Propylthiouracil and carbimazole associated-antineutrophil cytoplasmic antibodies (ANCA) in patients with Graves' disease.

OBJECTIVE: Propylthiouracil treatment of Graves' disease has been postulated to provoke antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We aimed to investigate whether carbimazole therapy was also associated with increased risk of ANCA. DESIGN: The occurrence of ANCA and the relationship to thionamide treatment was investigated in a cross-sectional study in a consecutive series of 407 patients' with Graves' disease, 200 with Hashimoto's thyroiditis and 649 normal euthyroid subjects. MEASUREMENTS: ANCA was measured by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) for proteinase 3 and myeloperoxidase-ANCA. RESULTS: The prevalence of ANCA, as measured by IIF, was increased in the Graves' disease cohort (19.9%) compared with euthyroid controls (4.6%; P < 0.001). The prevalence of MPO-ANCA (measured by ELISA) was also increased in Graves' disease (P = 0.019). ANCA prevalence was more strongly associated with propylthiouracil treatment than carbimazole (P = 0.0265), although risk of ANCA was also higher in Graves' patients treated with carbimazole than controls (RR 2.2, P < 0.0001). ANCA positivity was not increased in patients with Hashimoto's thyroiditis. CONCLUSION: 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.

Association of a rare thyroglobulin gene microsatellite variant with autoimmune thyroid disease.

Genetic and environmental factors contribute to the development of Graves' disease and Hashimoto's thyroiditis. These diseases, although clinically distinct, share many immunological and histological features. Susceptibility genes for autoimmune thyroid disease (AITD) have been investigated, although only the human leukocyte antigen and cytotoxic T lymphocyte-associated antigen-4 gene regions have been consistently associated with disease. Recent data, however, have shown linkage and association of chromosome 8q24 (containing the thyroglobulin gene) to AITD. Therefore, we performed a case-control association study on patients with AITD and controls using previously associated markers (D8S284 and Tgms2). No differences in allele frequencies were observed between AITD cases and controls for D8S284. Compared with the three common alleles (frequencies >10%), the rare alleles of Tgms2 were increased (chi(2)= 10.6; P = 0.001) at Tgms2. This group included the 336-bp allele (increased in cases vs. controls: chi(2)= 24.97; P < 0.001), which has previously been reported to be associated with AITD. The rarity of this allele in the United Kingdom, however, precluded analysis in our family dataset. Although these findings may represent a random chance event, in view of previous reports of linkage and association of this gene region to AITD, this may be an example of a rare causal variant of a complex disease.

Weight gain following treatment of hyperthyroidism.

OBJECTIVE: Patients frequently express concern that treating hyperthyroidism will lead to excessive weight gain. This study aimed to determine the extent of, and risk factors for, weight gain in an unselected group of hyperthyroid patients. DESIGN AND SUBJECTS: We investigated 162 consecutive hyperthyroid patients followed for at least 6 months. Height, weight, clinical features, biochemistry and management were recorded at each clinic visit. RESULTS: Documented weight gain was 5.42 +/- 0.46 kg (mean +/- SE) and increase in BMI was 8.49 +/- 0.71%, over a mean 24.2 +/- 1.6 months. Pre-existing obesity, Graves' disease causing hyperthyroidism, weight loss before presentation and length of follow-up each independently predicted weight gain. Patients treated with thionamides or radioiodine gained a similar amount of weight (thionamides, n = 87, 5.16 +/- 0.63 kg vs. radioiodine, n = 62, 4.75 +/- 0.57 kg, P = 0.645), but patients who underwent thyroidectomy (n = 13) gained more weight (10.27 +/- 2.56 kg vs. others, P = 0.007). Development of hypothyroidism (even transiently) was associated with weight gain (never hypothyroid, n = 102, 4.57 +/- 0.52 kg, transiently hypothyroid, n = 29, 5.37 +/- 0.85 kg, on T4, n = 31, 8.06 +/- 1.42 kg, P = 0.014). This difference remained after correcting for length of follow-up. In the whole cohort, weight increased by 3.95 +/- 0.40 kg at 1 year (n = 144) to 9.91 +/- 1.62 kg after 4 years (n = 27) (P = 0.008), representing a mean weight gain of 3.66 +/- 0.44 kg/year. CONCLUSION: We have demonstrated marked weight gain after treatment of hyperthyroidism. Pre-existing obesity, a diagnosis of Graves' disease and prior weight loss independently predicted weight gain and weight continued to rise with time. Patients who became hypothyroid, despite T4 replacement, gained most weight.

