Genes and mechanisms involved in common complex diseases, such as the autoimmune disorders that affect approximately 5% of the population, remain obscure. Here we identify polymorphisms of the cytotoxic T lymphocyte antigen 4 gene (CTLA4)--which encodes a vital negative regulatory molecule of the immune system--as candidates for primary determinants of risk of the common autoimmune disorders Graves' disease, autoimmune hypothyroidism and type 1 diabetes. In humans, disease susceptibility was mapped to a non-coding 6.1 kb 3' region of CTLA4, the common allelic variation of which was correlated with lower messenger RNA levels of the soluble alternative splice form of CTLA4. In the mouse model of type 1 diabetes, susceptibility was also associated with variation in CTLA-4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80/CD86 ligand-binding domain. Genetic mapping of variants conferring a small disease risk can identify pathways in complex disorders, as exemplified by our discovery of inherited, quantitative alterations of CTLA4 contributing to autoimmune tissue destruction.
Marked associations among age at diagnosis, disease severity, goiter, ophthalmopathy, smoking, and FH provide evidence for interactions between genetic and environmental/endogenous factors; understanding these may allow preventive measures or better tailoring of therapies.
It is increasingly apparent that the identification of true genetic associations in common multifactorial disease will require studies comprising thousands rather than the hundreds of individuals employed to date. Using 2,873 families, we were unable to confirm a recently published association of the interleukin 12B gene in 422 type I diabetic families. These results emphasize the need for large datasets, small P values and independent replication if results are to be reliable.
There is little consensus regarding the most appropriate dose regimen for radioiodine (131I) in the treatment of hyperthyroidism. We audited 813 consecutive hyperthyroid patients treated with radioiodine to compare the efficacy of 2 fixed-dose regimens used within our center (185 megabequerels, 370 megabequerels) and to explore factors that may predict outcome. Patients were categorized into 3 diagnostic groups: Graves' disease, toxic nodular goiter, and hyperthyroidism of indeterminate etiology. Cure after a single dose of 131I was investigated and defined as euthyroid off all treatment for 6 months or T4 replacement for biochemical hypothyroidism in all groups. As expected, patients given a single dose of 370 megabequerels had a higher cure rate than those given 185 megabequerels, (84.6% vs. 66.6%, P < 0.0001) but an increase in hypothyroidism incidence at 1 yr (60.8% vs. 41.3%, P < 0.0001). There was no difference in cure rate between the groups with Graves' disease and those with toxic nodular goiter (69.5% vs. 71.4%; P, not significant), but Graves' patients had a higher incidence of hypothyroidism (54.5% vs. 31.7%, P < 0.0001). Males had a lower cure rate than females (67.6% vs. 76.7%, P = 0.02), whereas younger patients (<40 yr) had a lower cure rate than patients over 40 yr old (68.9% vs. 79.3%, P < 0.001). Patients with more severe hyperthyroidism (P < 0.0001) and with goiters of medium or large size (P < 0.0001) were less likely to be cured after a single dose of 131I. The use of antithyroid drugs, during a period 2 wk before or after 131I, resulted in a significant reduction in cure rate in patients given 185 megabequerels 131I (P < 0.01) but not 370 megabequerels. Logistic regression analysis showed dose, gender, goiters of medium or large size, and severity of hyperthyroidism to be significant independent prognostic factors for cure after a single dose of 131I. We have demonstrated that a single fixed dose of 370 megabequerels 131I is highly effective in curing toxic nodular hyperthyroidism as well as Graves' hyperthyroidism. Because male patients and those with more severe hyperthyroidism and medium or large-sized goiters are less likely to respond to a single dose of radioiodine, we suggest that the value of higher fixed initial doses of radioiodine should be evaluated in these patient categories with lower cure rates.
PurposeTreatment options in Graves’ disease are clearly defined, but management practices and the perceptions of success are varied. The outcomes of treatment in large consecutive cohorts of Graves’ disease have not been well characterised. The study describes the epidemiology, management strategies and medium term outcomes following anti-thyroid drug treatment, radio-iodine ablation and surgery in Graves’ disease.MethodsAll patients (n = 659) who received treatment for a new diagnosis of Graves’ disease in secondary care over a 5 year period were included with a median (interquartile range) follow-up of 42.9 (29–57.5) months.ResultsThe age adjusted incidence of adult onset Graves’ disease in Sheffield, UK was 24.8 per 100,000 per year. Excluding 35 patients lost to follow-up, 93.1% (n = 581) were controlled on anti-thyroid drug treatment. Of these, 73.6% went into remission following withdrawal of anti-thyroid drugs; 5.2% were still undergoing initial therapy; 13.3% lost control whilst on anti-thyroid drugs; and 7.9% went on to have either surgery or radio-iodine ablation whilst controlled on anti-thyroid drugs. Of the 428 patients who achieved remission, 36.7% relapsed.Of 144 patients who had radio-iodine ablation treatment, 5.6% relapsed and needed further treatment. Of 119 patients having surgery, 5.2% had long-term hypoparathyroidism and none had documented long-term recurrent laryngeal nerve palsy.ConclusionsIn the follow-up, 39.9% of patients underwent surgery or radio-iodine ablation with little morbidity. Up to two-thirds of patients who achieved remission did not relapse. Data on effectiveness and risks of treatments for Graves’ disease presented in this study will help clinicians and patients in decision making.
Objective: For patients who remain hypothyroid despite the administration of what would seem adequate doses of levothyroxine (L-T 4 ), the underlying cause can be difficult to determine. The possibility of a biological cause should first be explored; however, in the majority of cases, poor adherence to medication is likely to be the main cause of treatment failure. When non-adherence is suspected but not volunteered, options to confirm the suspicion are limited. In this study, we identified patients for whom known drugs and pathological causes of L-T 4 malabsorption were excluded, and despite often high doses of L-T 4 , the patients remained hypothyroid. Design: Using a weight-determined oral L-T 4 bolus administration, absorption was initially assessed in 23 patients. In nearly all patients, this was shown to be maximal at 120 min post-ingestion. This was then followed by the continued administration of a weekly T 4 bolus for a 4-week period after which TSH and free T 4 (fT 4 ) levels were recorded. Results: All patients showed a rise in fT 4 at 120 min following the administration of the L-T 4 bolus, with a mean increase of 54G3% from baseline. Following the treatment period, using an equivalent weekly L-T 4 dose, which was significantly less than that of the daily dose taken by the patients before the test, TSH reduced from baseline in w75% of cases. Conclusion: Using this combination of tests allows significant malabsorptive problems to be identified first and then potential non-adherence to be demonstrated. A management plan can then be implemented to increase adherence, aiming to improve treatment outcomes.European Journal of Endocrinology 168 913-917
This study revealed a high prevalence of ANCA in treated patients with Graves' disease but not in those with Hashimoto's thyroiditis. Furthermore, within the Graves' disease population, ANCA development was associated with propylthiouracil usage to a greater extent than carbimazole. These findings suggest that the altered immune environment associated with autoimmune thyroid disease is not sufficient to develop ANCA but treatment with thionamides is important in promoting ANCA development.
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