Anti-Thyroperoxidase Antibody Levels >500 IU/ml Indicate a Moderately Increased Risk for Developing Hypothyroidism in Autoimmune Thyroiditis.

Autoimmune Thyroiditis (AIT) is the most common autoimmune disease, which is characterized by cellular and humoral immunity leading to thyroid destruction. The impact of the humoral immunity on the risk to develop hypothyroidism has not exactly been defined yet. The aim of the present study was to investigate the association between thyroid antibody levels and the risk for developing hypothyroidism. In this retrospective study, 335 untreated AIT patients were enrolled. Anti-thyroperoxidase (TPO) antibodies, anti-thyroglobulin (Tg) antibodies (Abs), and the TSH level were measured. Patients with TPO-Ab levels>500 IU/ml showed a moderately increased risk of having elevated TSH levels [p=0.0023; relative risk (95% confidence interval): 1.343 (1.108-1.627)] compared to those below this threshold. AIT patients with TPO- or Tg-Abs<100 IU/ml and between 100-500 IU/ml had no significantly different TSH levels. Presence of Tg-Abs alone or in combination with TPO-Abs did not help to increase the sensitivity to identify patients at risk. Long term follow-up of AIT patients with high TPO-Abs level (>500 IU/ml) showed an increase of TSH levels (mean: 0.5 mIU/l; range: 2.52±2.73 to 3.02±3.05 mIU/l; p=0.0420). Still, these patients remained euthyroid. Our data indicate largely elevated levels of TPO-Abs being associated with a moderately increased risk of developing hypothyroidism.

Prevalence of the metabolic syndrome in German women with polycystic ovary syndrome.

The aim of our study was to evaluate the prevalence of the metabolic syndrome (MBS) according to the current International Diabetes Federation definition in German PCOS women. Four hundred and eleven PCOS patients (age 28+/-6.3 years) and 82 controls (age 28+/-7.5 years) were evaluated for anthropometric and metabolic parameters by physical examination, blood testing and a personal interview including family history. A subgroup analysis of controls with BMI-matched PCOS women (BMI 22.9+/-2.8 kg/m (2)) was performed to detect PCOS specific differences in metabolic variables between the groups. The MBS was found in 33.8% of PCOS women compared to 7.3% in the control group. Parameters of insulin resistance, lipid-and glucose metabolism, mean values of all criteria of the MBS as well as the prevalence of the MBS were significantly different between the entire PCOS cohort and controls, but did not differ between BMI-matched PCOS women and controls. In addition, the prevalence of the MBS increased with age. Moreover, in PCOS women an increase in BMI and insulin resistance was accompanied by a further significant increase in the severity of clinical and biochemical hyperandrogenism. In PCOS women, while one out of three PCOS women had the MBS, the presence of metabolic abnormalities did not appear to be associated with PCOS per se, but rather correlated with age and the degree of obesity.

Low serum 25-hydroxyvitamin D concentrations are associated with insulin resistance and obesity in women with polycystic ovary syndrome.

Insulin resistance (IR) and central obesity are common features of the polycystic ovary syndrome (PCOS). Vitamin D is thought to play a role in the pathogenesis of type 2 diabetes by affecting insulin metabolism. The aim of our study was to investigate the effect of 25-hydroxyvitamin D (25-OH-VD) on metabolic parameters and IR in PCOS. In 120 untreated PCOS patients (median age 28 years) levels of 25-OH-VD (radioimmunoassay method provided by DiaSorin), calcium and anorganic phosphate were measured. In addition, endocrine and metabolic variables were evaluated and a glucose tolerance test was performed to assess indices of IR. In the entire PCOS cohort, 25-OH-VD concentrations were negatively correlated with body mass index (r=-0.2765), body fat (r=-0.2490), HOMA-IR (r=-0.1947), hyperinsulinemia (r=-0.1892) and leptin levels (r=-0.2834), and positively correlated with HDL cholesterol (r=0.2630) (all p<0.05). Subgroup analysis of lean, overweight and obese women revealed significant higher 25-OH-VD levels in lean women. Differences remained significant when women were divided according to their 25-OH-VD levels. Women with hypovitaminosis D (<9 ng/ml) had higher mean BMI, indices of IR and leptin levels compared to women with normal serum levels (all p<0.05). Analysis of vitamin D and biochemical endocrine PCOS features revealed a significant correlation only between 25-OH-VD and sex hormone-binding globulin as well as the free androgen index. In conclusion, in PCOS women, low 25-OH-VD levels are associated with obesity and insulin resistance but not with PCOS per se.