Radioiodine treatment of hyperthyroidism-prognostic factors for outcome.

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.

An audit of management of differentiated thyroid cancer in specialist and non-specialist clinic settings.

OBJECTIVE: Thyroid cancer is the most common endocrine malignancy but is none the less rare. Some aspects of its management remain controversial. Previous audits of patient management in the United Kingdom have revealed deficiencies, especially in communication between specialists. We have audited patient management in a large university-associated teaching hospital, assessing points of good practice identified from published guidelines and reviews, and have compared findings in groups of patients managed jointly by specialists with an interest in thyroid cancer (including surgeon, endocrinologist and oncologist) with a group managed by other clinicians outside that setting. DESIGN AND PATIENTS: Retrospective case-note review of 205 patients with differentiated (papillary or follicular) cancer including group A (n = 134; managed in a specialist multi-disciplinary clinic setting) and group B (n = 71; managed in other clinic settings). Points of good practice investigated were adequacy of surgery, surgical complications, prescription and adequacy of T4 treatment, adequacy of monitoring by measurement of serum thyroglobulin and action taken and appropriate administration of ablative radioiodine. RESULTS: Deficiencies in management of the cohort as a whole were identified, including inadequate surgery and inadequate TSH suppression in approximately one-fifth of the cases. Monitoring with thyroglobulin measurements and action when serum thyroglobulin was high were also inadequate in some cases and ablative radioiodine was not given, despite being indicated in 11.7% of the cohort. Inadequate surgery and failure to administer radioiodine were less common in those managed in a specialist clinic setting than in those managed in other clinic settings. CONCLUSIONS: The findings highlight the need for locally agreed protocols in managing relatively rare endocrine disorders such as thyroid cancer and argue in favour of centralization of expertise and patient management in multi-disciplinary specialist clinic settings.

Age and gender predict the outcome of treatment for Graves' hyperthyroidism.

The response to treatment in Graves' hyperthyroidism is unpredictable, and factors postulated to predict outcome have not generally proved clinically useful or been widely adopted in clinical practice. We audited outcome in 536 patients with Graves' hyperthyroidism presenting consecutively to determine whether simple clinical features predict disease presentation and response to treatment. At presentation males had slightly more severe biochemical hyperthyroidism [free T4: males, 64.3 +/- 3.0 pmol/L (mean +/- SE); females, 61.3 +/- 1.7 (P = 0.45); free T3: males, 24.3 +/- 1.5 pmol/L; females, 21.0 +/- 0.6, (P = 0.04)]. Patients less than 40 yr at diagnosis had more severe hyperthyroidism than patients more than 40 yr old [free T4: <40 yr, 64.3 +/- 2.0; >40 yr, 56.7 +/- 2.3 (P = 0.02); free T3: <40 yr, 22.8 +/- 0.8; >40 yr, 19.0 +/- 0.9 (P = 0.003)]. Males had a lower remission rate than females after a course of antithyroid medication [19.6% vs. 40%; odds ratio, 0.37; 95% confidence interval (CI), 0.17-0.79; P < 0.01]. Similarly, patients aged less than 40 yr had a lower remission rate than older patients (32.6% vs. 47.8%; odds ratio, 0.53; 95% CI, 0.32-0.87; P = 0.01). One dose of radioiodine cured hyperthyroidism in fewer males than females (47% vs. 74%; P < 0.0001). Logistic regression analysis demonstrated male sex (odds ratio, 2.80; 95% CI, 1.31-5.98; P = 0.008), serum free T4 concentration at diagnosis (odds ratio, 1.02; 95% CI, 1.0-1.04; P = 0.01), and dose of radioiodine administered (odds ratio, 0.99; 95% CI, 0.99-1.00; P = 0.001) were contributing factors associated with failure to respond to a single dose of radioiodine. As males and younger patients are more likely to fail to respond to medical treatment, and male patients are likewise less likely to respond to a single dose of radioiodine, we suggest that those groups with low remission rates should be offered definitive treatment with radioiodine or surgery soon after presentation and that the value of higher initial doses of radioiodine in males be evaluated.

