Sarcoidosis of the thyroid gland associated with hyperthyroidism: review of the literature and report of two peculiar cases.

Sarcoidosis is a systemic disease characterized by non-caseating granulomas that rarely involve the thyroid gland. Thyroid sarcoidosis has seldom been documented, and few cases have so far been described in association with hyperthyroidism. Here, we review the literature on this association, report two patients presenting with hyperthyroidism and histologically-proven sarcoidosis, and discuss related clinical, biochemical, pathological and genetic findings.

Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: A multicenter study.

BACKGROUND: The routine measurement of serum calcitonin (CT) has been proposed for patients with nodular thyroid disease (NTD), to detect unsuspected medullary thyroid carcinoma (MTC) before surgery. OBJECTIVE: To assess the prevalence of hypercalcitoninemia and MTC in NTD patients; to compare the ability of CT measurement and fine needle aspiration cytology (FNAC) to predict MTC; to identify age groups of NTD patients who should be better candidates than others to undergo routine measurement of CT. PATIENTS AND METHODS: 1425 consecutive patients, referred from April 1, 2003, through March 31, 2004, to four Italian endocrine centers due to NTD, were grouped depending on age, and underwent basal and, in some cases, pentagastrin (Pg)-stimulated CT measurement, FNAC and, when indicated, surgery. Serum CT concentrations were measured by an immunoluminometric assay (ILMA). RESULTS: Hypercalcitoninemia was found in 23 out of 1425 patients. MTC was discovered in 9 patients, all >40 yr old and showing high CT levels. Sensitivity of basal and Pg-stimulated CT to predict MTC before surgery was 100% for both tests, whereas specificity was 95 and 93%, respectively. CT specificity reached 100% when a cutoff value of 20 pg/ml was taken. FNAC showed an overall 86% sensitivity. When >10 mm MTC nodules were considered, FNAC sensitivity approached 100%. On the contrary, a correct cytological diagnosis was obtained in only one out of five patients with <10 mm MTC nodules (microMTC); in one patient with histologically proved microMTC, FNAC even demonstrated a benign lesion. Hypercalcitoninemia or MTC were associated with chronic thyroiditis in 30 or 33% of cases, respectively. C-cell hyperplasia was found in 57% of hypercalcitoninemic patients without MTC. CONCLUSIONS: Basal CT measurement detects elevated CT values in 1.6% of NTD patients. Although CT is not a specific marker of MTC, its routine measurement represents a useful tool in the pre-operative evaluation of NTD patients, particularly those >40 yr old presenting with nodules <10 mm, even when FNAC does not show malignant features. To our knowledge, this is the first trial using ILMA to assess the ability of pre-operative CT measurement to predict MTC in a large series of NTD patients.

Serum thyrotropin receptor antibodies concentrations in patients with Graves' disease before, at the end of methimazole treatment, and after drug withdrawal: evidence that the activity of thyrotropin receptor antibody and/or thyroid response modify during the observation period.

AIM AND METHODS: We performed a quantitative retrospective analysis of serum thyrotropin receptor antibody (TRAb) concentrations measured by a second-generation radioreceptor assay in 58 patients with Graves' disease (GD) at the onset of the disease, at the end of 18 month methimazole (MMI) treatment, and after MMI withdrawal in order to evaluate the correlation between the presence of these antibodies and the relapse of hyperthyroidism. Sixty healthy subjects were enrolled as a control group. RESULTS: Before MMI treatment the best cutoff TRAb value for identifying patients with GD was 1.45 UI/L (specificity, 100%; sensitivity, 98.3%). At the end of MMI treatment, serum TRAb concentrations were significantly lower (p < 0.001) than those measured at baseline, but they were still significantly higher (p < 0.001) than those found in the control subjects. At the end of MMI treatment, 44 patients (75.9%) had positive TRAb values (>1.45 UI/L). After MMI withdrawal (median, 15 months), 34 patients (58.6%) became hyperthyroid, 4 patients (6.9%) became hypothyroid, and 20 patients (34.5%) remained euthyroid. There was a significant correlation between serum TRAb concentrations at the end of MMI treatment and the percentage of patients who became hyperthyroid (r: 0.56; p < 0.001) and the time of appearance of hyperthyroidism (r: -0.38; p = 0.03). All 4 patients with TRAb values below 0.9 UI/L at the end of MMI treatment remained euthyroid throughout the follow-up period. Among the 27 patients who had serum TRAb values higher than 4.4 UI/L, 23 developed hyperthyroidism and 4 hypothyroidism. The TRAb values between 0.9 and 4.4 UI/L did not discriminate between the 27 patients (46.6%) who remained euthyroid from those who had relapse of hyperthyroidism. Thus a different TRAb end of treatment cutoff was calculated to identify patients who became again hyperthyroid. This TRAb cutoff value was 3.85 UI/L (sensitivity, 85.3%; specificity, 96.5%). All but 1 patient who had serum TRAb values above 3.85 UI/L became hyperthyroid after MMI was withdrawn (positive predictive value, 96.7%). In these patients, relapse of hyperthyroidism was independent of the changes in serum TRAb concentrations (r: 0.27; p = 0.15) and occurred after a median period of 8 weeks (range, 4-48). Hyperthyroidism also developed in 5 of 24 patients who had serum TRAb concentrations lower than 3.85 UI/L at the end of MMI treatment. In these 5 patients the relapse of hyperthyroidism occurred after a median period of 56 weeks (range, 24-120) and was always accompanied by an increase in serum TRAb concentrations. CONCLUSIONS: TRAb persist in the blood of most patients with GD after 18 months of MMI treatment. Both the frequency and the time of appearance of hyperthyroidism are closely correlated with serum TRAb concentrations at the end of MMI treatment. Our data would suggest that TRAb maintain stimulating activity after a full course of MMI treatment in the large majority of patients with GD. However, it is likely that the potency of these antibodies and/or the thyroid response to them change during treatment, as suggested by the different values measured in euthyroid control subjects and in euthyroid patients after MMI treatment.

