Progression Of Ophthalmopathy Research Articles

N6-methyladenosine modification of THBS1 induced by affluent WTAP promotes Graves’ ophthalmopathy progression through glycolysis to affect Th17/Treg balance

Graves’ ophthalmopathy (GO) obvious manifestation is the imbalance of Th17/Treg. N6-methyladenosine (m6A) methylation is an important regulator of Th17/Treg balance. However, few reports narrate how m6A regulators mediate the role of genes in GO progression. We explored the m6A modification of THBS1 mediated by WTAP, and the mechanism by which THBS1 regulated glycolysis and Th17/Treg balance. A total of 12 peripheral blood (4 GO samples, 4 GH samples, and 4 health samples) were collected to measure the percentage of Th17/Treg in monocytes by flow cytometry. RNA sequencing (RNA-seq) combined with MeRIP sequencing (MeRIP-seq) was used to screen differentially expressed and methylated genes. MeRIP-qPCR was performed to evaluate the m6A abundance of THBS1 after WTAP silencing. Glycolysis of CD4+ T cells was reflected by the lactate content and glucose uptake. The number of Th17 cells was increased in GO peripheral blood, whereas the Treg cells decreased. RNA-seq acquired 679 differentially expressed genes (308 up-regulated, and 371 down-regulated) in the CD4+ T cells of GO compared to healthy control. MeRIP-seq identified 3277 m6A peaks between the GO group and the healthy control group, corresponding with 2744 genes (1143 hypermethylated and 1601 hypomethylated). Combined analysis of RNA-seq and MeRIP-seq showed 81 hypermethylated and up-regulated genes. Among the six candidate genes in the PI3K-signaling pathway, THBS1 was the most significantly differentially expressed and hypermethylated. THBS1 silencing resulted in decreased lactate content and glucose uptake in CD4+ T cells. WTAP was significantly upregulated in CD4+ T cells of GO, and WTAP silencing significantly reduced m6A abundance and expression of THBS1. Upregulated and hypermethylated THBS1 mediated by WTAP promoted glycolysis of CD4+ T cells, affected Th17/Treg balance, and facilitated GO progression. We provided a novel potential target for GO treatment and revealed the molecular mechanism of WTAP and THBS1 in GO under the m6A perspective.

Селен и нарушения функции щитовидной железы: от патофизиологии к терапевтическим возможностям

The review focuses on the discussion of the role of selenium in the thyroid hormone metabolism and its impact on the risk of thyroid disorders, among which the most common are autoimmune thyroiditis (Hashimoto's disease) and Graves' disease. Selenium, which is a component of selenoproteins, such as glutathione peroxidase and iodothyronine deiodinases, is involved in the thyroid hormone synthesis and regulation and has an antioxidant effect on thyrocytes. Selenium deficiency can contribute to the development of thyroid disorders, aggravating the inflammatory processes and increasing the levels of antibodies against thyroid peroxidase (TPO AB) and thyroglobulin (TG AB). Clinical trials show that selenium supplements can reduce the levels of thyroid autoantibodies in patients with autoimmune thyroiditis, thereby improving the thyroid structure and reducing inflammation. In patients with Graves' disease, selenium supplements demonstrate a positive effect on the ophthalmopathy progression and quality of life. However, the effect of selenium varies depending on the mineral baseline levels, which emphasizes the need for individual approach to treatment. The literature review shows an important role of selenium in maintaining health of the thyroid gland and emphasizes the need for further research aimed to optimize therapy based on the selenium supplementation.

