The insulin-like growth axis in patients with autoimmune thyrotoxicosis: effect of antithyroid drug treatment.

OBJECTIVE: Hyperthyroidism is associated with altered growth hormone (GH) secretion. Many patients with thyroid dysfunction experience several poorly described complications such as symptoms and signs also seen in patients with growth hormone deficiency (GHD). We have therefore prospectively evaluated a possible relationship between the thyroid function, body composition, leptin levels and insulin-like growth factor (IGF) related peptides in patients with Graves' disease. DESIGN, PATIENTS, AND MEASUREMENTS: In a prospective group of 24 fasting female patients with Graves' disease (mean age (CI 95%): 40 years (33-47)), we measured serum thyroxine, triiodothyronine, thyrotropine (TSH), TSH receptor antibodies, anti-thyroid peroxidase, leptin, body composition, body mass index (BMI) and IGF-related peptides at diagnosis and after 12 months of treatment with thiamazol (ATD). RESULTS: In thyrotoxic patients IGF-I plus IGF-II correlated positively with IGFBP-3 at baseline (r = 0.90, p < 0.1 x 10(16)) and after 12 months follow-up (r = 0.87, p < 0.1 x 10(-16)). In the thyrotoxic state total IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid-labile subunit (ALS) but not free IGF-I decreased significantly from 223 microg/L (189-260) (mean (CI 95%), 877 microg/L (801-953), 4165 microg/L (3772-4577) and 22 mg/L (18-26)) to 198 microg/L (172-226), 788 microg/L (711-865), 3431 microg/L (3135-3741) and 19 mg/L (16-26) (p <0.006), respectively, after 12 months of ATD despite an increase in BMI from 22 (21-23) to 23 kg/m(2) (22-25) (p < 0.0004) but no significant changes in leptin. CONCLUSIONS: The complex IGF systems seemed intact in thyrotoxic patients but change in body composition and the regulation of leptin and insulin secretion during treatment of autoimmune thyroid disease influence IGF-related peptides leaving the patient in a state somewhat similar to partial GHD, but the mechanism behind these alterations remains unclear.     

Simple and practical parameters for differentiation between destruction-induced thyrotoxicosis and Graves' thyrotoxicosis

OBJECTIVE: Differentiation of destruction-induced thyrotoxicosis from Graves' thyrotoxicosis is important for selection of therapy. It is, however, often difficult to make this distinction without measurement of radioactive iodine uptake. We searched for simple and practical parameters that might allow differentiation between the two entities. PATIENTS: One hundred and eleven untreated patients with thyrotoxicosis (69 Graves' disease, 21 painless thyroiditis, 21 subacute thyroiditis) and 45 normal controls were examined. MEASUREMENTS: Serum levels of free T4 (FT4) and free T3 (FT3) were measured by radioimmunoassay, and anti-TSH receptor antibodies (TBII) were measured by radioreceptor assay. Peripheral leucocyte counts and the percentages of eosinophils and monocytes were measured using an automated leucocyte differential system. RESULTS: Peripheral eosinophils were significantly higher in Graves' disease (3.54 +/- 4.18%, P < 0.05) and lower in subacute thyroiditis (1.08 +/- 1.03%, P < 0.001) than in normal controls (2.26 +/- 1.33%). Peripheral monocytes were significantly higher in painless thyroiditis (6.87 +/- 2.85%, P < 0.01) than that in normal controls (4.63 +/- 2.14%). In comparison between groups, FT3 was higher with Graves' disease (20.55 +/- 10.29 pmol/l) than both painless thyroiditis (11.59 +/- 8.22 pmol/l, P < 0.001) and subacute thyroiditis (15.27 +/- 8.63 pmol/l, P < 0.05). The eosinophil to monocyte (Eo/Mo) ratio, FT3/FT4 ratio and Eo/Mo ratio multiplied by FT3 (pmol/ml) (Eo/Mo.FT3) were calculated and compared in these three disease groups. The Eo/Mo ratio, FT3/FT4 ratio and Eo/Mo.FT3 were significantly higher in patients with Graves' thyrotoxicosis (0.782 +/- 0.759, 0.399 +/- 0.089, 16.7 +/- 23.5 pmol/l, respectively) than in those with painless thyroiditis (0.259 +/- 0.157, 0.304 +/- 0.072, 2.43 +/- 1.49 pmol/l, respectively) and subacute thyroiditis (0.234 +/- 0.241, 0.335 +/- 0.057, 2.98 +/- 3.51 pmol/l, respectively). Twenty-two of 24 (91.7%) thyrotoxic patients with Eo/Mo < 0.2 had destruction-induced thyrotoxicosis (painless or subacute thyroiditis). Twenty-two of 28 (78.6%) thyrotoxic patients with FT3/FT4 < 0.3 had destruction-induced thyrotoxicosis. Thirty-six of 42 (85.7%) thyrotoxic patients with Eo/Mo.FT3 < 4.5 had destruction-induced thyrotoxicosis. The Eo/Mo ratio, FT3/FT4 ratio and Eo/Mo.FT3 were found to be similarly useful for differentiation between the two types of thyrotoxicosis. All thyrotoxic patients with TBII > or = 20% had Graves' disease and 76.4% of patients with TBII < 20% had destruction-induced thyrotoxicosis. CONCLUSION: The Eo/Mo ratio, FT3/FT4 ratio, and Eo/Mo.FT3 are simple, practical parameters and were as effective as TBII for differentiation of destruction-induced thyrotoxicosis (painless or subacute thyroiditis) from Graves' thyrotoxicosis. Eo/Mo < 0.2 and/or Eo/Mo.FT3 < 4.5 in untreated thyrotoxic patients are laboratory signals of destruction-induced thyrotoxicosis, and if these are determined, the radioactive iodine uptake test can be omitted for differential diagnosis of these two types of thyrotoxicosis.     