Thyroid hemiagenesis and incidentally discovered papillary thyroid cancer: case report and review of the literature.

Thyroid hemiagenesis (TH) is a rare congenital abnormality in which one thyroid lobe fails to develop. Its prevalence is uncertain, because the absence of one thyroid lobe does not usually cause clinical symptoms. The detection of TH is usually incidental when the evaluation of other thyroid disorders is requested. It is more frequently found in female than in male patients (3:1 ratio) and in the left lobe compared to the right lobe. We report the case of a 54-yr-old man, presenting with a large multinodular right-sided goiter, with mediastinal extension and dysphagia. Thyroid scan and ultrasound study showed the absence of the left lobe. The patient underwent surgery for compressive symptoms, and the operation confirmed the absence of the left lobe. Histological examination demonstrated a multi-nodular goiter with papillary carcinoma. To our knowledge, this case represents the first reported case of association between TH and papillary thyroid carcinoma in a male patient, and the second in which the tumor arose in the right lobe.

Molecular mechanisms for pituitary thyrotroph cell growth.

Neuroendocrine, endocrine and autocrine/paracrine signals contribute to the regulation of basal thyrotroph growth. Thyrotropin-releasing hormone (TRH), somatostatin, thyroid hormone (TH), estrogens (Es) and epidermal growth factor, all may play a role both in normal and tumoral thyrotroph proliferation, acting via either plasma membrane receptors and non-genomic steps or nuclear receptors and gene transcription. Signaling features common to all these ligands are involvement of G protein-coupled receptors, mitogen-activated protein kinase cascade and nuclear polyphosphoinositide cycle. In addition, each growth information, independently from the eliciting factor, may be routed intracellularly following a branched pathway, that often links different transduction systems at common check-points, as the Shc-Grb2-SOS complex. Finally, some ligands (e.g. TRH, TH, Es) may display opposite effects on thyrotroph growth, depending on environmental conditions and state of cell differentiation. These ambiguities of response can be interpreted using a "fuzzy" logic-based model of intracellular signaling. Accordingly, check-points common to different transduction cascades may be envisaged as targets for antitumoral therapy selective to the neoplastic thyrotroph cell.

New paradigms in neuroendocrinology: relationships between obesity, systemic inflammation and the neuroendocrine system.

Obesity may be an independent risk factor for coronary artery disease and contribute to a chronic state of systemic inflammation leading to atherosclerosis and metabolic abnormalities, such as diabetes, insulin resistance, dyslipidemia and hypertension. Visceral fat, in fact, may act as an endocrine organ, synthesizing and releasing atherogenic inflammatory cytokines, whose circulating levels depend on the individual's nutritional state, and the extent and anatomical location of fat stores. Unsuspected viral infections might also be involved in enhancing autocrine/paracrine mechanisms of cytokine release from omental fat. Elevated levels of blood cytokines may interact with the neuroendocrine system, autonomic nerves and peripheral lymphatic organs. This may lead to local inflammatory reactions in many body compartments, in particular in the heart tissue, possibly affecting the process of circulatory recovery in obese subjects, and predisposing these patients to a greater risk of myocardial inflammatory disease than individuals with normal body mass index. Circulating levels of inflammatory cytokines might be considered to determine risk categories for development of cardiovascular complications in obese subjects. In addition, their reduction with pharmacological antagonists might prevent and/or control acute cardiovascular events and increase energy expenditure in obese patients, especially after surgical treatment, through reduction of cytokine inhibition of the hypothalamic-pituitary-thyroid axis.