Dysregulation of TNF/TNFR superfamily members: a systemic link between intra- and extrathyroidal manifestations in Graves' disease.

Graves' disease (GD) coincides with the occurrence of disease-associated intrathyroidal dendritic cells (DC) and intraorbital inflammatory macrophages (Mphi). Physiologically, tumour necrosis factor-alpha (TNF-alpha) strongly affects the differentiation of DC and Mphi from monocytic precursors; we thus hypothesized that dysregulation of the TNF/TNFR superfamilies may provide a systemic pathogenic link in GD. In patients without eye symptoms, percentages of TNF-alpha-stimulated blood monocytes were highly significantly (P < 0.001) elevated, corresponding to both intrathyroidal DC maturation as well as increases in mature blood DC (MHC-II(hi)/CD40+/RFD1(hi)) and B cells (CD20(hi)/CD40+). GD patients also displaying eye symptoms revealed a striking reduction in blood monocytes, yet significantly (P < 0.05) increased CD40(hi) and TNF-alpha(hi) leucocytes. These findings suggest for GD that excess TNF-alpha induces monocytes to differentiate into hyperactivated thyroidal DC that, once emigrated, initiate systemic humoral autoimmunity associated with CD40/TNF-alpha upregulation. Such overexpression may instigate differentiation of periorbital inflammatory Mphi from CD14(hi)/CD16+ monocytes as a likely precursor subset. These results indicate that dysregulation of TNF/TNFR superfamily members provides a systemic pathogenic link in GD in that hyperactivated circulating monocytic precursors give rise to locally restricted, disease-associated DC and Mphi. Monocytes, therefore, may serve as a suitable target to therapeutically address the common precursor of key promoters of GD.

Impact of smoking on the course of Graves' disease after withdrawal of antithyroid drugs.

Cigarette smoking has been reported to alter relapse rate in patients with Graves' disease (GD). However, the predictive effect of smoking in GD patients after withdrawal of antithyroid drug treatment (ATDT) is still controversial. A prospective multicenter trial has previously identified smoking as an independent risk factor for relapse. Based on this study, the present paper gives a more detailed analysis of the impact of smoking on the long-term course of GD after ATDT withdrawal. To this end, 86 smokers and 177 non-smokers were followed during two years after ATDT cessation. At the end of ATDT (visit 1) and four weeks later (visit 2) smokers had significant higher TSH receptor antibody (TRAb) levels than non-smokers (10.0 IU/L+/-1.6; mean+/-SEM vs. 6.4 IU/L+/-0.9; 11.0 IU/L+/-1.8 vs. 6.8 IU/L+/-0.8, p < 0.01, respectively). During follow-up, Kaplan Meier analysis showed a significantly higher relapse rate in smokers than non-smokers. A subset of GD patients with TRAb levels >10 IU/L had the highest risk to develop relapse during follow-up. Among them, smokers more often relapsed than non-smokers irrespective of TRAb levels, p < 0.01. Thus, in smokers with TRAb levels > or =10 IU/L the predictive values of a positive and negative test for relapse was 68% and 73%, respectively (specificity 95%). In conclusion, we identified two effects by which smoking alters the course of GD. First, smoking is implicated to elevate TRAb levels and therefore increase the risk for relapse during follow-up. Second, smoking is an independent risk factor to worsen the clinical course of both, GD patients with low and high immunological risk to experience relapse after a successful outcome of ATDT. Thus, our data suggest that smoking has modifying immunological consequences and an adverse impact on the course of GD after withdrawal of ATDT. Therefore, patients should be encouraged to stop smoking.

Gadolinium as an alternative contrast agent during cardiac catheterization in patient with iodine-induced hyperthyroidism.

We report the first case of a male patient with iodine-induced hyperthyroidism and unstable angina pectoris in whom a diagnostic cardiac catheterization with gadolinium as contrast agent was chosen. The patient was hospitalized with an iodine-induced hyperthyroidism after angioplasty using an iodinated contrast agent. He presented with a continuous arrhythmia and unstable angina pectoris. A repeated cardiac catheterization using iodinated contrast agent was contraindicated. This case report shows that gadolinium is a useful alternative contrast agent for cardiac intervention in patients with iodine-induced hyperthyroidism.