World thyroidology news

The article is to overview papers: Effect of vitamin C on the absorption of levothyroxine in patients with hypothyroidism and gastritis. Management of neonates born to women with Graves’ disease: a cohort study. A prospective, randomized trial of intravenous glucocorticoids therapy with different protocols for patients with Graves’ ophthalmopathy. Glucocorticoid regimens for prevention of Graves’ ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis. Smoking induces overexpression of immediate early genes in active Graves’ ophthalmopathy. Obesity and the risk of papillary thyroid cancer: A pooled analysis of three case-control studies. Differentiation of postpartum Graves’ thyrotoxicosis from postpartum destructive thyrotoxicosis using antithyrotropin receptor antibodies and thyroid blood flow. Follow-up of newborns of mothers with Graves’ disease. Severity of birth defects after propylthiouracil exposure in early pregnancy. The attitude toward hypothyroid- ism during early gestation: time for a change of mind? Effect of iodine restriction on thyroid function in subclinical hypothyroid patients in an iodine-replete area: A long period observa- tion in a large-scale cohort. Subclinical hypothyroidism and risk for incident ischemic stroke among postmenopausal women. Hashimoto’s thyroiditis pathology and risk for thyroid cancer. Anxiety and depression are more prevalent in patients with Graves’ disease than in patients with nodular goitre. The TRHR gene is associated with hypothalamo-pituitary sensitivity to levothyroxine.

Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], p<0.01) in patients with mild to moderate GO. Two studies evaluated low-dose prednisone (0.2-0.3 mg/kg for 4-6 weeks) in patients with mild GO or risk factors, but were limited by not including patients with preexisting GO in the control groups. Therefore, the two low-dose groups were evaluated using indirect comparisons with control groups matched for age and clinical activity score, showing excellent efficacy versus no treatment or placebo (OR 0.20 [CI 0.07-0.60], p=0.004) and no significant difference compared with standard dose (OR 1.7 [CI 0.52-5.52], p=0.47). In patients without preexisting GO, steroid prophylaxis had no beneficial effect (OR 1.87 [CI 0.81-4.3]), though there were insufficient data regarding patients with risk factors for GO development. GC prophylaxis had no impact on hyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

A systematic review and meta-analysis of total thyroidectomy versus bilateral subtotal thyroidectomy for Graves' disease

Our aim was to perform a meta-analysis of high-quality published trials, randomized and observational, comparing total thyroidectomy (TT) and bilateral subtotal thyroidectomy (ST) for Graves' disease. All studies published from 1970 to August 2012 were identified. All randomized controlled trials (RCTs) were included. Selection of high-quality, nonrandomized comparative studies (NRCTs) was based on a validated tool (Methodological Index for Nonrandomized Studies). Recurrent hyperthyroidism during follow-up, progression of ophthalmopathy, postoperative temporary and permanent hypoparathyroidism, and permanent recurrent laryngeal nerve (RLN) palsy were compared using odds ratios (ORs). Twenty-three studies were included (4 RCTs and 19 NRCTs) compromising 3,242 patients (1,665 TT, 1,577 ST). TT was associated with a decrease in recurrent hyperthyroidism (P < .00001; OR, 0.10; 95% confidence interval [CI], 0.06-0.18), but with an increase in both temporary (P < .00001; OR, 2.70; 95% CI, 2.04-3.56) and permanent hypoparathyroidism (P = .005; OR, 2.91; 95% CI, 1.59-5.32). Progression of ophthalmopathy (P = .76; OR, 0.90; 95% CI, 0.48-1.71) and permanent RLN palsy (P = .82; OR, 0.91; 95% CI, 0.41-2.02) were similar. TT offers a better chance of cure of hyperthyroidism than bilateral ST and can be accomplished safely with only a small increase in temporary and permanent hypoparathyroidism.