Free and bound leptin in prepubertal children with Down's syndrome and different degrees of adiposity.

OBJECTIVE: To evaluate plasma total, free (FL) and protein-bound (BL) leptin in children with Down's syndrome (DS) and different degrees of adiposity and its relationship with thyroid stimulating hormone (TSH), free thyroxine (FT(4)), and free triiodothyronine (FT(3)). SUBJECTS: A total of 24 prepubertal clinically euthyroid DS children. METHODS: Plasma leptin, TSH, FT(4), and FT(3) concentrations were determined by immunometric/radioimmunologic assays. FL and BL were evaluated by fast protein liquid chromatography. RESULTS: In DS children, leptin circulates in two fractions, corresponding to BL and FL. The amount of BL and FL is negatively and positively correlated to body mass index (BMI), respectively. Plasma leptin concentrations correlate with BMI, but not with TSH, FT(4), and FT(3). CONCLUSIONS: In prepubertal DS children, leptin circulates as both BL and FL, correlates with adiposity and its concentration appears independent of thyroid function.

Serum thyroglobulin concentrations and (131)I whole-body scan results in patients with differentiated thyroid carcinoma after administration of recombinant human thyroid-stimulating hormone.

UNLABELLED: The use of recombinant human thyroid-stimulating hormone (rhTSH) has recently become available as an alternative diagnostic tool to assess the persistence and recurrence of differentiated thyroid carcinoma (DTC) in patients on thyroid hormone-suppressive therapy (THST) after near-total or total thyroidectomy and ablative doses of (131)I. We report the results of rhTSH administration in patients who were monitored for DTC. METHODS: Thirty-three adult DTC patients (13 men, 20 women; mean age +/- SE, 45.6 +/- 2.31 y; age range, 21-65 y) underwent diagnostic follow-up after rhTSH administration at a dose of 0.9 mg once a day for 2 d. Whole-body scanning and serum thyroglobulin (Tg) measurement were performed after rhTSH administration. Patients were divided into 2 groups depending on serum Tg concentrations on THST: 29 patients had Tg concentrations of <2 ng/mL (group A) and 4 patients had Tg values of >2 ng/mL (group B). RESULTS: In group A, Tg values remained at <2 ng/mL in 25 patients and increased from 1.1 +/- 0.14 ng/mL to 22.0 +/- 5.75 ng/mL (mean +/- SE) in 4 patients after rhTSH administration. Whole-body scanning did not reveal any uptake of (131)I in the 25 patients without an increase in Tg, whereas (131)I uptake was evident in 2 of the 4 patients with a rise in Tg. In group B, Tg values increased in all 4 patients from 17.3 +/- 6.35 ng/mL to 55.3 +/- 12.75 ng/mL, and (131)I uptake was evident in 3 of the 4 patients. No major adverse effects were reported after rhTSH administration. CONCLUSION: Our results show that the measurement of serum Tg concentrations after rhTSH has a higher diagnostic value than whole-body scanning in detecting the persistence of thyroid tissue. Therefore, rhTSH should be administered in TSH-suppressed patients with basal serum Tg concentrations of <2 ng/mL because the increment in serum Tg concentrations may reveal the persistence of thyroid tissue in these patients.

Iodine excess and hyperthyroidism.

