Long-term follow-up of ophthalmic Graves' disease.

Sixteen patients with ophthalmic Graves'' disease (clinically euthyroid with ophthalmopathy or exophthalmos) were followed up for 4.3 to 14.3 (mean 9.1) years to determine whether thyroid dysfunction developed and whether their ophthalmopathy progressed, regressed or remained stable. Five patients (31%) manifested hyperthyroidism or hypothyroidism, all before the end of the fifth year of follow-up. The ophthalmopathy was mild, and none of the patients required specific treatment. The thyroid function of patients with ophthalmic Graves'' disease should be periodically monitored for at least 5 years.     

Graves' disease and atrial fibrillation: the case for even higher doses of therapeutic iodine-131.

Seventy five consecutive patients with Graves'' disease complicated by atrial fibrillation were given a large single therapeutic dose of 600 MBq (16.2 mCi) iodine-131 in an effort to control their hyperthyroidism rapidly and thus restore sinus rhythm. Patients were initially followed up every three months after treatment and then at yearly intervals. The mean period of follow up was 3.1 years. A total of 44 of the patients became hypothyroid and 31 euthyroid, and 33 (75%) and 14 (45%) of these patients, respectively, reverted to sinus rhythm (p less than 0.01). Of the 33 who became hypothyroid and reverted to sinus rhythm, 30 had developed the hypothyroidism within six months after treatment. These results are a strong case for increasing the dose of radioiodine in patients with Graves'' disease complicated by atrial fibrillation in an effort to speed the onset of thyroid failure and thus maximise the rate of reversion to sinus rhythm.     

Color-Flow Doppler Sonography in Patients with Subclinical Thyroid Dysfunction

ObjectiveTo assess the value of color-flow Doppler sonography (CFDS) in evaluating intrathyroidal blood flow and velocity in patients with subclinical thyroid dysfunction.MethodsIn this prospective study, patients with subclinical hypothyroidism, patients with subclinical hyperthyroidism, and euthyroid patients without known thyroid autoimmune disease who served as controls were included. Subclinical thyroid dysfunction was defined as normal serum free thyroxine (FT₄) and free triiodothyronine (FT₃) in the presence of high (subclinical hypothyroidism), or lowsuppressed (subclinical hyperthyroidism) serum thyrotropin (TSH) levels. Serum FT₄, FT₃, TSH, and antibodies to thyroid peroxidase and thyroglobulin were measured in all participants. In addition, TSH receptor antibody levels were determined in patients with subclinical hyperthyroidism. All participants underwent conventional sonography and CFDS. Mean peak systolic velocity (PSV) and resistive index were obtained from multiple extranodular thyroid parenchyma samplings and inferior thyroid artery measurements.ResultsThe study population included 27 patients with subclinical hypothyroidism, 15 patients with subclinical hyperthyroidism, and 20 euthyroid patients. Patients with subclinical hypothyroidism had significantly higher mean intrathyroidal PSV values than control patients (19.9 ± 5.6 cm/s vs 15.7 ± 4.4 cm/s; P = .008), whereas patients with subclinical hyperthyroidism had significantly higher mean PSV values than control patients at the inferior thyroid artery level (29.7 ± 10.7 cm/s vs 21.9 ± 6.8 cm/s; P = .014). Compared with control patients, a greater proportion of patients with subclinical hypothyroidism and patients with subclinical hyperthyroidism had marked CFDS patterns (78% vs 15% [P <.001] and 53% vs 15%; [P <.001], respectively). A significant association was found between positivity for thyroid autoantibodies and intense CFDS patterns. No correlation was found between TSH or thyroid hormone levels and CFDS pattern or blood flow velocity.ConclusionWe have demonstrated that significantly increased thyroid blood flow velocity and vascularity are already present in patients with mild thyroid dysfunction.(Endocr Pract. 2010;16:376-381)     

Serum thyrotrophin concentration: an unreliable test for detection of early hypothyroidism after thyroidectomy.

