Background Thyrotoxicosis has multiple etiologies, manifestations, and potential therapies. Appropriate treatment requires an accurate diagnosis and is influenced by coexisting medical conditions and patient preference. This document describes evidence-based clinical guidelines for the management of thyrotoxicosis that would be useful to generalist and subspecialty physicians and others providing care for patients with this condition. Methods The American Thyroid Association (ATA) previously cosponsored guidelines for the management of thyrotoxicosis that were published in 2011. Considerable new literature has been published since then, and the ATA felt updated evidence-based guidelines were needed. The association assembled a task force of expert clinicians who authored this report. They examined relevant literature using a systematic PubMed search supplemented with additional published materials. An evidence-based medicine approach that incorporated the knowledge and experience of the panel was used to update the 2011 text and recommendations. The strength of the recommendations and the quality of evidence supporting them were rated according to the approach recommended by the Grading of Recommendations, Assessment, Development, and Evaluation Group. Results Clinical topics addressed include the initial evaluation and management of thyrotoxicosis; management of Graves' hyperthyroidism using radioactive iodine, antithyroid drugs, or surgery; management of toxic multinodular goiter or toxic adenoma using radioactive iodine or surgery; Graves' disease in children, adolescents, or pregnant patients; subclinical hyperthyroidism; hyperthyroidism in patients with Graves' orbitopathy; and management of other miscellaneous causes of thyrotoxicosis. New paradigms since publication of the 2011 guidelines are presented for the evaluation of the etiology of thyrotoxicosis, the management of Graves' hyperthyroidism with antithyroid drugs, the management of pregnant hyperthyroid patients, and the preparation of patients for thyroid surgery. The sections on less common causes of thyrotoxicosis have been expanded. Conclusions One hundred twenty-four evidence-based recommendations were developed to aid in the care of patients with thyrotoxicosis and to share what the task force believes is current, rational, and optimal medical practice.

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2016 American Thyroid Association Guidelines for Diagnosis and Management of Hyperthyroidism and Other Causes of Thyrotoxicosis

http://medclerk.weebly.com/uploads/6/8/9/5/6895084/aace_hyper_thyroidism.pdf

Hyperthyroidism and Other Causes of Thyrotoxicosis: Management Guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.

/pdf/vegf-a-stimulates-lymphangiogenesis-and-hemangiogenesis-in-1ekoeyvhov.pdf

VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment

OBJECTIVE
Approximately 35% of patients with Graves' ophthalmopathy do not respond to immunosuppressive treatment. A possible explanation for this finding is that only patients with active ophthalmopathy respond to immunosuppressive treatment, whereas patients with fibrotic end stage disease do not. To distinguish between these two groups and to predict the outcome of immunosuppressive treatment, we developed a clinical activity score (CAS) based on four of the five classical signs of inflammation and tested its efficacy in a double-blind, prospective study.

DESIGN, PATIENTS AND MEASUREMENTS
The CAS was determined by an ophthalmologist before, on the day of, and after the start of either oral prednisone or retrobulbar irradiation in 43 patients with moderate to severe Graves' ophthalmopathy. The therapeutic outcome was determined by a second ophthalmologist unaware of the CAS stores given. Success of treatment was defined as an improvement in NOSPECS class or grade.

RESULTS
Responders (22) and non-responders (21) did not differ in age, sex, duration or severity of their Graves' ophthalmopathy. The pretreatment CAS, however, was significantly higher in responders than in non-responders. Twelve of 22 responders and three of 21 non-responders had a CAS  ≥  4 (80% vs 36%; P  <  0.01). Using this CAS cut-off point, the accuracy of CAS in predicting the therapeutic outcome was: specificity 86%, sensitivity 55%, positive predictive value 80%, negative predictive value 64%. Patients with a CAS  ≥  4 had a similar duration of Graves' ophthalmopathy as patients with a CAS  <  4.

CONCLUSIONS
The clinical activity score has a high predictive value for the outcome of immunosuppressive treatment in Graves' ophthalmopathy. Disease activity, and not disease duration, is the prime determinant of therapeutic outcome.