150 microg iodine are daily required for thyroid hormone synthesis. The thyroid gland has intrinsic mechanisms that maintain normal thyroid function even in the presence of iodine excess. Large quantities of iodide are present in drugs, antiseptics, contrast media and food preservatives. Iodine induced hyperthyroidism is frequently observed in patients affected by euthyroid iodine deficient goiter when suddenly exposed to excess iodine. Possibly the presence of autonomous thyroid function permits the synthesis and release of excess quantities of thyroid hormones. The presence of thyroid autoimmunity in patients residing in iodine-insufficient areas who develop iodine-induced hyperthyroidism has not been unanimously observed. In iodine-sufficient areas, iodine-induced hyperthyroidism has been reported in euthyroid patients with previous thyroid diseases. Euthyroid patients previously treated with antithyroid drugs for Graves' disease are prone to develop iodine-induced hyperthyroidism. As well, excess iodine in hyperthyroid Graves' disease patients may reduce the effectiveness of the antithyroid drugs. Occasionally iodine-induced hyperthyroidism has been observed in euthyroid patients with a previous episode of post-partum thyroiditis, amiodarone destructive or type II thyrotoxicosis and recombinant interferon-alpha induced destructive thyrotoxicosis. Amiodarone administration may induce thyrotoxicosis. Two mechanisms are responsible for this condition. One is related to excess iodine released from the drug, approximately 9 mg of iodine following a daily dose of 300 mg amiodarone. This condition is an iodine-induced thyrotoxicosis or type I amiodarone-induced thyrotoxicosis. The other mechanism is due to the amiodarone molecule that induces a destruction of the thyroid follicles with a release of preformed hormones. This condition is called amiodarone-induced destructive thyrotoxicosis or type II thyrotoxicosis. Patients developing type I thyrotoxicosis in general have preexisting nodular goiter whereas those developing type II thyrotoxicosis have a normal thyroid gland. The latter group of patients, after recovering from the destructive process, may develop permanent hypothyroidism as the consequence of fibrosis of the gland.

Thyroid hormone metabolism in obesity.

Serum thyroid hormone concentrations and their metabolic fate are within the normal range limits in obese subjects. Also serum TSH concentrations and its response to TRH are normal, suggesting that tissue availability of thyroid hormones is normally preserved in these subjects. In contrast, during caloric restriction serum T3 concentrations decrease as a consequence of its reduced production rate from peripheral deiodination of T4. Opposite, serum rT3 concentrations markedly increase as a result of its decreased metabolic clearance rate. During caloric overfeeding serum T3 concentration increase whereas serum rT3 concentrations decrease. In this condition the production rate of T3 increases. During caloric restriction and overfeeding serum T4 concentrations and its production and degradation are not modified.

Serum concentrations of proinflammatory cytokines in Graves' disease: effect of treatment, thyroid function, ophthalmopathy and cigarette smoking.

OBJECTIVE: In the present study we have measured the concentrations of interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6R), tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and IL-1 receptor antagonist (IL-1Ra) in the serum of patients with Graves' disease (GD). By multivariate analysis, we have evaluated the effect of antithyroid treatment, thyroid function, the presence or absence of active thyroid-associated ophthalmopathy (TAO), the patient's smoking habits and the relation to circulating anti-thyrotropin (TSH) receptor (TRAb) and anti-thyroperoxidase antibodies (TPOAb). SUBJECTS: We studied 84 GD patients, 51 untreated and 33 receiving methimazole (MMI) therapy. Twenty-three (45%) untreated patients and 18 (54%) patients on MMI had active TAO. We also studied 67 normal subjects as controls. Thirty-one GD patients (43%) and 16 controls (36%) were smokers. RESULTS: Serum IL-6 concentrations were significantly higher in both untreated patients (P<0.001) and treated patients (P<0.006), when compared with controls. Serum sIL-6R concentrations were significantly affected by treatment (P=0.001). Serum IL-1Ra concentrations were not different in GD patients, whether treated or untreated, compared with controls. Serum IL-6 concentrations were not influenced by thyroid function and there was a significant interaction between treatment and the presence of active TAO (P=0.003). In hyperthyroid patients with active TAO serum, sIL-6R concentrations were significantly higher than in those with inactive TAO (P=0.003). In untreated GD patients there was no significant effect of thyroid function and TAO activity on the serum concentrations of TNF-alpha and IL-1 beta. Serum IL-1Ra concentrations were not affected by the presence of TAO. Smoking had no effect on serum IL-6, sIL-6R, TNF-alpha, IL-1 beta and IL-1Ra concentrations, even in the presence of an active TAO. Serum concentrations of IL-6, sIL-6R, TNF-alpha and IL-1 beta and IL-1Ra were not different in patients with and without TRAb or TPOAb, in relation to either thyroid function, TAO activity or smoking. CONCLUSIONS: Our work shows that: (i) the proinflammatory cytokine pattern in GD is greatly influenced by antithyroid drug treatment; (ii) the increased circulating IL-6/sIL-6R concentrations observed in patients with active TAO may derive from the activation of humoral reactions in sites other than the thyroid; and, (iii) cigarette smoking has no effect on serum IL-1/IL-1Ra concentrations in TAO.