Coeliac disease in Dutch patients with Hashimoto＇s thyroiditis and vice versa

AIM To define the association between Hashimoto's thyroiditis and coeliac disease in Dutch patients.METHODS A total of 104 consecutive patients with Hashimoto's thyroiditis underwent coeliac serological tests (antigliadins, transglutaminase and endomysium antibodies) and HLA-DQ typing. Small intestinal biopsy was performed when any of coeliac serological tests was positive. On the other hand, 184 patients with coeliac disease were subjected to thyroid biochemical (thyroid stimulating hormone and free thyroxine) and thyroid serological tests (thyroglobulin and thyroid peroxidase antibodies).RESULTS Of 104 patients with Hashimoto's thyroiditis, sixteen (15%) were positive for coeliac serology and five patients with documented villous atrophy were diagnosed with coeliac disease (4.8%; 95% CI 0.7-8.9). HLA-DQ2 (and/or -DQ8) was present in all the five and 53 patients with Hashimoto's thyroiditis (50%; 95% CI 43-62). Of 184 patients with coeliac disease, 39 (21%) were positive for thyroid serology. Based on thyroid biochemistry, the 39 patients were subclassified into euthyroidism in ten (5%; 95% CI 2-9), subclinicalhypothyroidism in seven (3.8%; 95% CI 1.8-7.6), and overt hypothyroidism (Hashimoto's thyroiditis) in 22 (12%; 95% CI 8-16). Moreover, four patients with coeliac disease had Graves' disease (2%; 95% CI 0.8-5) and one patient had post-partum thyroiditis.CONCLUSION The data from a Dutch population confirm the association between Hashimoto's thyroiditis and coeliac disease. Screening patients with Hashimoto's thyroiditis for coeliac disease and vice versa is recom mended.     

Thyrotoxicosis in the very old

The records of 25 patients older than 75 years of age with the diagnosis of hyperthyroidism were reviewed. The mean age of the group (22 women and three men) was 81.5 years, the eldest being 95 years old. Twenty-one patients had Graves' disease, three had multinodular goiter, and one had toxic adenoma. Major presenting symptoms included weight loss (44 percent), palpitations (36 percent), and weakness (32 percent). The average number of thyrotoxic symptoms was only two per patient. Two patients were asymptomatic. Clinical signs included fine skin (40 percent), tremor (36 percent), atrial fibrillation (32 percent), and tachycardia (28 percent). The thyroid was palpable in only three patients with Graves' disease. Mean blood thyroxine level was 15.6 micrograms/dl (range, 11.5 to 24); blood triiodothyronine level was elevated in only half of the patients. One patient had triiodothyronine toxicosis. Mean 24-hour radioiodine uptake was 52 percent. Five patients had normal uptake. No correlation could be established between age, clinical symptoms, signs, and hormone blood levels. Because signs and symptoms of hyperthyroidism in the very old may be too subtle for clinical diagnosis, all elderly subjects should have periodic screening of blood thyroxine levels.     