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Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy

Purpose The authors attempted to immortalize human corneal epithelial cells; it is difficult to propagate primary human corneal epithelial cells because of scarcity of available tissue. However, cell immortalization by virus is always accompanied by shedding of free virus. The current study was performed to establish a cell line that produces no free viral particle. Methods Primary cultured human corneal epithelial cells were infected with a recombinant sv40-adenovirus vector and were cloned three times to obtain a continuously growing cell line. Morphologic, cytologic, and biochemical characteristics of this cell line were analyzed. Results This cell line continued to grow for more than 400 generations, exhibiting a cobblestone-like appearance similar to normal corneal epithelial cells in culture. Transmission electron microscopy showed the evidence for the characteristic features of epithelial cells, including desmosome formation and development of microvilli. It expressed cornea-specific, 64-kD cytokeratin in addition to five major insoluble proteins. By enzymatic analysis using NADP as a coenzyme and a gas chromatograph mass spectrometer, this cell line was found to possess 8.71 IU/mg protein of aldehydedehydrogenase activity. When this cell line was grown at air-liquid interface on collagen type I gel, it differentiated in a multilayered fashion. Conclusions The authors have established an SV40-immortalized human corneal epithelial cell line with properties similar to normal corneal epithelial cells.

An SV40-immortalized human corneal epithelial cell line and its characterization.

Patients with serious inflammatory Graves' ophthalmopathy should be treated with anti-inflammatory drugs or radiotherapy to prevent complications like fibrosis, while those with non-inflammatory ophthalmopathy may be treated by surgery immediately. It is often difficult, however, to distinguish inflammatory from non-inflammatory Graves' disease. We therefore present a simple clinical classification here to differentiate between these two conditions. This classification is based on the classical signs of inflammation--pain, redness, swelling, and impaired function. After two consecutive clinical examinations an 'activity score' can be determined, ranging from 0 to 10 points. In a retrospective study testing the efficacy of this classification we found that patients with an activity score of 3 or more at the beginning of therapy responded well to anti-inflammatory drugs, while those with a lower activity score mostly did not. Comparing the pretreatment activity score with the degree of enlargement of the extraocular muscles on the CT scan, we found a significant correlation between these two parameters: the higher the activity score, the more the enlargement of the muscles. We conclude that this classification facilitates the proper selection of patients for treatment.

https://bjo.bmj.com/content/bjophthalmol/73/8/639.full.pdf

Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.

It is uncertain what is the most appropriate medical therapy for patients with severe Graves' ophthalmopathy. Therefore, we carried out a single-blind, randomized clinical trial to compare the efficacy of prednisone with that of cyclosporine in 36 patients who had been euthyroid for at least two months. The two groups, each consisting of 18 patients, were similar in age, sex, and the duration and severity of ophthalmopathy. The initial dose of cyclosporine was 7.5 mg per kilogram of body weight per day, and that of prednisone was 60 mg per day, which was subsequently tapered to 20 mg per day. During the 12-week treatment period, 11 prednisone-treated and 4 cyclosporine-treated patients responded to therapy (61 percent vs. 22 percent; P = 0.018); response was manifested by decreases in eye-muscle enlargement and proptosis and improved visual acuity and total and subjective eye scores. There were no differences at base line between the patients who later responded and those who did not. Prednisone was tolerated less well than cyclosporine. After 12 weeks, patients who did not respond were treated for another 12 weeks with a combination of cyclosporine and a low dose of prednisone. Among the 9 patients who initially received prednisone, the addition of cyclosporine resulted in improvement in 5 (56 percent); among the 13 patients who received cyclosporine initially, 8 (62 percent) improved after the addition of prednisone. Combination therapy was better tolerated than prednisone treatment alone. We conclude that single-drug therapy with prednisone is more effective than cyclosporine in patients with severe Graves' ophthalmopathy. The combination can be effective in patients who do not respond to either drug alone.