Gender, clinical findings, and serum thyrotropin measurements in the prediction of thyroid neoplasia in 1005 patients presenting with thyroid enlargement and investigated by fine-needle aspiration cytology.

One thousand five euthyroid patients (870 females and 135 males, mean age 47 years), who presented with thyroid enlargement were evaluated by fine-needle aspiration cytology (FNAC) of the thyroid as the first-line investigation. The final cytological or histological diagnosis was determined after surgery (n = 312) or clinical follow-up for a minimum period of 2 years (range 2-14 years, mean 6.7 years). Goiter type was assessed clinically and was classified as diffuse in 147, multinodular in 247, or solitary nodule in 611. The overall sensitivity and specificity of the procedure in the detection of thyroid neoplasia was 88% and 89%, respectively. Males who presented with thyroid enlargement had significantly higher rates of malignancy (p = 0.007) and neoplasia (benign + malignant) (p = 0.002) than females, as did subjects with solitary nodule compared with diffuse or multinodular goiters (malignancy p = 0.001, neoplasia p < 0.001). Subjects with normal thyrotropin (TSH) (>0.4 mU/L) at presentation had a nonsignificantly increased risk of thyroid neoplasia (p = 0.07) and malignancy, in contrast to those with low TSH (<0.4 mU/L). We confirmed FNAC of the thyroid to be an accurate test in the detection of thyroid neoplasia. Gender and goiter type at presentation both contribute significantly to the prediction of the diagnosis of thyroid neoplasia.

The development of Graves' disease and the CTLA-4 gene on chromosome 2q33.

Case-control studies suggest that the CTLA-4 gene may be a susceptibility locus for Graves' disease. The previously reported A/G polymorphism at position 49 in exon 1 of the CTLA-4 gene was, therefore, investigated in a case-control (n = 743) and family-based (n = 179) dataset of white Caucasian subjects with Graves' disease. The relationship between CTLA-4 genotype and severity of thyroid dysfunction at diagnosis was also investigated. An increase in frequency of the G (alanine) allele was seen in Graves' patients compared with control subjects (42% vs. 31.5%, respectively; corrected P<0.0002; odds ratio = 1.58), and a significant difference in the distribution of GG, GA, and AA genotypes was observed between the groups (chi2 = 21.7; corrected P<0.00003). Increased transmission of the G allele was seen from heterozygous parents to affected offspring compared to unaffected offspring (chi2 = 5.7; P = 0.025). Circulating free T4 concentrations at diagnosis were significantly associated with CTLA-4 genotype (F = 3.26; P = 0.04). These results support the hypothesis that CTLA-4 may play a role in regulating self-tolerance by the immune system and in the pathogenesis of autoimmune disorders such as Graves' disease.

No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies.

OBJECTIVE: The cytotoxic T lymphocyte associated-4 (CTLA-4) gene is a candidate for T-cell mediated autoimmune disease and polymorphism has been reported to be associated with both type 1 diabetes and autoimmune thyroid disease. A previously unreported polymorphism of the promoter region of the human CTLA-4 gene has recently been described in a sample of a normal control population. We investigated the distribution of this polymorphism, situated at position -318 to the ATG start codon and resulting in a C-T change leading to an Mse I restriction site, in both population based case control studies and family studies in patients with Graves' disease (Caucasian and Hong Kong Chinese), autoimmune hypothyroidism and systemic lupus erythematosus (SLE). DESIGN: Target DNA was amplified using the polymerase chain reaction and the resulting product was digested using the Mse I restriction enzyme. PATIENTS: One hundred and ninety-one white UK Caucasian and 98 Hong Kong Chinese patients with Graves' disease, 78 white UK Caucasian patients with Graves' disease plus family members, 92 white UK Caucasian patients with autoimmune hypothyroidism, 13 white UK Caucasian patients with autoimmune hypothyroidism plus family members, 132 white UK Caucasian patients with systemic lupus erythematosus, 355 white UK Caucasian control subjects and 82 Hong Kong Chinese control subjects. MEASUREMENTS: Frequencies of the C and T alleles were compared between patients and control subjects using the chi 2-test and Fisher's exact test for small numbers. RESULTS: No association with the T allele was observed in any of the patient groups studied. CONCLUSION: These data suggest that the C-T change in exon 1 of the promoter region of the CTLA-4 gene does not play a role, nor is in linkage disequilibrium with a disease causing mutation, in the development of autoimmune disease.

