R-Ab titers, as determined by dilution analysis, significantly differentiate between GD and GD + GO.
We demonstrate, for the first time, that dilution analysis of TSH receptor antibody levels markedly differentiates Graves thyroidal disease only vs Graves thyroidal and orbital disease.
Abstract
Purpose
The purpose of this article is to investigate the characteristics of Th1-cell and Th17-cell lineages for very severe Graves orbitopathy (GO) development.
Methods
Flow cytometry was ...performed with blood samples from GO and Graves disease (GD) patients and healthy controls, to explore effector T-cell phenotypes. Lipidomics was conducted with serum from very severe GO patients before and after glucocorticoid (GC) therapy. Immunohistochemistry and Western blotting were used to examine orbital-infiltrating Th17 cells or in vitro models of Th17 polarization.
Results
In GD, Th1 cells predominated in peripheral effector T-cell subsets, whereas in GO, Th17-cell lineage predominated. In moderate-to-severe GO, Th17.1 cells expressed retinoic acid receptor-related orphan receptor-γt (RORγt) independently and produced interleukin-17A (IL-17A), whereas in very severe GO, Th17.1 cells co-expressed RORγt and Tbet and produced interferon-γ (IFN-γ). Increased IFN-γ–producing Th17.1 cells positively correlated with GO activity and were associated with the development of very severe GO. Additionally, GC therapy inhibited both Th1-cell and Th17-cell lineages and modulated a lipid panel consisting of 79 serum metabolites. However, in GC-resistant, very severe GO, IFN-γ–producing Th17.1 cells remained at a high level, correlating with increased serum triglycerides. Further, retro-orbital tissues from GC-resistant, very severe GO were shown to be infiltrated by CXCR3+ Th17 cells expressing Tbet and STAT4 and rich in triglycerides that promoted Th1 phenotype in Th17 cells in vitro.
Conclusions
Our findings address the importance of Th17.1 cells in GO pathogenesis, possibly promoting our understanding of the association between Th17-cell plasticity and disease severity of GO.
Introduction
Graves’ orbitopathy (GO), thyroid dermopathy (also called pretibial myxedema) and acropachy are the extrathyroidal manifestations of Graves’ disease. They occur in 25, 1.5, and 0.3 % of ...Graves’ patients, respectively. Thus, GO is the main and most common extrathyroidal manifestation. Dermopathy is usually present if the patient is also affected with GO. The very rare acropachy occurs only in patients who also have dermopathy. GO and dermopathy have an autoimmune origin and are probably triggered by autoimmunity to the TSH receptor and, likely, the IGF-1 receptor. Both GO and dermopathy may be mild to severe.
Management
Mild GO usually does not require any treatment except for local measures and preventive actions (especially refraining from smoking). Currently, moderate-to-severe and active GO is best treated by systemic glucocorticoids, but response to treatment is not optimal in many instances, and retreatments and use of other modalities (glucocorticoids, orbital radiotherapy, cyclosporine) and, in the end, rehabilitative surgery are often needed. Dermopathy is usually managed by local glucocorticoid treatment. No specific treatment is available for acropachy.
Perspectives
Novel treatments are presently being investigated for GO, and particular attention is paid to the use of rituximab. It is unknown whether novel treatments for GO might be useful for the other extrathyroidal manifestations. Future novel therapies shown to be beneficial for GO in randomized studies may be empirically used for dermopathy and acropachy.
Graves’ orbitopathy (GO) is the main extrathyroidal manifestation of Graves’ disease (GD). Choice of treatment should be based on the assessment of clinical activity and severity of GO. Early ...referral to specialized centers is fundamental for most patients with GO. Risk factors include smoking, thyroid dysfunction, high serum level of thyrotropin receptor antibodies, radioactive iodine (RAI) treatment, and hypercholesterolemia. In mild and active GO, control of risk factors, local treatments, and selenium (selenium-deficient areas) are usually sufficient; if RAI treatment is selected to manage GD, low-dose oral prednisone prophylaxis is needed, especially if risk factors coexist. For both active moderate-to-severe and sight-threatening GO, antithyroid drugs are preferred when managing Graves’ hyperthyroidism. In moderate-to-severe and active GO i.v. glucocorticoids are more effective and better tolerated than oral glucocorticoids. Based on current evidence and efficacy/safety profile, costs and reimbursement, drug availability, long-term effectiveness, and patient choice after extensive counseling, a combination of i.v. methylprednisolone and mycophenolate sodium is recommended as first-line treatment. A cumulative dose of 4.5 g of i.v. methylprednisolone in 12 weekly infusions is the optimal regimen. Alternatively, higher cumulative doses not exceeding 8 g can be used as monotherapy in most severe cases and constant/inconstant diplopia. Second-line treatments for moderate-to-severe and active GO include (a) the second course of i.v. methylprednisolone (7.5 g) subsequent to careful ophthalmic and biochemical evaluation, (b) oral prednisone/prednisolone combined with either cyclosporine or azathioprine; (c) orbital radiotherapy combined with oral or i.v. glucocorticoids, (d) teprotumumab; (e) rituximab and (f) tocilizumab. Sight-threatening GO is treated with several high single doses of i.v. methylprednisolone per week and, if unresponsive, with urgent orbital decompression. Rehabilitative surgery (orbital decompression, squint, and eyelid surgery) is indicated for inactive residual GO manifestations.