Clinical and subclinical autoimmune thyroid disorders in systemic sclerosis

OBJECTIVE: Several studies have reported the association of systemic sclerosis (SSc) with thyroid autoimmune disorders, but most of them have neither an appropriate control group nor include a complete thyroid work-up. DESIGN: The aim of our study was to evaluate the prevalence of thyroid disorders in a large number of patients with SSc using a complete clinical evaluation. METHODS: Thyroid-stimulating hormone (TSH), free triiodothyronine, free thyroxine, antithyroglobulin and antithyroid-peroxidase (AbTPO) autoantibodies, thyroid ultrasonography and blood flow and fine needle aspiration were performed in 202 SSc patients versus 404 gender- and age-matched controls from the general population, with similar iodine intake, to evaluate the prevalence of clinical and subclinical thyroid disorders. RESULTS: Odds ratio (OR) for female SSc versus controls was: for subclinical hypothyroidism, 3.2 (95% CI)=1.8-5.7); for clinical hypothyroidism, 14.5 (95% CI=2.3-90.9); for AbTPO positivity, 2.7 (95% CI=1.8-4.1); for hypoechoic pattern, 3.2 (95% CI=2.2-4.7); for thyroid autoimmunity, 3.7 (95% CI=2.6-5.4); for thyroid volume <6 ml, 1.8 (95% CI=1.2-2.7). OR for thyroid autoimmunity in male SSc versus controls was 10.8 (95% CI=2.2-52.4). Mean values of TSH in female SSc, and of AbTPO in female and male SSc were higher (P<0.01) than in controls. We observed three cases of Graves' disease in female SSc versus zero in controls (P=0.0140), and two cases of papillary thyroid cancer in SSc patients. CONCLUSIONS: Thyroid function, AbTPO and ultrasonography should be tested as part of the clinical profile in SSc patients. Females, subjects with positive AbTPO and hypoechoic and small thyroid should have thyroid function follow-up and appropriate treatment in due course.     

Propylthiouracil reduces the effectiveness of radioiodine treatment in hyperthyroid patients with Graves' disease.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of 131I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T3), thyroxine (T4), free thyroxine (FT4), antithyroid autoantibody levels, 24-hour radioiodine uptake and 131I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively (p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of 131I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82-18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.     

Smoking and other lifestyle factors and the risk of Graves' hyperthyroidism

BACKGROUND: Hyperthyroidism caused by Graves' disease is common in women, yet little is known about risk factors for the disease. We sought to determine whether lifestyle factors, including smoking, alcohol consumption, physical activity level, and body mass index, are risk factors for Graves' hyperthyroidism. METHODS: This analysis was conducted using data from the Nurses' Health Study II, among 115109 women aged 25 to 42 at entry. Incident reports of women with Graves' hyperthyroidism, confirmed to have the disorder, were included. RESULTS: During 1 328 270 person-years of follow-up, incident diagnoses of Graves' hyperthyroidism were confirmed in 543 women; the 12-year incidence was 4.6 per 1000 women. Cigarette smoking was a predictor of Graves' hyperthyroidism. The hazard ratio among current smokers was 1.93 (95% confidence interval [CI], 1.54-2.43), and among past smokers it was 1.27 (95% CI, 1.03-1.56), after adjusting for recent pregnancy, parity, and other variables. Among current smokers, the hazard ratio increased with the intensity of smoking and was 2.63 (95% CI, 1.71-4.04) among women who smoked 25 or more cigarettes daily. Obesity was associated with a decreased risk of Graves' hyperthyroidism. The hazard ratio for the disorder among women with a body mass index of 30 kg/m(2) or higher was 0.68 (95% CI, 0.49-0.92). Alcohol intake and physical activity level were not associated with risk of Graves' hyperthyroidism. CONCLUSIONS: Smoking is a risk factor for Graves' hyperthyroidism in women. Obesity may be associated with a reduced risk, although weight loss as the first manifestation of hyperthyroidism cannot be excluded.     