Eficacia del tratamiento con 131I en la enfermedad de Graves pediátrica

IntroductionRadioiodine is an important therapeutic option in young patients with Grave's disease (GD). In the United States it is a widespread therapy, but in Europe its use in paediatrics is still controversial. AimTo report our experience in radioiodine therapy of paediatric GD patients and analyse its effectiveness and safety. Patients and methodsWe retrospectively studied our paediatric population (<18 years of age) with GD, diagnosed from 1982 to 2012. A curative option was offered to patients who did not respond to anti-thyroid drug (AT) at puberty. We analysed, the patient characteristics, TSH, T4, T3 and thyroid antibodies levels, AT response, remission post I131, side effects, and hypothyroidism rates. ResultsA total of 50 patients were diagnosed with GD from 1982 to 2012. All patients received AT as initial treatment (mean duration: 35.3±25.9 months). Permanent remission was achieved in 46%. Thyroidectomy was performed in 5 patients, and 14 patients received I131 (mean dose: 10.9±1.09 mCi). Remission with I131 was obtained in 100%. The rate of permanent hypothyroidism was 90%. There was no progression of ophthalmopathy or side effects in any patients treated with I131. ConclusionRadioiodine treatment of paediatric GD patients is safe, leads to complete remission at the expense of hypothyroidism, and does not exacerbate ophthalmopathy. It can be considered in patients older than 5 years, who do no not respond to AT or with significant side effects with this medication.

Total thyroidectomy vs bilateral subtotal thyroidectomy in patients with Graves’ diseases: a meta‐analysis of randomized clinical trials

Conducting total thyroidectomy (TT) or subtotal thyroidectomy (ST) in patients with Graves' disease remains controversial. We performed a meta-analysis based on the published randomized controlled trials to evaluate the complications of TT vs ST. We searched multiple electronic databases for prospective, randomized, controlled trials related to safety and effectiveness of TT vs ST. Relative risk (RR) was estimated with 95% confidence interval (CI) based on an intention-to-treat analysis. We considered the following outcomes: recurrent hyperthyroidism, ophthalmopathy progression, temporary and permanent hypoparathyroidism, temporary and permanent recurrent laryngeal nerve palsy (RLNP) and post-operative bleeding. Four trials with 674 patients (342 with TT, 332 with ST) were analysed. Although the overall rates of ophthalmopathy progression were similar between TT and ST (RR 0·92, 95% CI = 0·50-1·71; P = 0·80), TT was associated with a significant reduction in recurrent hyperthyroidism (RR 0·14, 95% CI = 0·05-0·41; P < 0·01). The pooled RR of post-operative bleeding for TT was similar to that for ST (RR 0·32, 95% CI = 0·05-1·96; P = 0·22). However, comparing with ST, the RR of temporary hypoparathyroidism was significantly higher for TT (RR 2·66, 95% CI = 1·89-3·73; P < 0·01). There was no significant difference in permanent hypoparathyroidism (RR 2·30, 95% CI = 0·78-6·76; P = 0·13), temporary (RR 1·08, 95% CI = 0·47-2·48; P = 0·85) and permanent RLNP (RR 1·54, 95% CI = 0·41-5·73; P = 0·52) between the two groups. With regard to ophthalmopathy progression, post-operative bleeding, permanent hypoparathyroidism, temporary and permanent RLNP, TT is consistent with ST in patients with Graves' disease. However, TT is associated with a reduced incidence of recurrent hyperthyroidism and results in an increase in temporary hypoparathyroidism. Therefore, TT should be proposed for the treatment of Graves' disease.

Randomized clinical trial of bilateral subtotal thyroidectomy versus total thyroidectomy for Graves' disease with a 5-year follow-up11

The extent of thyroid resection in Graves' disease remains controversial. The aim of this study was to evaluate long-term results of bilateral subtotal thyroidectomy (BST) compared with total thyroidectomy (TT) in patients with Graves' disease and mild active ophthalmopathy. Participants were assigned randomly to BST or TT, and followed for 5 years after surgery. The primary endpoints of the study were the prevalence of recurrent hyperthyroidism and changes in Graves' ophthalmopathy. Secondary endpoints were postoperative transient and permanent paresis of the recurrent laryngeal nerve, and postoperative hypocalcaemia and hypoparathyroidism. Two hundred patients were included, of whom 191 (BST 95, TT 96) completed the 5-year follow-up. Recurrent hyperthyroidism occurred in nine patients after BST and in none after TT (P = 0·002). Progression of Graves' ophthalmopathy was observed in nine patients after BST compared with seven following TT (P = 0·586). Transient hypoparathyroidism occurred in 13 and 24 patients respectively (P = 0·047). Permanent hypoparathyroidism was diagnosed in no patient after BST and in one after TT (P = 0·318). No differences were noted in transient or permanent recurrent laryngeal nerve injury. TT for Graves' disease prevented recurrent hyperthyroidism but did not prevent the progression of ophthalmopathy compared with BST.