https://www.nejm.org/doi/pdf/10.1056/NEJM198911163212002?listPDF=true

Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy

• Many clinicians have the impression that treatment of thyroid dysfunction ameliorates ophthalmopathy in Graves' disease. The aim of our study was to relate thyroid function to the severity of Graves' ophthalmopathy. We studied 90 patients with Graves' ophthalmopathy and Graves' hyperthyroidism in whom severity of Graves' ophthalmopathy and thyroid function (regardless of antithyroid treatment) were assessed when referred to our institution. Patients were assigned to four groups (A through D) with increasingly severe Graves' ophthalmopathy using Total Eye Score based on the NOSPECS classification. The percentage of dysthyroid patients in each group was determined: group A had 23% dysthyroid patient (5); group B, 32% (9); group C, 61% (14); and group D, 47% (8). More dysthyroid patients were in the groups with severe Graves' ophthalmopathy. We also compared the severity of Graves' ophthalmopathy between euthyroid (n = 54) and dysthyroid (n = 36) patients: euthyroid patients had less proptosis (19.9±3.5 vs 20.8±3.4 mm), better visual acuity (0.93±0.17 vs 0.88±0.18), and lower Total Eye Score (8.6±6.6 vs 10.6±6.6). We conclude that dysthyroidism is associated with more severe Graves' ophthalmopathy. Our findings suggest that meticulous control of thyroid function also during antithyroid treatment is important in the management of Graves' ophthalmopathy. (Arch Intern Med.1990;150:1098-1101)

https://jamanetwork.com/HttpHandlers/ArticlePdfHandler.ashx?journal=intemed&articleId=613355&pdfFileName=archinte_150_5_027.pdf

Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy.

The temporal relationship between the onset of Graves’ ophthalmopathy and the onset of thyroidal Graves’ disease was evaluated in 125 consecutive patients with Graves’ ophthalmopathy. Thyroidal Graves’ disease — past or present — was clinically evident in 99 patients (79%): hyperthyroidism in 96 and hypothyroidism in 3 cases. Thyroid disease preceded the eye disease in 37 patients, it occurred simultaneously with the eye disease in 39 patients, and it developed after the eye disease in 23 patients (in 16 cases within one yr after the onset of eye disease). The age at the onset of thyroid disease (38.7 ± 12.9 yr) was lower than the age at the onset of ophthalmopathy (41.8 ± 12.5 yr; p< 0.001). Among the 26 clinically euthyroid patients (21%) laboratory evidence of thyroidal Graves’ disease was found in 14 cases (11%): abnormal TRH test, n = 9; normal TRH test but abnormal T3-suppression test, n = 4; normal TRH and T3-suppression tests but positive thyroid stimulating antibodies, n = 1). We conclude that Graves’ ophthalmopathy as a rule develops at a time when thyroid autoimmunity also exists. This strongly suggests a common factor in the pathogenesis of thyroidal and ocular expressions of Graves’ disease.

Temporal relationship between onset of graves'ophthalmopathy and onset of thyroidal graves' disease

The eye findings of Graves' ophthalmopathy were prospectively recorded in 90 consecutive untreated patients (66 females, 24 males; mean age 44.5 years) according to the 1977 NOSPECS classification. Soft-tissue involvement was observed in 90%, proptosis greater than or equal to 23 mm in 30%, eye muscle involvement in 60%, corneal involvement in 9% and sight loss in 34%. No differences in the distribution of eye changes between right and left eye were found. Values for proptosis (mean +/- SD, 20.2 +/- 3.6 mm) had a near-normal distribution. Orbital computed tomography (CT) scanning (performed in 80 cases) demonstrated enlargement of inferior rectus in 60%, medial rectus in 50%, superior rectus in 40% and lateral rectus in 22%. Unilateral eye disease was present in 13 patients (14%); in 4 of these patients the CT scan showed eye muscle enlargement also in the fellow eye and in 2 patients bilateral eye disease subsequently developed. The distribution of age, sex and NOSPECS classes in patients with unilateral eye disease was similar to that in patients with bilateral eye disease, but the interval between the onset of thyroid and eye disease was much shorter in cases of unilateral than in cases of bilateral eye disease. Patients without clinically evident thyroid disease (n = 20, 22%) were not different from patients with thyroid disease in age, sex or ophthalmological presentation. The various data suggest: (1) the 1977 NOSPECS classification under-represents significant proptosis in 12% of cases; (2) the age and sex distribution of patients with Graves' ophthalmopathy is similar to that of cases with thyroidal Graves' disease, and (3) unilateral Graves' ophthalmopathy may represent an early stage of the disease, that as a rule already is or develops shortly afterwards into a bilateral disease.

R van der Gaag

Papers

Clinical criteria for the assessment of disease activity in Graves' ophthalmopathy: a novel approach.

Prednisone and Cyclosporine in the Treatment of Severe Graves' Ophthalmopathy

Effect of abnormal thyroid function on the severity of Graves' ophthalmopathy.

Temporal relationship between onset of graves'ophthalmopathy and onset of thyroidal graves' disease

Clinical presentation of Graves' ophthalmopathy.