Serum ratio of triiodothyronine to thyroxine, and thyroxine-binding globulin and calcitonin concentrations in Graves' disease and destruction-induced thyrotoxicosis

The serum ratios of T3 to T4, and T4-binding globulin (TBG) and calcitonin concentrations were studied in cases of thyrotoxic Graves' disease and destruction-induced thyrotoxicosis. In 272 patients with Graves' disease, 209 of 240 (87%) untreated patients without complications had high T3 to T4 ratios (nanograms per micrograms) of more than 20. Six of 32 (19%) patients with Graves' disease who had complications (15 with pregnancy, 14 with increased TBG, and 3 with conditions associated with a low T3 syndrome) had high T3 to T4 ratios. Eleven of 74 (15%) patients with destruction-induced thyrotoxicosis (24 with subacute thyroiditis, 39 with postpartum transient thyrotoxicosis, and 11 with spontaneous transient thyrotoxicosis) had high T3 to T4 ratios. Patients who had serum T4 levels of more than 30 micrograms/dl and/or T3 levels of more than 800 ng/dl had Graves' disease. There was no significant correlation between the T3 to T4 ratio and activities of thyroid-stimulating immunoglobulins in thyrotoxic patients with Graves' disease who had no complications. The average serum levels of TBG in destruction-induced thyrotoxicosis and thyrotoxic Graves' disease were 20.7 +/- 4.3 micrograms/ml (mean +/- SD; n = 22), and 19.9 +/- 4.0 (n = 41), respectively, which were significantly lower than that in healthy subjects (22.7 +/- 4.4 micrograms/ml; n = 165), but there was no difference between the values in the two groups of thyrotoxicosis patients. The average serum level of calcitonin in destruction-induced thyrotoxicosis patients was 96.7 +/- 66.7 pg/ml (n = 21), which was significantly (P less than 0.05) higher than the values in patients with thyrotoxic Graves' disease (62.0 +/- 44.7 pg/ml; n = 26) and in healthy subjects (63.9 +/- 31.2 pg/ml; n = 29), but the difference in values in the two groups of thyrotoxicosis was not clinically useful because of considerable overlap of individual values. The T3 to T4 ratio is a simple and helpful index for the differentiation of the two types of thyrotoxicosis. A T3 to T4 ratio less than 20 in thyrotoxic patients before therapy is a laboratory signal of destruction-induced thyrotoxicosis or Graves' disease with complications, but final differentiation should be confirmed by measuring radioactive iodine uptake.     

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.     

Prevalence of thyroid disease in an older Australian population

Aim: To determine the prevalence of thyroid disease in an older Australian population in a population‐based cross‐sectional study. Background: Community‐living subjects, aged 49 years or older, in two Blue Mountains postcodes were invited to participate in an eye, nutrition and health study between 1997 and 2000. Methods: Three thousand five hundred and nine of the 4489 identified persons participated. Fifty‐seven per cent of 3504 who completed questionnaires were women; their mean age was 66.8 years. Thyroid‐stimulating hormone (TSH) was measured in 2665 subjects (76% of those completing the questionnaire). The main outcome measures were serum TSH and free thyroxine levels, serum lipids, urate and sugar levels and questionnaire responses. Results: The prevalence of recognized thyroid disease (either self‐reported history of thyroid disease or current thyroxine treatment) was 10% (95% confidence interval (CI) 8.9–11.1%). An additional 3.6% (95%CI 2.9–4.3%) of participants had unrecognized thyroid disease (abnormal TSH). The TSH was abnormal in 7.1% (95%CI 5.8–8.4%) of women and 3.7% (95%CI 2.6–4.8%) of men. Sixty‐five per cent of those with an abnormal TSH did not report a history of thyroid disease, whereas 25% of those taking thyroxine replacement therapy had an abnormal TSH level. The prevalence of hypothyroidism increased with increasing age in women. The mean fasting cholesterol was 0.36 mmol/L (95%CI 0.15–0.57) higher in hypothyroid subjects than in euthyroid subjects. Conclusion: Thyroid disease in older Australian women is relatively common and may be undiagnosed. Ongoing monitoring of patients on thyroxine replacement therapy is important, given that 25% of treated patients had an abnormal TSH.     