Antithyroid drug regimen for treating Graves' hyperthyroidism

Antithyroid drugs are widely used in the therapy of hyperthyroidism. There are wide variations in the dose, regimen or duration of treatment used by health professionals. To assess the effects of dose, regimen and duration of antithyroid drug therapy for Graves' hyperthyroidism. We searched seven databases and reference lists. Randomised and quasi-randomised trials of antithyroid medication for Graves' hyperthyroidism. Two authors independently extracted data and assessed risk of bias. Pooling of data for primary outcomes, and select exploratory analyses were undertaken. Twenty-six randomised trials involving 3388 participants were included. Overall the quality of trials, as reported, was poor. None of the studies investigated incidence of hypothyroidism, changes in weight, health-related quality of life, ophthalmopathy progression or economic outcomes. Four trials examined the effect of duration of therapy on relapse rates, and when using the titration regimen 12 months was superior to six months, but there was no benefit in extending treatment beyond 18 months. Twelve trials examined the effect of block-replace versus titration block-regimens. The relapse rates were similar in both groups at 51% in the block-replace group and 54% in the titration block-group (OR 0.86, 95% confidence interval (CI) 0.68 to1.08) though adverse effects (rashes (10% versus 6%) and withdrawing due to side effects (16% versus 9%)) were significantly higher in the block-replace group. Three studies considered the addition of thyroxine with continued low dose antithyroid therapy after initial therapy with antithyroid drugs. There was significant heterogeneity between the studies and the difference between the two groups was not significant (OR 0.58, 95% CI 0.05 to 6.21). Four studies considered the addition of thyroxine alone after initial therapy with antithyroid drugs. There was no significant difference in the relapse rates between the groups after 12 months follow-up (OR 1.15, 95% CI 0.79 to 1.67). Two studies considered the addition of immunosuppressive agents. The results which were in favour of the interventions would need to be validated in other populations. The evidence suggests that the optimal duration of antithyroid drug therapy for the titration regimen is 12 to 18 months. The titration (low dose) regimen had fewer adverse effects than the block-replace (high dose) regimen and was no less effective. Continued thyroxine treatment following initial antithyroid therapy does not appear to provide any benefit in terms of recurrence of hyperthyroidism. Immunosuppressive therapies need further evaluation.

Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review*

An association between radioiodine therapy (RAI) for Graves' disease (GD) and the development or worsening of Graves' ophthalmopathy (GO) is widely quoted but there has been no systematic review of the evidence. We undertook a systematic review of randomized controlled trials (RCTs) to assess whether RAI for GD is associated with increased risk of ophthalmopathy compared with antithyroid drugs (ATDs) or surgery. We also assessed the efficacy of glucocorticoid prophylaxis in the prevention of occurrence or progression of ophthalmopathy, when used with RAI. We identified RCTs regardless of language or publication status by searching six databases and trial registries. Dual, blinded data abstraction and quality assessment were undertaken. Random effects meta-analyses were used to combine the study data. Ten RCTs involving 1136 patients permitted 13 comparisons. Two RCTs compared RAI with ATD. Two RCTs compared RAI with thyroidectomy. Four RCTs compared the use of adjunctive ATD with RAI vs. RAI. Five RCTs examined the use of glucocorticoid prophylaxis with RAI. RAI was associated with an increased risk of ophthalmopathy compared with ATD [relative risk (RR) 4.23; 95% confidence interval (CI): 2.04-8.77] but compared with thyroidectomy, there was no statistically significant increased risk (RR 1.59, 95% CI 0.89-2.81). The risk of severe GO was also increased with RAI compared with ATD (RR 4.35; 95% CI 1.28-14.73). Prednisolone prophylaxis for RAI was highly effective in preventing the progression of GO in patients with pre-existing GO (RR 0.03; 95% CI 0.00-0.24). The use of adjunctive ATD with RAI was not associated with any significant benefit on the course of GO. RAI for GD is associated with a small but definite increased risk of development or worsening of Graves' ophthalmopathy compared with ATDs. Steroid prophylaxis is beneficial for patients with pre-existing GO.