Binding, stimulating and blocking TSH receptor antibodies to the thyrotropin receptor as predictors of relapse of Graves' disease after withdrawal of antithyroid treatment.

TSH-receptor autoantibodies (TRAbs) are a valuable diagnostic tool for confirming a diagnosis of Graves' disease (GD). While there is evidence that high TRAb levels are associated with relapse of GD, whether a discrimination of TRAb into stimulating (TSAb) and blocking (TBAb) autoantibodies would benefit the clinician in terms of outcome prediction remains unclear. To address this issue, we have determined TRAb, TSAb and TBAb levels in serum samples of ninety-six euthyroid patients with GD taken four weeks after antithyroid drug withdrawal (ATDT). Forty-seven patients (49 %) underwent relapse of GD within two years. Amongst those, forty-one (87 %) had been positive for TRAb and thirty-five (74 %) for TSAb after treatment. All patients except one were negative for TBAb. The correlation between TRAb and TSAb in those treated GD patients was relatively weak (r = 0.268, p < 0.001). Based on a cut-off limit of 1.5 IU/l, the positive and negative predictive values with respect to prediction of relapse were too low for any clinical relevance (TRAb: 49 % and 54 %; TSAb: 51 % and 55 %). However, when a cut-off level above 10 IU/l was used, the positive and negative predictive values increased to 83 % and 62 %. The additional measurement of TSAb or TBAb in those samples after therapy did not add additional information, even at higher decision thresholds. In conclusion, differentiation of TRAb into TSAb and TBAb is of no help in the prediction of relapse of GD in euthyroid patients at the end of ATDT, and only high TRAb levels are associated with relapse.

Clinical and biochemical characterization of women with polycystic ovary syndrome in North Rhine-Westphalia.

Polycystic ovary syndrome (PCOS), defined as the combination of oligoanovulation and hyperandrogenism, affects more than 5% of women of reproductive age. Insulin resistance and hyperinsulinemia appear to play an important role in its pathogenesis. Here, we will present a characterization of a PCOS cohort from North Rhine-Westphalia in Germany. Clinical features, family history as well as endocrine and metabolic parameters were prospectively recorded from 200 successive patients. All patients were evaluated for insulin resistance and beta-cell-function by oral glucose tolerance test. Patient data were compared with those of 98 age-matched control women. PCOS patients showed significantly higher BMI, body fat mass and androgen levels as well as impaired glucose and insulin metabolism. A positive family history of PCOS and diabetes was more frequent in PCOS patients. Insulin resistance (71%) was the most common metabolic abnormality in PCOS patients followed by obesity (52%) and dyslipidemia (46.3%), with an incidence of 31.5% for the metabolic syndrome. C-reactive protein and other cardiovascular risk factors were frequently elevated even in young PCOS patients. While the clinical characteristics and endocrine parameters of this German PCOS cohort were heterogeneous, they were comparable to those from other Caucasian populations.

[Problems and new developments in the management of Graves' disease: medical therapy]. / Therapie des Morbus Basedow: Probleme und neue Entwicklungen: Medikamentöse Therapie.

Since no causative treatment of Graves' disease is available, symptomatic therapy has been derived from clinical studies (evidence class I and II). To date, conservative treatment still has a relapse rate of 30-50% that is most likely due to the heterogeneity of patients. There is no clear data about the duration of therapy necessary for the individual patient. Previous prospective randomised studies have evaluated prognostic parameters including the use of levothyroxine for relapse prevention. For an improved characterisation of the natural course of Graves' disease, the period after drug withdrawal was studied. As patients treated with high doses of antithyroid drugs (< 10 mg thiamazole) and patients with large goitres (< 50 ml) often develop hyperthyroidism, they make likely candidates for radioiodine therapy or surgery. Smoking is a very strong independent risk factor for relapse. A prospective multi-centre trial of the Thyroid Chapter of the German Endocrine Society (DGE-SSD) demonstrated that the basal TSH is the strongest prognostic parameter to predict relapse of hyperthyroidism with an accuracy of 75%. In the present study, levothyroxine supplementation did not prevent recurrent hyperthyroidism. In order to avoid hypothyroidism levothyroxine should only be used in combination with antithyroid drugs. In the face of the amelioration of nutritional iodine uptake in Germany, the application of low doses of antithyroid drugs will very likely no longer be sufficient. Future therapeutic recommendations will be based on selection criteria such as iodine supplementation, volume of goitre, smoking habits and basal TSH. used in combination with antithyroid drugs. In the face of the amelioration of nutritional iodine uptake in Germany, the application of low doses of antithyroid drugs will very likely no longer be sufficient. Future therapeutic recommendations will be based on selection criteria such as iodine supplementation, volume of goitre, smoking habits and basal TSH.