The role of CARD15 mutations and smoking in the course of Crohn's disease in a Mediterranean area

AIM: To evaluate the role of CARD15 mutations and smoking in the main events of Crohn's disease (CD). PATIENTS AND METHODS: A total of 182 patients with CD were included in a prospective study in order to evaluate the role of CARD15 mutations and smoking in the main outcomes of disease course: first operation and surgical recurrence. The following variables were evaluated in a univariable and multivariable analysis: age, sex, site of disease, pattern, smoking habit, extraintestinal manifestations, duration of disease, and CARD15 mutation. The Kaplan-Meier method for survival curves and Cox model for multivariable analysis were, respectively, used. RESULTS: A total of 110 patients were operated on and 32 were reoperated on. The 7-yr cumulative free rate of surgery was 42% (95% CI 34-51%). At multivariate analysis only stricturing and penetrating pattern were predictors of surgery (HR 1.7, 95% CI 1-2.8; HR 3.2, CI 1.8-5.5, respectively). The 7-yr cumulative free rate of reoperation was 75% (95% CI 0.52-0.88). At multivariable analysis in the model with any CARD15 mutation, only smoking habit at diagnosis (HR 3.6, 95% CI 1.4-9.1) was predictive of surgical recurrence. When single mutations were considered in the model smoking (HR 4.2, 95% CI 1.8-10.1) and L1007fs mutation (HR 2.9, 95% CI 1.1-7.3) were predictive of reoperation. CONCLUSIONS: In CD, smoking predicts recurrence after surgery. The role of CARD15 mutations in the clinical course of CD remains undefined.     

Fracture experience of patients with coeliac disease: a population based survey

BACKGROUND: While coeliac disease is now recognised as being associated with both osteoporosis and osteomalacia, the size of any increase in the risk of fracture in patients with coeliac disease compared with the general population has not been quantified. Aim: To examine the fracture experience of adults with coeliac disease compared with the general population. SUBJECTS: Patients with coeliac disease diagnosed in adulthood and born before 1950, selected from two large population based disease registers, and age and sex frequency matched controls identified from local general practitioner lists. METHODS: A four page lifestyle and general health questionnaire which included specific questions about fracture experience. RESULTS: Analysis was performed on 244 patients with coeliac disease and 161 controls, giving response rates of 89% and 72%, respectively. Eighty two (35%) coeliac patients and 53 (33%) controls reported ever having sustained one or more fractures, giving an age and sex adjusted odds ratio of 1.05 (95% confidence interval (CI) 0.68-1.62). The most common fracture site reported was the forearm or wrist, with an adjusted odds ratio of 1.21 (95% CI 0.66-2.25) for patients with coeliac disease having had a forearm or wrist fracture. Low trauma fractures were reported by 37 patients with coeliac disease (15.7%) and by 21 controls (13.8%), with an adjusted odds ratio of 1.16 (95% CI 0.65-2.10). The risk of low trauma fracture was slightly higher in coeliac men than women (odds ratio 1.28 compared with 1.12), but this difference was not statistically significant (p=0.84). After adjustment for age, sex, body mass index, and smoking status, patients with coeliac disease reported 13% more low trauma fractures than controls (odds ratio 1.13, 95% CI 0.60-2.12). There was no difference in low trauma fracture risk before and after diagnosis of coeliac disease. CONCLUSION: No overall increased fracture risk in patients with coeliac disease was observed. Although severe osteoporosis may develop in a subset of patients, as a whole patients with coeliac disease do not represent a population at particularly high risk of osteoporotic fracture and thus targeting them for osteoporosis screening and treatment is not justified.     

Smoking as a risk factor for Graves' disease, toxic nodular goiter, and autoimmune hypothyroidism.