Three groups of patients who had undergone subtotal thyroidectomy for Graves''s disease, toxic multinodular goitre, or euthyroid multinodular goitre 12 to 15 years before and in whom a normal serum thyroxine (T-4) level was found were each divided into two subgroups on the basis of a normal or a raised serum thyrotrophin concentration. There was no difference in mean serum T-4 concentration between patients with normal and those with raised serum thyrotrophin concentrations, and the values were similar to the mean T-4 values of the normal population. The mean serum triiodothyronine values of all groups were higher than normal, but the mean values of the groups with a normal and a raised serum thyrotrophin were similar. After thyroidectomy a mildly raised serum thyrotrophin does not in itself indicate the presence of hypothyroidism.     

Optimum duration of antithyroid drug treatment determined by assay of thyroid stimulating antibody in patients with Graves' disease.

OBJECTIVE--To determine the optimal duration of antithyroid drug treatment by monitoring serum thyroid stimulating antibody values in patients with Graves'' disease. DESIGN--Prospective longitudinal trial of patients with Graves'' disease followed up for 24 months after withdrawal of treatment. SETTING--Tertiary referral centre. PATIENTS--A total of 64 consecutive patients with untreated Graves'' disease, eight of whom were subsequently excluded. Fifty six patients completed the study. INTERVENTIONS--All patients were treated initially with carbimazole 40 mg, then with decreasing doses that maintained a euthyroid state. Treatment was scheduled to continue for 18 months but was withdrawn earlier if serum thyroid stimulating antibody became undetectable. END POINT--Serum values of thyroid stimulating antibody (assayed by stimulation of human thyroid cells in vitro) and thyroid hormones and thyroid state every three months during treatment and afterwards every six months for 24 months. MEASUREMENTS AND MAIN RESULTS--In 44 patients serum thyroid stimulating antibody became undetectable during treatment and treatment was withdrawn (median duration of treatment nine months, range 3-18 months). In 12 patients the antibody could be detected during 18 months of treatment. Among the first group of 44 patients initial values of the antibody before treatment were significantly lower than in the second group of 12 patients (median 225% (range 138-1236%) v 570% (250-1480%), p less than 0.001); the incidence of relapse was also lower (41% v 92%, p less than 0.001); and among those who did relapse the disease free interval after treatment was longer (median 12 months v 1 month, p less than 0.001). Moreover, the initial median serum values of thyroid stimulating antibodies were not related to the occurrence of relapse or remission as these did not differ between patients who did and did not have a relapse (median 267% (range 139-1480%) v 220% (range 138-1236%). CONCLUSION--Monitoring of serum thyroid stimulating antibody was a good guide to the duration of treatment as it allowed the treatment period to be considerably shortened in a large group of patients with no loss of efficiency.     

Clinical applications of assays for thyrotropin-receptor antibodies in Graves' disease.

Graves'' disease is characterized by hyperthyroidism, diffuse goitre, infiltrative ophthalmopathy and, rarely, pretibial myxedema. In 1956 a substance capable of prolonged thyroid stimulation was discovered in the serum of some patients with Graves'' disease and termed long-acting thyroid stimulator (LATS). It was shown to be an antibody that could interact with the receptor for thyroid-stimulating hormone (TSH). The term LATS is usually reserved for the activity measured in a laborious in-vivo bioassay in mice. Today the activity of TSH-receptor antibodies (TSH-R Ab) can be measured by in-vitro bioassays or by radioreceptor assays. These assays are now becoming commercially available. TSH-R Ab assays may be useful in predicting the response to therapy for Graves'' disease, investigating euthyroid ophthalmopathy and predicting the likelihood of neonatal hyperthyroidism.     

Intravenous methylprednisolone in the treatment of Graves' ophthalmopathy.

Eleven euthyroid patients with severe Graves'' eye disease were treated with intravenous methylprednisolone and followed up for six months or more by ophthalmological assessment, orbital computed tomography (CT), photographs, and antibody measurements. Papilloedema resolved in the single patient in whom it was present; visual acuity was abnormal in seven eyes initially and in only one eye after treatment; the intraocular pressure differential, which reflects muscle dysfunction, was initially abnormal in 18 eyes but showed a progressive and distinct improvement; nine patients showed substantial improvement in inflammatory signs. Exophthalmos improved early after treatment, but this improvement was not maintained. Orbital CT showed a pronounced reduction in the bulk of eye muscles after treatment in eight of nine patients. Autoantibodies to the thyroid stimulating hormone receptor declined. Adverse effects were trivial. Thus eight patients showed a clear response to intravenous methylprednisolone as judged by ophthalmic assessment and CT scan. The two patients who showed little response and one who had none all had a long history (more than a year) of ophthalmopathy. Results were better than those with oral steroids and adverse effects less. Treatment of Graves'' eye disease is more likely to be effective if given early; patients should be referred promptly to specialist centres, where treatment with intravenous methylprednisolone should be considered.     