[Metformin, an efficacious drug in the treatment of polycystic ovary syndrome]. / Metformin--ein effektiver Therapieansatz in der Behandlung des Polyzystischen Ovarsyndroms.

BACKGROUND AND OBJECTIVE: Polycystic ovary syndrome (PCOS), with an incidence of 5% in women of reproductive age, is defined as the presence of oligo- or amenorrhea in combination with hyperandrogenism. Most patients also suffer from impaired insulin action (insulin resistance). PCOS thus resembles the metabolic syndrome (type 2 diabetes mellitus, hypertension, lipid disorders, atherosclerosis). International studies showed a beneficial effect of metformin treatment on biochemical and reproductive parameters in PCOS. The aim of our study is the evaluation of metformin treatment in a German PCOS sample. PATIENTS AND METHODS: 103 PCOS women (age 18-40) were treated, according to their body weight, with either 1000 mg or 1700 mg metformin per day after assessment of insulin resistance. Clinical features as well as endocrine and metabolic parameters were recorded at baseline and at 1, 6, and 12 months of treatment. Additionally, baseline data were compared with those of 98 control subjects (age 18-38). RESULTS: PCOS women showed significantly higher body mass index, body fat mass and androgen levels, as well as an impaired glucose- and insulin metabolism compared to controls. Metformin treatment ameliorated acne (36% to 4%), hirsutism-score (11.2 to 9.7) and restarted normal menstrual cycles in 66.7% of PCOS-women. Sixteen of 48 patients with unfulfilled wish to conceive became pregnant during therapy. Metformin restored menses in all previously amenorrheic women. Comparing post-metformin versus baseline levels, HOMA-IR (4.6 to 2.3), AUC-I (379 to 225) and 2-h glucose (117 to 90 mg/dl) decreased significantly. Furthermore, metformin decreased testosterone (2.9 to 1.8 nmol/l), free androgen index (9.1 to 5.3) and dehydroepiandrosterone levels (5.1 to 3.9 mg/l). CONCLUSION: Metformin improves significantly hyperandrogenism and insulin resistance in PCOS patients and appears to be an efficacious mode of therapy.

Thyroid associated ophthalmopathy: evidence for CD4(+) gammadelta T cells; de novo differentiation of RFD7(+) macrophages, but not of RFD1(+) dendritic cells; and loss of gammadelta and alphabeta T cell receptor expression.

AIM: To characterise periorbital immune cells (stages, kinetics) in active and inactive thyroid associated ophthalmopathy (A-TAO; I-TAO). METHODS: In orbital tissue cryosections of patients with A-TAO (n = 15), I-TAO (n = 11), and healthy controls (n = 14), adipose and fibrovascular areas were evaluated for MHC II(+) cells, CD45(+) total leukocytes, myeloid cells (CD33(+) monocytes; CD14(+) macrophages; mature RFD7(+) macrophages; RFD1(+) dendritic cells (DCs)), and lymphoid cells (CD4(+) T cells; alphabeta and gammadelta T cells; CD20(+) B cells). Results are expressed as medians and 5% confidence intervals. RESULTS: In fibrovascular septae, a surge of CD33(+) immigrants clearly correlating with disease activity generated significantly increased (p<0.05) percentages of CD14(+) and RFD7(+) macrophages. Intriguingly, CD4(+) cells were mostly gammadelta T cells, while alphabeta T helper cells were much less frequent. Successful treatment rendering TAO inactive apparently downregulates monocyte influx, macrophage differentiation, and T cell receptor expression. Similar trends were recorded for adipose tissue. Interestingly, RFD1(+) DCs were completely absent from all conditions examined. CONCLUSION: A-TAO coincides with periorbital monocyte infiltration and de novo differentiation of macrophages, but not DCs. The authors discuss a novel potential role for inflammatory CD4(+) gammadelta T cells in TAO. Successful treatment apparently downregulates orbital monocyte recruitment and effects functional T cell knockout.

[Diagnosis and treatment of autoimmune thyroiditis]. / Diagnostik und Therapie der Immunthyreoiditis. Substituieren Sie, bevor die Hypothyreose manifest wird!