Is radioiodine more likely than antithyroid drugs to worsen ophthalmopathy in patients with Graves disease?

This Practice Point commentary discusses the findings and limitations of a systematic review by Acharya et al. that assessed the utility of radioiodine to treat Graves hyperthyroidism. The authors examined 10 randomized controlled trials, and focused on the potential causative relationship between radioiodine and Graves ophthalmopathy. They concluded that the risk of Graves ophthalmopathy following radioiodine therapy is higher than that after treatment with antithyroid drugs (relative risk [RR] 4.23). The risk of severe Graves ophthalmopathy was also found to be increased after treatment with radioiodine (RR 4.35). Glucocorticoid prophylaxis was highly effective in preventing disease progression in patients with pre-existing Graves ophthalmopathy (RR 0.03). Here, I highlight the issues to consider when interpreting and generalizing these results, such as the limitations imposed by the inconsistency of disease classification and description in the various trials. Although this systematic review highlighted the small but real risk of Graves ophthalmopathy progression following radioiodine therapy, it could not provide insight into the extent of this progression or identify which patients are at highest risk and so might benefit most from prophylaxis.

Radioiodine plus prednisone prevented development or progression of ophthalmopathy in patients with Graves hyperthyroidism

Source Citation Bartalena L, Marcocci C, Bogazzi F, et al. Relation between therapy for hyperthyroidism and the course of Graves' ophthalmopathy. N Engl J Med. 1998 Jan 8;338:73-8.

Treatment of Graves' disease and the course of ophthalmopathy

Contradictory results have been obtained with regards to the effect of various treatment modes on the exacerbation of Graves' ophthalmopathy, probably because the number of patients in each study was small and some studies were analyzed only in relation to one type of treatment. To circument these problems, we studied the course of Graves' ophthalmopathy after various modes of therapy for thyrotoxicosis among 537 patients with Graves' disease. A total of 537 patients with Graves' disease were prospectively studied over an 11-year period. Thirty-one patients were lost to follow-up during the first six months after treatment and were excluded from the study. Of those remaining, 426 received one form of treatment, 79 received two kinds of therapy, and one received three kinds of therapy. Thus, surgical treatments numbered 164, radioactive iodine-131 (131I) treatments numbered 241, and medical treatments numbered 182. Ocular signs were considered improved or exacerbated by the following criteria: decrement or increment of the exophthalmos of 2 mm or more, improvement or deterioration of visual acuity, and regression or progression of extraocular muscle involvement causing diplopia. Among patients who did not have infiltrative ophthalmopathy before treatment, there was no difference in the occurrence of posttreatment exophthalmos in the surgically, medically, and 131I-treated patients (7.1%, 6.7%, and 4.9%, respectively). The incidence and the degree of progression of ophthalmopathy in patients who already had exophthalmos before treatment were similar in the medically, surgically, and 131I-treated groups (19.2%, 19.8%, and 22.7%, respectively). Most of the progression occurred in the posttreatment euthyroid stage. The incidence of improvement of ophthalmopathy was also similar (14.1%, 12.6%, and 12.3% in the medically, surgically, and 131I-treated patients). In conclusion, we found no influence of type of therapy for thyrotoxicosis on the clinical course of Graves' ophthalmopathy in this retrospective study of 537 patients.