Graves' ophthalmopathy and subclinical hypothyroidism: diagnostic value of the thyrotropin releasing hormone test.

Five patients with Graves'' ophthalmopathy and no previously documented clinical or laboratory evidence of hyperthyroidism were studied. Their serum levels of thyroxine and triiodothyronine (T3) and their T3 uptake were normal. Although the baseline serum level of thyrotropin (TSH) was normal in two patients, it was increased on the other three, and when TSH releasing hormone (TRH) was administered the T3 response was impaired in three patients and the TSH response was exaggerated in all five. These findings facilitated the diagnosis of subclinical hypothyroidism and distinguished the patients from those with Graves'' ophthalmopathy and normal thyroid function or subclinical hyperthyroidism. Thyroid antibodies were detected in the serum of four of the five patients, suggesting the coexistence of chronic autoimmune thyroiditis; this disorder could account in part for the subclinical hypothyroidism, which was even present in the two patients in whom thyroid-stimulating immunoglobulin was found in the serum. These observations indicate the value of a TRH stimulation test in detecting subclinical hypothyroidism in patients with Graves'' ophthalmopathy who appear from clinical and routine laboratory studies to have normal thyroid function but could have normal function or subclinical hyperthyroidism.     

Obituaries

The outcome in 110 patients first treated with radioiodine (mean dose 6.56 mCi) for hyperthyroid Graves'' disease in 1980 was reviewed. In 23% of the patients the disease had not been controlled by the initial dose after 3 months, and 17% were given one or two more doses. Within 2 years 65% of the patients required replacement thyroxine therapy. Although about half of the patients were biochemically hypothyroid 3 months after the last dose of iodine 131, this condition was transient in a third of them; five of these patients even became hyperthyroid again. Patients with transient, as opposed to permanent, hypothyroidism at 3 months tended to be clinically euthyroid but to have residual palpable thyroid tissue and only a modest reduction in the serum thyroxine level. It is therefore recommended that patients not overtly hypothyroid 3 months after treatment with 131I be observed still longer before thyroxine replacement therapy is instituted.     

Thyrotoxicosis in the African: Clinical and Immunological Observations

The clinical manifestations of thyrotoxicosis are described in 20 African patients with toxic diffuse goitre (Graves''s disease) and five with toxic nodular goitre. Antibody to thyroglubulin was detected in the serum of one patient and antibody to thyroid microsomes in four patients. Round-cell infiltration of the thyroid gland was present in 27% of 30 African thyrotoxic patients and 73% of appropriately matched Caucasian patients. It is suggested that the low incidence of thyrotoxicosis in the African race is related to an inability to form thyroid autoantibodies.     

Graves' disease: immunological and immunogenetic indicators of relapse

The use of measurements of antibody to the thyroid stimulating hormone receptor and HLA-DR3 phenotype for predicting relapse of hyperthyroidism in patients with Graves'' disease receiving medical treatment is controversial. Fifty eight new patients with Graves'' disease were followed up prospectively for up to 96 months after treatment with antithyroid drugs for 12 months. The presence of antibody to the thyroid stimulating hormone receptor before the start of treatment, measured as immunoglobulins inhibiting binding of thyroid stimulating hormone, was not associated with relapse. Patients who remained positive for antibodies after treatment tended to relapse within six months, but no relation with long term relapse was found. HLA-Cw7 but not HLA-DR3 was significantly associated with relapse. The presence of HLA-DR4 was significantly associated with remission and with absence of antibodies to thyroid stimulating hormone receptor. HLA-DR4 may therefore protect against relapse of thyrotoxicosis by immunomodulation triggered by antithyroid drugs, which results in the synthesis of antibodies to the thyroid stimulating hormone receptor being inhibited.     