Thyroid eye disease (TED) develops in around 25% of those with Graves' disease (GD). Patients with TED may present late to ophthalmologists, when debilitating orbital inflammatory changes have ...already occurred. The reasons for this are multifactorial, but poor knowledge of TED in GD patients may be contributory. This study aimed to assess the knowledge of TED in those with established TED, GD without orbitopathy, and control subjects.
A validated, anonymized questionnaire, with 20 knowledge-based questions, was prospectively completed by 100 GD patients, 100 TED patients, and 100 age- and sex-matched controls (with no history of thyroid disease or TED) in two tertiary referral thyroid and orbital diseases clinics. Demographic data and details of highest educational level, disease duration, and follow-up were gained. Residence postcode was used to determine Index of Multiple Deprivation (2015) quintile. Knowledge score was established for each of the study groups of interest. Statistical analysis was undertaken with Kruskal-Wallis test, chi-square test, and multivariable logistic regression.
There was no significant difference in median knowledge scores (out of 20) between GD (13.71, range 9-18) and TED (14.25, range 9-18) patients. However, both groups had significantly higher scores than controls (11.53, range 4-16; p < 0.001). Multivariable analysis determined no particular independent factor associated with lower knowledge score. There were a number of important areas in which patient knowledge of TED was poor. While almost all (99% TED, 89% GD) knew that TED involved orbital tissue inflammation, a large proportion (60% TED, 50% GD) were unaware that TED may develop in the absence of hyperthyroidism or did not know that cigarette smoking is associated with more severe TED (21%TED, 33% GD).
TED patients had equivalent levels of TED knowledge compared to GD patients without orbitopathy. While subjects in both disease groups had greater knowledge than controls, each had significant misconceptions regarding aspects of TED diagnosis, management, and treatment. These findings should guide the future provision of patient information for TED, with educational materials being targeted to address existing gaps in knowledge.
Purpose
According to a few recent studies, the clinical phenotype of Graves’ disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter ...and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries.
Materials and methods
We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations.
Results
Eighty selected articles were related to the period before the year 2000, 30 to the years 2000–2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% 95% CI 79–82, mean estimated age of the entire population was 39.8 years 95% CI 38.4–41.1, with no significant differences between pre- and post-2000 groups (
p
> 0.05). The overall estimated prevalence of smokers was 40% 95% CI 33–46, with no significant difference between the two groups (
p
> 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl 95% CI 4.5–4.9 for FT4 and 14.2 pg/ml 95% CI 13.3–15.1 for FT3, as compared to the post-2000 group: 3.9 ng/dl 95% CI 3.6–4.2 for FT4 and 12.1 pg/ml 95% CI 11.0–13.3 for FT3 (all
p
< 0.01). Goiter estimated prevalence was higher in the pre-2000 group, 87% 95% CI 84–90, than in the post-2000 group, 56% 95% CI 45–67. Estimated prevalence for Graves’ Orbitopathy (GO) was 34% 95% CI 27–41 in the pre-2000 group and 25% 95% CI 19–30 in the post-2000 group (
p
= 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (− 0.040 ± 0.008 ng/dl,
p
< 0.0001), FT3 (− 0.316 ± 0.019 pg/ml,
p
< 0.0001), goiter prevalence (− 0.023 ± 0.008%,
p
= 0.006), and goiter size (− 0.560 ± 0.031 ml,
p
< 0.0001).
Conclusions
Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.
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