To study the association between smoking and thyroid disease (Graves' disease [E05.0], nodular toxic goiter [E05.2], and autoimmune hypothyroidism [E03.9]) in a low-iodine intake area a case-control study was undertaken. A self-administered questionnaire was issued to 864 consecutive patients with hyperthyroidism and 628 patients with autoimmune hypothyroidism treated at five university or regional endocrinologic clinics in Denmark between January 1, 1990 and December 31, 1998. Each respondent was compared to an age- (+/- 5 years) and gender-matched normal control person randomly drawn from the background population. A total of 621 patients with hyperthyroidism (72%) and 411 patients with autoimmune hypothyroidism (66%) responded. Of these, 617 (542 females) and 408 (364 females) could be analyzed, respectively. There was an increased risk of both Graves' disease (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.8-3.5), toxic nodular goiter (OR = 1.7, 95% CI: 1.1-2.5), and autoimmune hypothyroidism (OR = 1.5, 95% CI: 1.1-2.1) with ever smoking compared to never smoking in women, but not in men. With the high proportion of ever-smokers among women (56%), the attributable risk of smoking in women was 45% in Graves' disease, 28% in toxic nodular goiter, and 23% in autoimmune hypothyroidism. Ever use of oral contraceptives was associated with a slightly lower risk of Graves' disease in women, but not of toxic nodular goiter or autoimmune hypothyroidism. In conclusion, smoking is a powerful risk factor for thyroid disease, especially in populations with a high smoking frequency. Oral contraceptive use is associated with a slightly lower frequency of Graves' disease.     

Graves' disease associated with familial deficiency of thyroxine-binding globulin.

Five patients presented with symptoms of Graves' disease and a marked decrease in their thyroxine-binding globulin (TBG) capacity. While thyrotoxic, mean values +/- SD for the 5 patients were: total thyroxine (TT4) 8.8+/-2.0 mug/100 ml (normal range 4.4-9.3); TBG capacity 6.1+/-1.1 mug T4/100 ml (normal range 16-24); free thyroxine index (FTI) 25.3+/-8.9 (normal range 3.6-9.3); and total triiodo-thyronine (TT3) 244+/-56 ng/100 ml (normal range 80-160). When euthyroid, both TT4 (2.8+/-0.8 mug/100 ml) and TT3 (68+/-12 ng/100 ml) were below the normal range and FTI (5.8+/-0.6) was normal. All patients were male, and family studies revealed decreased TBG capacity in blood relatives consistent with X-chromosome linked inheritance. All examined relatives relatives of the propositi, whether hemizygous or heterozygous, were euthyroid. Over the same period of time 7 additional patients (excluding family members of propositi) were found to be euthyroid but had decreased TBG capacity. The occurrence of thyrotoxicosis in 5 out of 12 patients with inherited TBG deficiency suggests an association rather than a coincidental finding, although initial tests were performed because of suspected thyroid dysfunction. The incidence of thyrotoxicosis in patients with inherited TBG deficiency is also high on the basis of the reported prevalence of the latter genetic abnormality. This study stresses the importance of determining TT3 and FTI on patients who are clinically thyrotoxic but have normal TT4.     

Increased serum concentration of interleukin-12 in patients with silent thyroiditis and Graves' disease.

We previously reported that interleukin-5 (IL-5), secreted from Th2 cells, was increased in patients with Graves' disease, but not in patients with silent thyroiditis. In this study, we investigated serum levels of interleukin-12 (IL-12) in order to examine the role of Th1-type immune response in the pathogenesis of autoimmune thyroid diseases. Serum levels of IL-12 were determined by a highly sensitive sandwich enzyme-linked immunosorbent assay in 68 patients with Hashimoto's thyroiditis (26 of whom had silent thyroiditis), 74 patients with Graves' disease, 8 patients with subacute thyroiditis, and 27 normal controls. Serum levels of IL-12 in thyrotoxic patients with silent thyroiditis (385.2 +/- 164.5 pg/mL, mean +/- SD), and in thyrotoxic patients with Graves' disease (343.6 +/- 163.8 pg/mL) were significantly increased compared with serum levels in normal subjects (163.9 +/- 66.8 pg/mL, p < 0.0001, p < 0.0001, respectively) or in thyrotoxic patients with subacute thyroiditis (241.9 +/- 46.5 pg/mL, p < 0.01, < 0.05, respectively). The ratio of IL-12 to IL-5 in thyrotoxic patients with silent thyroiditis (64.2 +/- 39.7) was significantly higher than that in normal controls (33.7 +/- 13.3, p < 0.01) or in thyrotoxic patients with Graves' disease (40.6 +/- 36.0, p < 0.05). These data suggest that Th1-type immune response is predominant in silent thyroiditis, and that not only Th2-type immune response but also Th1-type immune response is important in the pathogenesis of Graves' disease.     