High TSH concentrations in "euthyroidism": explanation based on control-loop theory.

High concentrations of thyroid-stimulating hormone (TSH) in the serum have often been reported in apparently euthyroid patients with damaged thyroids. We have confirmed this finding in 14 patients 18 months after subtotal thyroidectomy for Graves''s disease (group 1) and in 14 patients with manic-depressive psychosis (group 2) receiving lithium carbonate, which reduces thyroid reserve. One factor common to groups 1 and 2 but not to the controls was reduced thyroid reserve or functioning capacity, and, using established physical principles of servo-control, we have tried to define the mechanism. A series of curves were projected to indicate how TSH might be expected to vary with functioning thyroid capacity.     

促甲状腺素受体抗体及白细胞介素-2、白细胞介素-6在Graves病131I治疗中的变化及临床意义

目的:研究促甲状腺素受体抗体(TRAb)及白细胞介素-2(IL-2)、白细胞介素-6(IL-6)在Graves病~(131)I治疗中的变化并分析其临床意义。方法:选取2015年8月-2016年8月于我院接受~(131)I治疗的Graves病患者112例为研究对象,按照第6个月的甲状腺功能检查结果的不同分为治愈组(n=54),缓解组(n=21)和甲减组(n=37)。分别比较治疗前、治疗3个月、6个月后三组患者的甲状腺功能指标以及TRAb、IL-2、IL-6水平。结果:治疗前三组患者游离T3(FT3)、游离T4(FT4)、促甲状腺激素(TSH)水平比较差异无统计学意义(P0.05),治疗3个月、6个月后三组患者FT3、FT4水平均明显低于治疗前,而TSH水平明显高于治疗前(P0.05)。治疗3个月、6个月后甲减组FT3、FT4水平均明显低于治愈组、缓解组,治愈组又明显低于缓解组,TSH水平明显高于治愈组、缓解组,治愈组又明显高于缓解组(P0.05)。治疗前三组患者TRAb、IL-2、IL-6水平比较差异无统计学意义(P0.05)。治疗3个月后三组患者TRAb水平均明显高于治疗前(P0.05),治疗6个月后治愈组与甲减组患者TRAb水平与治疗前比较无统计学差异(P0.05),但缓解组患者TRAb水平高于甲减组,差异有统计学意义(P0.05)。治疗3个月、6个月后,治愈组与甲减组患者IL-2、IL-6水平均低于治疗前,而缓解组高于甲减组,差异均有统计学意义(P0.05)。结论:TRAb、IL-2、IL-6可作为评估Graves病~(131)I治疗后的指标,通过检测三项指标治疗前后水平变化情况,从而为临床预后评估提供指导作用。     

Idiopathic heart block: association with vitiligo,thyroid disease,pernicious anaemia,and diabetes mellitus.

Out of 100 patients with chronic heart block 16 had one or more autoimmune disorders-namely, vitiligo (5,) hypothyroidism (4), Graves''s disease (1), pernicious anaemia (2), and diabetes mellitus (9). All these disorders occurred with greater frequency than normal and were more prevalent than in a group of hospital inpatients of comparable age. Autoantibodies were not increased. We suggest that among patients with idiopathic heart block there is a subgroup with multiple autoimmune disorders.     

THE USE OF RADIOACTIVE IODINE IN THE TREATMENT OF GRAVES' DISEASE

Fifty patients with uncomplicated Graves'' disease were treated with radioactive iodine (I₁₃₁). Twenty-six patients who were followed for one year or longer are the basis of this report. Twenty-five are now euthyroid; only one is not completely well.The total dose of radioiodine administered varied from 0.5 to 10 millicuries. The average length of time necessary for return to a euthyroid state was from three to four months.Hypometabolism developed in three patients, and in one the signs and symptoms of myxedema developed. No other complications ensued. One patient who apparently relapsed had complete return to normal after further iodine administration.The determination of the uptake of radioactive iodine by the thyroid gland is a useful diagnostic procedure in differentiating conditions simulating hyperthyroidism.Following treatment with radioactive iodine, the thyroid gland becomes smaller, the uptake of iodine by the gland is reduced, and the level of organic iodine in the plasma becomes normal.In acute thyroiditis, in spite of a high basal metabolic rate, high content of organic iodine in the plasma and other evidences of “hyperthyroidism,” the uptake of I₁₃₁ has been very low.     