In Germany, autoimmune thyroiditis usually manifests as atrophic thyroiditis with functional hypothyroidism affecting elderly women in particular. Sonography and thyroid peroxidase antibodies (TPO antibodies) point the way to the diagnosis. Manifest hypothyroidism always requires substitution with levothyroxine. Many patients with subclinical hypothyroidism, especially those with positive thyroid antibodies, benefit from at least partial thyroxine substitution. Early treatment not only alleviates the clinical symptoms, but may possibly also diminish the associated cardiovascular risk. In pregnant and sterile women subclinical hypothyroidism should always be treated.

[Drug treatment of immune hyperthyroidism (Basedow disease). Patient selection, long-term follow-up and prevention of recurrence]. / Medikamentöse Behandlung der Immunhyperthyreose (Typ Morbus Basedow). Patientenselektion, Langzeitverlauf und Rezidivprophylaxe.

Since theraphy of Graves' disease is not directed towards the cause of the disease, medical theraphy is still the first choice and symptomatically effective in treating hyperthyroidism. Antithyroid drugs are effective in restoring euthyroidism in >90% of the patients durning 4-6 weeks, but 30-50% of the patients experience relapse after withdrawal. Previous prospective randomized studies evaluated prognostic parameters and the use of levothyroxine for prevention of relapse of hyperthyroidism. Recent studies have addressed the period after withdrawal amd focused on the natural course of disease. The results of a recent prospective randomized and controlled multicenter study were as follows: supplementation of levothroxine does not prevent relapse of hyperthyroidism. Basal TSH (4 weeks after withdrawal of antithyroid drugs) is the best prognostic marker. Smoking and positive TSH-receptor-antibodies at the end of antithyroid theraphy are other risk factors.

Impact of smoking on the response to treatment of thyroid associated ophthalmopathy.

BACKGROUND: In patients with Graves' disease, smoking considerably increases the incidence and severity of thyroid associated ophthalmopathy (TAO). The authors sought to determine if smoking also influences the course of TAO during treatment, and the efficacy of therapy. METHODS: 41 smokers and 19 non-smokers with moderate untreated TAO were included in this prospective study. All patients were treated with steroids and, 6 weeks after the beginning of drug therapy, with orbital irradiation. Follow up was performed 1.5, 4.5, 7.5, and 12 months after the beginning of the study. Proptosis, clinical activity score (CAS), and motility were evaluated. The extent of smoking was derived from the concentration of the haemoglobin adduct N-2-hydroxyethylvaline (HEV), a parameter of long term smoking. RESULTS: There was no difference in the clinical manifestations of TAO between smokers and non-smokers at the beginning of treatment. However, CAS decreased (p<0.05) and motility improved (p<0.02) significantly faster and to a greater extent in non-smokers than smokers. Inverse correlations between the CAS decrease and the HEV levels observed 4.5 and 7.5 months after the beginning of treatment and between the improvement of motility and the HEV levels after 1.5, 4.5, and 7.5 months indicated a dose dependence. Mean HEV levels did not vary much during the follow up period and were significantly different in smokers (mean 5.4 (SD 2.7) micro g/l) and non-smokers (mean 1.8 (1.3) micro g/l; p<0.01). CONCLUSION: Smoking influences the course of TAO during treatment in a dose dependent manner. The response to treatment is delayed and considerably poorer in smokers.

Long-term follow-up of thyroid nodule growth.

Benign thyroid nodules are common in iodine deficient countries. Although many recent studies have addressed the molecular basis and short-term outcome of treatment in nodular thyroid disease, data on the long-term follow-up of thyroid nodule growth are widely lacking. The aim of the present study was to evaluate the long-term behaviour of benign thyroid nodules growth. We followed 109 consecutive patients seen at yearly intervals in our Outpatient Clinic for at least 3 years (range 3-12 years, mean 4.9 +/- 2.6 years) presenting with 139 benign nodules in uni- or multinodular goiters. The size of the nodules and thyroid glands was analysed retrospectively. The study included a spectrum of benign thyroid nodules, 86 functioning and 53 non-functioning. 27 patients were treated with levothyroxine, 8 with iodide and 16 with a combination of both. 58 patients were not treated mainly because of thyroid functional autonomy. Patients with overt hyperthyroidism or suspected malignancy by fine-needle aspiration were excluded from the study. The nodules and glands were assessed by ultrasonography at yearly intervals and documented by photoprints. Relevant growth was defined as an increase in nodule volume of at least 30%. For statistical analyses, Cox Proportional Hazard Model and life-table analyses according to Kaplan-Meier were performed. Most thyroid nodules grew slowly but continuously during follow-up. After about 3 years, half of the nodules had increased their volume by at least 30%. Growth of the nodules was significantly faster than of the corresponding thyroid glands (p < 0.0001). Age and sex of the patients and size or function of the nodules at initial presentation were not significantly related to their growth. Suppression of TSH did not affect growth of the nodules irrespective of the source of thyroid hormones, endogenous or by administration of levothyroxine. In conclusion, benign thyroid nodules have a slow intrinsic growth potential, which is apparently higher than that of the non-nodular tissue. In this study, not only nodular but even non-nodular goiter growth continues in the majority of patients. Exogeneous factors, including therapy with levothyroxine and/or iodide, appear to have little effect on the growth behaviour.