Recombinant interferon alpha (rIFN-alpha) does not potentiate the effect of iodine excess on the development of thyroid abnormalities in patients with HCV chronic active hepatitis.

OBJECTIVE: To determine whether the administration of pharmacological quantities of iodine during interferon-alpha (rIFN-alpha) treatment of chronic viral hepatitis B and C (HCV) would exacerbate the potential adverse effects of rIFN alpha on thyroid function. DESIGN: Thyroid function tests were carried out in 48 euthyroid patients before and during rIFN-alpha therapy of HCV. Twenty-one of these patients were also treated with 10 drops saturated solution of potassium iodine (SSKI, approximately 350 mg iodine daily). Eight patients with HCV but not treated with rIFN-alpha received 10 drops SSKI. PATIENTS: All patients were enthyroid prior to rIFN-alpha therapy for HCV or iodine and thyroid function tests were similar in the three groups. MEASUREMENTS: Serum free T4, free T3, and TSH concentrations were measured prior to and at 30 and 60 days of rIFN-alpha therapy in the three groups of patients. The serum TSH response to TRH was assessed before rIFN-alpha therapy and on day 60. Thyroid peroxidase antibodies were measured before and during therapy. RESULTS: During the 2-month study period, similar small but significant decreases in serum FT4 and FT3 and compensatory small significant increases in TSH concentrations were observed in the patients treated with rIFN-alpha + iodine and iodine alone but not in the patients receiving rIFN-alpha alone. Abnormal thyroid function tests were observed more frequently in patients receiving rIFN-alpha + iodine and iodine alone compared to those receiving rIFN-alpha alone. CONCLUSIONS: Excess iodine administered to patients treated with rIFN-alpha induced small changes in thyroid function similar to those observed in patients treated with iodine alone. Thus, rIFN-alpha and iodine do not appear to be synergistic in the development of abnormal thyroid function tests over a 2-month treatment period.

Are thyroid function tests too frequently and inappropriately requested?

In spite of data supporting the use of the serum thyrotropin (TSH) concentration as the best test to detect abnormal thyroid function, measurement of circulating thyroid hormones with or without a serum TSH continues to be frequently requested to evaluate thyroid function. We have analyzed how combinations of thyroid function tests were ordered by referring physicians and the results of the tests in order to offer some suggestions as to how to use thyroid function tests in a cost effective manner. During 1995, 19,181 inpatient and outpatient requests (45,865 different tests) for thyroid function tests were received by the laboratory of a 1600 bed University Hospital in Parma, Italy. The following tests were carried out: T4, free T4, T3, free T3 and TSH. Serum TSH values below and above the normal range were considered to reflect abnormal thyroid function i.e. hyperthyroidism, or hypothyroidism including subclinical disease independent of the results of the other tests. Combinations of ordered tests and the percent of the total for each combination were: TSH+T4+T3 (56%), TSH+FT4+FT3 (14%), TSH (12%), TSH+FT4 (9%), TSH+T4 (1%), TSH+T4+T3+FT4+FT3 (5%), others (3%). The T4+T3+TSH panel (10,780 requests) had normal serum TSH values in 80.6% and the FT4+ FT3+TSH panel (2,590 requests) had normal TSH values in 73.2%. Elevated serum TSH concentrations were observed more frequently in hospitalized than in ambulatory patients (9.7% vs 7.4% p<0.001). T3 (elevated serum T3, normal T4 and low TSH concentrations) and T4 (elevated serum T4, normal T3 and low TSH concentrations) toxicosis were observed in 8.1% and 9.4%, respectively, of the requested test (NS). FT3 and FT4 toxicosis, defined as for T3 and T4 toxicosis, were observed in 7.5% and 4.9%, respectively (NS). The low T3 and low FT3 syndrome in hospitalized patients was present in 1.6% and 2.3% of the requests, respectively (NS). The low T4+low T3 and low FT4+low FT3 syndrome was present in only 0.3% and 0.2%, respectively, of the requests. Our study shows that a) in hospitalized patients thyroid function tests were requested in 20% of the patients and only one in 14 of these patients at the highest could have abnormal thyroid function, as indicated by abnormal TSH value b) FT4 (or T4) is as useful as FT3 (or T3) in the diagnosis of hyperthyroidism, c) in hospitalized patients the low T3 syndrome was far less common than that reported in the literature, probably due to the lower severity of illness, d) panels which include T3 and FT3 are not justified, and e) serum TSH alone is the most appropriate initial thyroid function test.