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PubMed2005

Subclinical hyperthyroidism in patients with nodular goiter represents a hypermetabolic state.

The aim of the study was to examine the metabolic status in patients with suppressed TSH but values of FT4I and T3 within the reference range (subclinical hyperthyroidism [sH]). Thirteen patients and 13 control persons with nodular goiter were included. The metabolic state was determined by measurements of basal oxygen consumption (VO2), bone mineral density (BMD), and the circadian variation of TSH. Further was the pituitary thyroid axis examined by studying the effect of lowering thyroid hormones by methimazol treatment. The circadian variation of TSH varied from that of normal persons as the night surge was abolished. The basal VO2 was significantly higher and BMD was significantly lower in patients with sH compared to control persons. Restoration of TSH by lowering of thyroid hormone concentrations lead to a normalization of VO2 and restoration of the circadian variation of TSH. The preserved pituitary thyroid axis, the abolished circadian TSH variation, the increased VO2, and decreased BMD in patients with suppressed TSH, but peripheral thyroid hormone concentrations within the reference range, indicate a hyper metabolic state, which might reflect either an altered cellular set point or an increased sensitivity towards thyroid hormones in peripheral cells and in the thyrotrope cells.

Bone Density↗
PubMed2006

Incidence of radioiodine induced Graves' disease in patients with multinodular toxic goiter.

In this study, we assessed the incidence of Graves' disease (GD) following radioiodine therapy (RIT) in a large cohort of well characterized patients with autonomy in comparison to the clinical course of control patients with thyroidal autonomy not definitively treated with (131)I or surgery. 622 consecutive patients were treated with (131)I for autonomy (unifocal: n = 321; multifocal: n = 199; disseminated: n = 102) and followed up for at least 6 months post RIT. 108 consecutive patients with autonomy not definitively treated (unifocal: n = 49; multifocal: n = 42; disseminated: n = 11) followed up for at least 6 months served as controls. Initial evaluation and follow-up included determination of FT3, FT4, TSH, autoantibodies against the thyroid peroxidase (anti-TPO) and TSH-receptor antibodies (TRAb) by highly sensitive radio receptor-assay, quantitative thyroid scintigraphy and sonography. After 6 months, GD was newly diagnosed in 1/321 patients with unifocal autonomy, in 1/199 patients with multifocal autonomy and in 0/108 control patients. In patients with disseminated autonomy (group C), GD was diagnosed significantly more often compared to the other groups (5/102 patients; 4,1 %; p < 0.05). In conclusion, RIT may induce Graves' disease in a few cases with toxic multinodular goiter. The incidence in this population is small. Compared with patients suffering from uni- or multifocal autonomy, subjects with disseminated autonomy have a more than tenfold higher risk for the development of GD.

Adult↗
PubMed1994

Identification of delta-iodolactone in iodide treated human goiter and its inhibitory effect on proliferation of human thyroid follicles.

There is evidence that iodoarachidonates are mediators of iodide in thyroid autoregulation, however, their occurrence in vivo has not yet been demonstrated. We therefore tried to identify delta-iodolactone (5-Hydroxy-6-iodo-8,11,14-eicosatrienoic delta-lactone, IL-delta) in thyroid tissue from a patient with Graves' disease treated with high doses of iodide. Lipids were extracted from thyroid tissue, purified by reversed phase chromatography and analyzed by gas chromatography--tandem mass spectrometry (GC-MSMS). The retention time in gas chromatography and fragmentation pattern in tandem mass spectrometry were determined with biochemically synthesized non-deuterated and deuterated IL-delta. According to retention time (13.44 min) and specific fragments (m/z 303, m/z 259) the occurrence of IL-delta could be demonstrated in the extract of iodide treated goiter. In vitro, potassium iodide (40 microM) as well as IL-delta (1.0 microM) significantly inhibited the proliferation of human thyroid follicular cells induced by phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate). These results demonstrate for the first time that Il-delta is present in iodide treated human thyroid. As cell proliferation is under negative control of IL-delta, a crucial role in thyroid involution following iodide treatment may be possible.

Arachidonic Acids↗
PubMed1999

Prader-Willi syndrome associated with fetal goiter: a case report.

We describe a unique case of a newborn with Prader-Willi syndrome who presented with fetal goiter as well as neonatal thyroid abnormalities, marked hypotonia, and thrombocytopenia. These new clinical observations may correlate with the uniparental monodisomy form of inheritance of this genetic condition.

Adult↗
PubMed1986

[Computed tomographic determination of thyroid iodine concentration in an endemic goiter area].

We determined the CT density of the thyroid gland in 60 patients with normal thyroids and 176 patients with various thyroid disorders. The density was 75 +/- 6.2 H.U. in normal thyroids, which was markedly higher than in goiters (66 +/- 6.0 H.U.), while there was a considerable further decrease in patients with immunogenic hyperthyroidism, the density being 48.5 +/- 7.9 H.U. The thyroids of patients with nonimmunogenic hyperthyroidism differed from these by virtue of a significantly greater density, 79.8 +/- 12.5 H.U. The clinical importance of CT investigation of the thyroid is its ability to distinguish rapidly between immunogenic hyperthyroidism without ocular symptoms and the (mostly iodine induced) non-immunogenic form. There is a linear correlation between CT density and iodine concentration in the thyroid tissue; this was determined in surgical specimens from 17 patients. Iodine concentration in the thyroid, as well as the iodine content of the whole gland, can thus be calculated from the measured CT density at any time by estimating the volume of the gland with ultrasound and combining this value with the measured iodine concentration. The results correlate well with those found using the x-ray fluorescence method.