Surveillance of TSH-suppressive levothyroxine treatment in thyroid cancer patients: TRH testing versus basal TSH determination by a third generation assay.

OBJECTIVE, DESIGN AND METHODS: Although TRH testing has been eliminated in the diagnosis of most benign thyroid diseases, it is still controversial whether or not it can be replaced by ultrasensitive determination of basal TSH for monitoring optimal TSH suppression in thyroid cancer patients. We compared basal and TRH-stimulated TSH values measured by a 2 nd generation assay (lower detection limit 0.1 mU/l) and by a 3 rd generation assay (lower detection limit 0.005 mU/l) in 209 thyroidectomized thyroid cancer patients under suppressive levothyroxine treatment. RESULTS: In the 2 nd generation assay all patients had basal TSH values < 0.1 mU/l (criterion of admission in the study), and the TRH-stimulated TSH values were above the lower detection limit in 47% of the patients (range < 0.1-1.0 mU/l). In the 3 rd generation assay TSH was above the lower detection limit in 67% under basal conditions (range < 0.005-0.098 mU/l), and in 83% after TRH stimulation (range < 0.005-1.000 mU/l). We observed close correlations (p < 0.001) between basal and TRH-stimulated TSH in the 3 rd generation assay (r = 0.86), between TRH-stimulated TSH in the 2 nd and 3 rd generation assay (r = 0.95), and between TRH-stimulated TSH in the 2 nd generation assay and basal TSH in the 3 rd generation assay (r = 0.73). The ratio between TRH-stimulated and basal TSH values was in the average range 7-9 : 1. Subdividing the patients in three subgroups based on the TRH-stimulated TSH values from the 2 nd generation assay, the corresponding basal TSH values (median and [25.-75. percentile]) from the 3 rd generation assay were < 0.005 [< 0.005-0.010] mU/l in subgroup A (2 nd generation stim. TSH: < 0.15 mU/l), 0.032 [0.021-0.040] mU/l in subgroup B (2 nd generation stim. TSH: 0.15-0.4 mU/l), and 0.066 [0.046-0.085] mU/l in subgroup C (2 nd generation stim. TSH: > or = 0.5 mU/l). CONCLUSIONS: Even in those thyroid cancer patients where a high degree of TSH suppression is the therapeutic goal, 3 rd generation TSH assays enable a reliable adjustment of the levothyroxine dose by basal TSH determinations. In laboratories still using 2 nd generation assays, the monitoring of maximal TSH suppression in patients with high-risk thyroid cancer should be performed by TRH testing.

Maturation of thyroidal dendritic cells in Graves' disease.

Because thyroidal dendritic cells (t-DC) may be implicated in the pathogenesis of Graves' disease (GD), we compared t-DC in thyroid sections of patients with GD (n = 15) and control patients with toxic (TG; n = 12) or non-toxic goitre (NG; n = 12). Goitres in GD, but not TG or NG, were populated with three discernible t-DC phenotypes. (i) Immature t-DC (major histocompatibility complex (MHC) II+/CD40-/CD80-) were located perifollicularly (95% of the patients with GD, but only 55% of TG and 51% of NG patients); numbers of such t-DC were significantly elevated in GD (P < 0.001). (ii) Partially matured CD80+ t-DC were present in connective tissue (73% of the patients) and focal interstitial clusters (40% of the patients). In 53% of the patients with GD, single as well as clustered interstitial t-DC expressed CD40. (iii) However, phenotypically mature t-DC (MHC II+/CD40+/CD80+/RFD1+) were only present in clusters and colocalized with activated CD4+/MHC class II+ T-helper (Th) cells. Expression of CD54 and CD83 did not significantly differ among the groups. The phenotype of intrathyroidal DC in GD thus supports their role as potential (co)stimulators of thyroid autoimmunity.