Smoking and thyroid disorders--a meta-analysis

BACKGROUND: Smoking has been associated with Graves' disease, but it remains unclear if the association is present in other thyroid disorders. OUTCOME VARIABLES: Graves' disease, Graves' ophthalmopathy, toxic nodular goitre, non-toxic goitre, post-partum thyroid disease, Hashimoto's thyroiditis, or hypothyroidism. MATERIAL AND METHODS: A search of MEDLINE identified 25 studies on the association between smoking and thyroid diseases. RESULTS: In Graves' disease eight studies were available showing an odds ratio (OR) of 3.30 (95% confidence interval (CI): 2.09-5.22) in current smokers compared with never smokers. In ex-smokers there was no significant excess risk of Graves' disease (OR=1.41, 95% CI: 0.77-2.58). The OR associated with ever smoking in Graves' ophthalmopathy (4.40, 95% CI: 2.88-6.73, six studies) was significantly higher than in Graves' disease (1.90, 95% CI: 1.42-2.55, two-sided P-value <0.01). Ever smoking was not associated with toxic nodular goitre (OR=1.27, 95% CI: 0.69-2.33, three studies), while there was an increased risk of non-toxic goitre in smokers if men were excluded (OR=1.29, 95% CI: 1.01-1.65, eight studies). The risk associated with smoking was significantly lower in men than in women for both Graves' disease and non-toxic goitre. Hashimoto's thyroiditis and post-partum thyroid dysfunction were also associated with smoking while the association with hypothyroidism did not reach statistical significance. CONCLUSIONS: Cessation of smoking seems associated with a lower risk of Graves' disease than current smoking. Smoking increases the risk of Graves' ophthalmopathy beyond the risk associated with Graves' disease alone. Smoking cessation may lead to a decrease in morbidity from Graves' disease, especially in women.     

Polymorphism in the transmembrane region of the major histocompatibility complex class I chain-related gene A: association of five GCT repetitions with Graves' disease in children.

Graves' disease is an autoimmune disease involving a complex interplay of multiple genetic and environmental influences. An association between the disorder and the major histocompatibility complex (MHC; human leukocyte antigen [HLA]) region has long been reported. The major histocompatibility complex class I chain-related gene A (MICA) has a triplet repeat polymorphism in the transmembrane region consisting of six alleles. For this study, the polymorphism in question was analyzed for 129 unrelated children with Graves' disease (97 girls and 32 boys, 10.0 +/- 3.0 years of age) and 396 randomly selected, unrelated subjects (205 females, 191 males, 8.4 +/- 13.5 years of age). The frequencies of genotype A5/A5 and A5/A5.1 were significantly higher in patients than in controls (relative risk [RR] = 2.49, 95% confidence interval [CI] 1.52-4.10, p = 0.00024, pc = 0.0035 and RR = 2.13, 95% CI 1.31-3.47, p = 0.0020, pc = 0.030; respectively). The frequency of genotype A5.1/A5.1 was significantly lower in patients than in controls (RR = 0.09, 95% CI 0.01-0.66, p = 0.0030, pc = 0.044). Allele frequency for allele A5 was significantly higher for children with Graves' disease compared to controls (RR = 2.12; 95% CI = 1.59-2.82; p = 1.9 x 10(-7); pc = 9.5 x 10(-7)). This study demonstrates that MICA allele A5 confers the risk for Graves' disease.     

Graves' disease: an analysis of thyroid hormone levels and hyperthyroid signs and symptoms

PURPOSE: Assessment of disease severity for patients with hyperthyroidism involves clinical evaluation and laboratory testing. To determine if there is a correlation between symptoms and thyroid function test results, we prospectively studied hyperthyroid patients using a standardized symptom rating scale and serum thyroid function parameters. PATIENTS AND METHODS: We examined 25 patients with untreated, newly diagnosed Graves' disease using the Hyperthyroid Symptom Scale (HSS) and serum levels of thyroxine (T4), triiodothyronine (T3) relative insulin area (RIA), and estimates of free thyroxine index (FTI). In addition, we compared thyroid hormone levels with standard measures of depression and anxiety in these patients. RESULTS: When regression analyses controlling for age were performed, none of these symptom ratings were associated with FTI or T3 RIA. The HSS was correlated with goiter size and anxiety ratings and was inversely correlated with age. CONCLUSION: The present study suggests that there is no relationship between the clinical assessment of disease severity and serum levels of thyroid hormone in untreated Graves' disease.     