Treatment of Graves' disease and the course of ophthalmopathy☆

<h3>Purpose</h3> Contradictory results have been obtained with regards to the effect of various treatment modes on the exacerbation of Graves' ophthalmopathy, probably because the number of patients in each study was small and some studies were analyzed only in relation to one type of treatment. To circument these problems, we studied the course of Graves' ophthalmopathy after various modes of therapy for thyrotoxicosis among 537 patients with Graves' disease. <h3>Patients and methods</h3> A total of 537 patients with Graves' disease were prospectively studied over an 11-year period. Thirty-one patients were lost to follow-up during the first six months after treatment and were excluded from the study. Of those remaining, 426 received one form of treatment, 79 received two kinds of therapy, and one received three kinds of therapy. Thus, surgical treatments numbered 164, radioactive iodine-131 (¹³¹I) treatments numbered 241, and medical treatments numbered 182. Ocular signs were considered improved or exacerbated by the following criteria: decrement or increment of the exophthalmos of 2 mm or more, improvement or deterioration of visual acuity, and regression or progression of extraocular muscle involvement causing diplopia. <h3>Results</h3> Among patients who did not have infiltrative ophthalmopathy before treatment, there was no difference in the occurrence of posttreatment exophthalmos in the surgically, medically, and ¹³¹I-treated patients (7.1%, 6.7%, and 4.9%, respectively). The incidence and the degree of progression of ophthalmopathy in patients who already had exophthalmos before treatment were similar in the medically, surgically, and ¹³¹I-treated groups (19.2%, 19.8%, and 22.7%, respectively). Most of the progression occurred in the posttreatment euthyroid stage. The incidence of improvement of ophthalmopathy was also similar (14.1%, 12.6%, and 12.3% in the medically, surgically, and ¹³¹I-treated patients). <h3>Conclusion</h3> In conclusion, we found no influence of type of therapy for thyrotoxicosis on the clinical course of Graves' ophthalmopathy in this retrospective study of 537 patients.

Treatment of Graves' ophthalmopathy with cyclosporin A.

To evaluate the effect of Cyclosporin A in the management of Graves' ophthalmopathy, we treated 13 patients with severe euthyroid endocrine eye disease with the immunosuppressive drug. Follow up consisted of clinical investigation, laboratory evaluation with detailed thyroid function tests and complete ophthalmological assessments including A and B scan ultrasound and computerized tomography (CT) of the orbits. Cyclosporin A given over 4-7 months resulted in improvement of clinical signs and symptoms of the disease due to a positive effect of the drug on soft tissue changes. The more objective methods did not demonstrate any unequivocal change in proptosis, visual acuity, intraocular pressure and thickness of extraocular muscles. Cyclosporin A was not able to stop acute progression of ophthalmopathy in one patient and did not obviate surgical decompression of the orbits in two more patients. There was no measurable effect of treatment on the underlying immunological process with regard to thyroid disease.

Total thyroidectomy in the management of thyrotoxic and euthyroid Graves' disease

Total surgical thyroidectomy can be performed as safely as can subtotal thyroidectomy, as the latter is performed for Graves' disease. The benefits obtained from total surgical thyroidectomy are: (1) elimination of a diseased thyroid; (2) no recurrence of thyroid disease; (3) no initiation of ophthalmopathy when not existing at the time of surgery; (4) cessation in the progression of ophthalmopathy; (5) satisfactory regression of the infiltrative changes of Graves' disease; (6) markedly less amounts of I 131 required to eliminate ectopic, remnant, or microscopic thyroid tissue, when further treatment is indicated in the continued management of stationary ophthalmopathy. The small price paid by the patient for these benefits is the need to take thyroid for life. This is a relatively minor problem when one considers the fact that hypothyroidism is encountered in 35 to 70 per cent of patients treated by subtotal thyroidectomy or I 131 therapy. Because of the difficulty in prognosticating the evolution of eye pathology in Graves' disease, and based on our experience with I 131 and surgical ablation when these two modalities are under consideration in the presence of persistent or progressive ophthalmopathy, we suggest that total surgical thyroidectomy be selected as the treatment of choice as early as possible in the course of the disease.