[Thyroid carcinoma. Diagnosis--nonoperative therapy--after care]. / Schilddrüsenkarzinom. Diagnostik--nicht operative Therapie--Nachsorge.

Thyroid carcinomas may originate in the thyroid cells (follicular and papillary, carcinoma, so-called differentiated carcinomas, constituting roughly 80-90% of cases), and the calcitonin-producing parafollicular C cells (medullary carcinoma, roughly 10%). The suspected diagnosis is clarified with the aid of ultrasonography, scintigraphy and fine-needle aspiration cytology. Primarily, carcinomas of the thyroid are treated surgically; in the case of differentiated carcinomas, surgery is followed by radio-iodine treatment, and in the follow-up period 131I scintigraphy is performed. During this period, physical examination, ultrasonography of the neck, monitoring of the tumours markers, and treatment with levothyroxine are applied (TSH-suppressive in cases of differentiated carcinoma). In the event of a recurrence showing rapid progression, when surgical and nuclear medical treatment modalities have been exhausted, chemotherapy can be given.

Second generation assay for thyrotropin receptor antibodies has superior diagnostic sensitivity for Graves' disease.

Detection of autoantibodies to the TSH receptor (TSH-R) in Graves' disease has found widespread use in clinical routine and is performed mostly by commercial RRAs measuring TSH binding inhibitory activity. We report in this study on a second generation TSH binding inhibitory assay using the human recombinant TSH-R with two major improvements: 1) superior diagnostic sensitivity for Graves' disease, and 2) for the first time, nonradioactive and radioactive coated tube (CT) technology. Full-length human recombinant TSH-R was expressed in the K562 leukemia cell line and grown in suspension at a high density. A murine monoclonal antibody was selected for binding to the native TSH-R without interfering with autoantibodies or TSH and was coated to polystyrene tubes. After detergent extraction, TSH-R was affinity immobilized on antibody-coated tubes. The binding of TSH to the TSH-R could be demonstrated by the addition of 125I- or acridinium ester-labeled bovine TSH, and this binding could be inhibited by sera from patients with Graves' disease up to 95%. Subsequently, these novel assays, a CT RRA and a CT luminescence receptor assay, were compared to the conventional RRA based on porcine antigen in a blinded clinical multicenter trial. Sera from 328 patients with Graves' disease (86 untreated, 116 treated, and 126 in remission) and 520 controls (comprised of healthy blood donors and patients with autoimmune diseases or goiter) were tested in all 3 assays. Receiver-operating characteristic plot analysis resulted in a specificity of 99.6% with a sensitivity of 98.8% for both CT assays, compared to 99.6% specificity and 80.2% sensitivity for the conventional RRA (P < 0.001). In all 3 groups of patients with Graves' disease, the 2 CT assays were significantly more sensitive for the disease than the conventional assay, without loss of specificity in the control groups. This increase in sensitivity and the nonradioactive or radioactive CT format constitute a significant improvement over the currently available assays.

Course of thyroid nodules.

Thyroid nodules are present in up to 30% of the German population. The causative role of iodine deficiency which is still endemic in this country has long been established. Recent progress has shed some light on the pathogenesis of nodular thyroid disease which still remains less well understood than goitrogenesis. Most thyroid nodules appear to be of clonal origin. Functional abnormalities have been related to alterations within the TSH signaling cascade, particularly mutations in the TSH receptor and stimulating G-protein-alpha-subunit. Proliferation which is dissociable from thyroid function has been linked to genetic differences of the thyroid cells themselves and growth factors being partly overexpressed by thyroid nodules. Data regarding the correlation of the molecular characteristics to the clinical behavior and growth potential have not yet been elucidated. On the other hand, there are only a few clinical studies that have addressed the long-term natural history of thyroid nodules. From these studies at least it appears that thyroid nodules tend to grow slowly and their increase in size may even by modern ultrasonography technique become apparent only after several years. Those in vitro and in vivo observations have important implications for the planning of therapeutical trials. Studies have focused so far mainly on short term effects of different therapeutic regimens such as iodine or levothyroxine. However, pathophysiological considerations and clinical observation would encourage studies over more prolonged periods of time.