Recurrent Thyrotoxicosis after Subtotal Thyroidectomy

A study of patients with recurrent thyrotoxicosis after subtotal thyroidectomy has shown that the operation has a profound effect on the natural history of Graves''s disease. It is followed by pronounced changes in the immunological features of the disease, with a fall in the prevalence of serum thyroid autoantibodies, including the long-acting thyroid stimulator. Thyroid suppression returns to normal in 70% of patients. The treatment produces two populations of patients. In the larger group there is a permanent remission of the disease process. In the smaller group the disease process persists and, consequently, recurrent hyperthyroidism may develop. The mechanism of the change in the larger group of patients probably has an immunological basis.     

Critical study of 5% guanethidine in ocular manifestations of Graves's disease

Assessment was made of 5% local guanethidine in treating eye manifestations in euthyroid patients with either treated thyrotoxicosis or ophthalmic Graves''s disease. In a double-blind crossover study guanethidine caused greater improvement in lid retraction than a control solution. A long-term study showed that this improvement was maintained. A much lower incidence of side-effects was noted with 5% guanethidine than with 10% solution.     

Effects of Long-acting Thyroid Stimulator (LATS) and LATS Protector on Human Thyroid Adenyl Cyclase Activity

The long-acting thyroid stimulator (LATS) has been thought to be responsible for the hyperthyroidism of Graves''s disease. It is detected by its effect on the mouse thyroid gland but cannot be found in all patients with hyperthyroidism. In an attempt to clarify the problem of LATS-negative hyperthyroidism, serum was obtained from untreated patients and its effect in vitro on human thyroid tissue examined, using the activation of adenyl cyclase as a measure of stimulation. Human thyroid adenyl cyclase was activated by both thyroid-stimulating hormone (TSH) and LATS. Thyroid tissue obtained from patients with Graves''s disease was relatively less responsive to LATS than was non-toxic thyroid tissue. Of the 24 samples studied five contained LATS and all of these activated adenyl cyclase. The presence of LATS protector in LATS-negative hyperthyroid patients was confirmed but LATS-negative sera had no effect on human thyroid adenyl cyclase activity.     

Serum long acting thyroid stimulator protector in pregnancy complicated by Graves' disease.

Activities of serum long acting thyroid stimulator protector were measured in a series of nine pregnancies in eight mothers who had Graves'' disease, one of whom had been successfully treated by surgery. In all but two instances the activities tended to decline as pregnancy progressed. After delivery activities rose in three out of five patients in whom these had disappeared in pregnancy and, as this occurred, the patients relapsed. In the two patients whose activities did not decline thyrotoxicosis persisted throughout pregnancy and after delivery. None of the nine babies in this study suffered from neonatal thyrotoxicosis because maternal activities of the thyroid stimulator protector, though high enough to induce Graves'' disease in adults, were not above the threshold for the induction of thyroid overactivity in neonates.     

Genetic Factors in Hashimoto's Struma

It has previously been established that there is a significant history of thyroid disorders in families of patients with Hashimoto''s struma or chronic thyroiditis. In the present study, 99 relatives of 20 patients with Hashimoto''s struma or chronic thyroiditis were studied with regard to the incidence of circulating thyroid autoantibodies; 42 of these 99 relatives were found to have such antibodies. Twenty of the 99 relatives were shown to have thyroid abnormalities (chiefly goitre); of this group of 20, antibodies were found in 12. In the remaining 79 persons (who had no clinical evidence of thyroid disease), 30 were found to have circulating antithyroid antibodies. The incidence of such antibodies among these relatives is very significantly greater than in the general population.From these and other similar studies, there is strong evidence favouring a genetic predisposition for Hashimoto''s struma and chronic thyroiditis. The mode of inheritance is not yet established, and the pathogenesis of the disease has not yet been elucidated.