Lack of association between polymorphism of the thyrotropin receptor gene and Graves' disease in United Kingdom and Hong Kong Chinese patients: case control and family-based studies.

The thyrotropin receptor (TSH-R) gene is a candidate for genetic susceptibility to Graves' disease (GD). Previous case control studies investigating allelic association of a polymorphism at position 253 (C253 to A253) of the TSH-R gene have shown conflicting results. We genotyped two independent case control datasets (UK Caucasian and Hong Kong Chinese), for the A253 polymorphism. The Transmission Disequilibrium Test was also used in a third family-based dataset that included 89 UK Caucasian families (both parents, a GD sibling and an unaffected sibling). Genotyping was performed by polymerase chain reaction (PCR)-amplification of genomic DNA and Tth111 I restriction enzyme digestion. No difference in frequencies of the A253 polymorphism between GD (21/204, 10.3%) and controls (34/358, 9.5%) was found in the UK Caucasians (chi2 = 0.093; p = NS). A similar finding was observed in GD (0/96, 0%) and controls (2/71, 2.8%) in Hong Kong Chinese subjects (chi2 = 2.73; p = NS). Results from the 89 UK families showed no deviation from the expected transmission frequency of 0.5, from parents heterozygous for the A253 allele to either Graves' or unaffected offspring (Fisher's exact test p = 0.22) and, therefore, confirmed a lack of evidence of linkage disequilibrium between the A253 allele and GD.

Linkage disequilibrium between the human leukocyte antigen class II region of the major histocompatibility complex and Graves' disease: replication using a population case control and family-based study.

Early case control studies found association of the DRB1 allele, DR3, with Graves' disease (GD). Recent reports, claim the DQA1 allele, DQA1*0501, to be the primary susceptibility determinant within the human leukocyte antigen (HLA) class II region. We typed 228 GD patients, 364 controls, and 98 families (parents, GD, and unaffected sibling) at the DRB1, DQB1, and DQA1 loci. The case control study showed an increased frequency in GD, compared to controls, of DRB1*0304 (47% vs. 24%; pc < 1.4 x 10(-5)), DQB1*02 (58% vs. 46%; pc < 0.035), DQB1*0301/4 (42% vs. 28%; pc < 3.5 x 10(-3)) and DQA1*0501 (67%, vs. 39%; pc < 7 x 10(-6)). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in GD (47%) vs. controls (24%; pc < 1.8 x 10(-5); odds ratio = 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to GD siblings (72%) was seen in the families (chi2 = 11.95; 1 d.f.; P = 0.0005). Lack of preferential transmission to unaffected siblings (53%; chi2 = 0.19; 1 d.f.; P = NS) excluded segregation distortion. These results show that linkage disequilibrium between GD and the HLA class II region is due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

Measurement of serum TSH in the investigation of patients presenting with thyroid enlargement.

In otherwise euthyroid patients presenting with thyroid enlargement, reduction in serum thyrotrophin (TSH) concentrations measured in a sensitive assay may be a marker of thyroid autonomy and may therefore indicate a benign underlying pathology. We investigated prospectively a cohort of 467 subjects presenting consecutively to our thyroid clinic with nodular or diffuse enlargement of the thyroid. Subjects were divided into those with normal (0.4-5.5 mU/l), low but detectable (0.1-0.39 mU/l) or undetectable (< 0.1 mU/l) serum TSH concentrations. The final pathological diagnosis was defined by fine-needle aspiration cytology and clinical follow-up of at least 2 years or by fine-needle aspiration cytology and histology following surgical treatment. Serum TSH concentrations below normal were found in 75 patients (16.1%), those with low serum TSH results having higher mean free T4 concentrations, were older and were more likely to be female. In those with undetectable serum TSH, no patient had a diagnosis of thyroid neoplasia and in those with low but detectable TSH, thyroid neoplasms were diagnosed in two patients (3.4%). In those with normal serum TSH, 12.0% had a final diagnosis of thyroid neoplasm (p = 0.013). Overall, thyroid malignancy was found in one patient (1.3%) of those with a serum TSH measurement below the normal range and 6.9% of those with normal serum TSH (p < 0.06). Reduction in serum TSH at presentation may identify a group which requires less intensive investigation and follow-up than those without biochemical evidence of thyroid autonomy.