Validation of a French translation of the Edinburgh claudication questionnaire among general practitioners' patients

OBJECTIVES: Intermittent claudication is one of the clinical symptoms of peripheral arterial disease (PAD). The presence of PAD is a high risk marker of cardiac events and stroke. The PAD screening can be enhanced by the use of questionnaires. The Edinburgh Questionnaire presents in its English version better diagnostic performances compared to the Rose (WHO) Questionnaire. The aim of this study is to precise the performances of the French version of the Edinburgh Questionnaire among a population consulting general practitioners. METHODS: Four centers instructed 10 general practitioners each to the measurement of ankle pressure with a Doppler stethoscope. The physicians administrated the Questionnaire to 10 consecutive consultants in a same day, and measured the pressure on posterior tibial, dorsalis pedis and humeral arteries. With a second questionnaire they collected data concerning age, weight, height, and the presence of major risk factors. The same protocol was repeated a second day on new patients. The diagnosis of PAD was based on an ankle-arm index lower than 0.85 for at least on limb. RESULTS: The population studied consisted of 727 subjects (351 females and 376 males). The mean age was at 58.3 +/- 16.1 years (ranging from 18 to 83.3 years). The sensitivity of the Questionnaire is at 47% (95% CI: 32.3-61.7%), the specificity at 98.8% (95% CI: 97.5-99.4%), the positive and negative predictive values are respectively at 73.3% (95% CI: 54.1-87.7%) and 94.8% (95% CI: 94.7-97.6%). Among this population of general practitioners consultants, the prevalence of a low ankle-arm index under 0.85 is at 6.7%. DISCUSSION: The French version of the Edinburgh Questionnaire maintains the very good specificity of the English version. The lower sensitivity could be explained by the choice of the gold standard, namely the ankle-arm index which includes asymptomatic patients with authentic PAD. The use of this Questionnaire can be recommended for the screening of this disease as well as in epidemiological studies.     

Evaluation of the phadiatop test in the diagnosis of allergic sensitization in a general adult population.

BACKGROUND: Phadiatop is a commercially available qualitative serological test employed for screening of allergic sensitization in patients with suspected allergic diseases. AIM: The study evaluated the diagnostic accuracy of Phadiatop for the diagnosis of allergic sensitization in a general adult population. METHODS: A total of 469 subjects from the population of A-Estrada (Spain) were selected by age-stratified random sampling (age range, 18-92 years). Phadiatop test (Uni-CAP method) was performed in serum samples from 465 of these subjects. Skin prick tests to a panel of 13 relevant aeroallergens in the studied area (including mites, pollens, moulds, and animal dander) were employed as the reference diagnostic procedure. Subjects with at least a positive skin prick test (> or =4 mm, n= 120) were considered to have allergic sensitization. RESULTS: Phadiatop sensitivity was 70.8% (95% CI 61.7-78.6%), specificity 90.7% (95% CI 87.0-93.5%), positive predictive value 72.6% (95% CI 63.5-80.3%), negative predictive value 89.9% (95% CI 86.2-92.8%), global accuracy 85.6% (95% CI 82.0-88.6%), negative likelihood ratio 0.3 (95% CI 0.2-0.4), and positive likelihood ratio 7.6 (95% CI 5.4-10.8). A high proportion of false-positive Phadiatop cases showed (a) increased total serum IgE levels, (b) significant alcohol consumption, and (c) small-sized (below the diagnostic cut-off) wheal reactions on SPT. A high proportion of false-negative Phadiatop cases showed exclusive storage mite sensitization. Sensitivity and positive predictive value of Phadiatop were somewhat higher among individuals with a history of nasal or bronchial symptoms. CONCLUSIONS: Phadiatop is a valuable tool for the diagnosis of allergic sensitization in a general adult population. However, limitations of the test should be taken into account in similar surveys.