Goiter, Endemic↗
PubMed1987

The congenital goiter mutation is linked to the thyroglobulin gene in the mouse.

Rat thyroglobulin (TG) cDNA clones were used to identify DNA restriction fragment variants among inbred mouse strains. One of these variants was shown to be closely linked to the recessive mutation congenital goiter (cog), which had previously been mapped to mouse chromosome 15. These results indicate that the structural gene for thyroglobulin is on chromosome 15 and suggest that a mutation at the site of the TG gene is the basis of the cog defect. No differences were observed between cog/cog and +/+ DNA in Southern blots using TG cDNA probes corresponding to 88% of the coding sequences, suggesting that the cog mutation is not due to a large deletion of this portion of the gene. Neither was there any obvious qualitative or quantitative difference between mutant and normal TG mRNA as judged by blot hybridization of electrophoretically fractionated thyroid RNAs. The thyroglobulin gene locus (Tgn) was mapped near the glutamic-pyruvic transaminase isoenzyme locus Gpt-1. The Tgn locus is syntenic with the c-myc protooncogene locus (Myc) in the mouse as in the rat and man.

Animals↗
PubMed1998

A single amino acid change in the acetylcholinesterase-like domain of thyroglobulin causes congenital goiter with hypothyroidism in the cog/cog mouse: a model of human endoplasmic reticulum storage diseases.

Newly synthesized thyroglobulin (Tg), the major secretory glycoprotein of the thyroid gland, folds and homodimerizes in the endoplasmic reticulum (ER) before its export to the site of iodination, where it serves as the precursor for thyroid hormone synthesis. In families with defective Tg export, affected individuals suffer from a thyroidal ER storage disease characterized by a distended thyrocyte ER containing misfolded Tg, along with induced ER molecular chaperones. Inherited as an autosomal recessive trait, deficient Tg causes congenital hypothyroidism in newborns that, if untreated, results in goiter along with serious cognitive and growth defects. Recently, a similar phenotype has been observed in inbred cog/cog mice, although the precise molecular defect has remained undefined. Here, we have isolated and cloned a full-length 8.5-kb Tg cDNA from cog/cog mice and unaffected isogenic AKR/J mice. Comparison of the complete sequences reveals that cog/cog mice express a Leu-2263 --> Pro missense mutation in the acetylcholinesterase-homology domain of Tg. Heterologous expression studies in COS cells indicate that cog Tg exhibits a severe defect in exit from the ER. Site-directed mutagenesis of cog Tg to convert the single amino acid back to Leu-2263 restores normal Tg secretion. We conclude that the cog mutation in Tg is responsible for this ER storage disease that causes thyroid dyshormonogenesis.

Acetylcholinesterase↗
PubMed1995

Serum concentrations of osteocalcin in pregnant women with multinodular thyroid goiter undergoing treatment with levothyroxine.

In this study we measured serum osteocalcin (Bone Gla-Protein) to investigate bone metabolism in pregnant women with multinodular thyroid goiter undergoing treatment with levothyroxine (L-T4). Serum concentration of BGP was measured in 18 pregnant women and in 20 non-pregnant women (ages raging from 21-34 years) receiving L-T4 (75-125 micrograms/day). Venous blood samples for RIA determination of serum BGP, plasma thyroid hormone (T3, T4, free T3, free T4) and TSH were collected from the two groups. The samples of the pregnant women group were collected before pregnancy (at the moment the disease was diagnosed without L-T4 therapy) during pregnancy (at the 3rd, 6th and 9th month) and one month after delivery. The normal TSH levels (measured with Irma method) before pregnancy, were significantly reduced during treatment with L-T4 during pregnancy and after delivery (p < 0.005), respectively. Also in the control group TSH levels were reduced during treatment. Serial measurement of serum BGP before pregnancy, (3.4 +/- 1 ng/ml) during pregnancy (3rd: 4.2 +/- 1.5 ng/ml; 6th: 4.2 +/- 1.4 ng/ml; 9th: 2.8 +/- 1.6 ng ml, month respectively) and one month after delivery (3.5 +/- 1.3 ng/ml) did not demonstrate significant variations. Furthermore, in the control group the BGP levels were 3.2 +/- 1.7 ng/ml. There was no correlation between BGP, thyroid hormones and TSH in these groups. These data indicate that the administration of moderate doses of L-T4 in pregnant and in non-pregnant women did not modify the serum BGP levels.

Adult↗
PubMed1999

Solitary nodular disease and multinodular goiter: a retrospective study on suppressive versus replacement levothyroxine therapy.

The aim of the present study was to ascertain whether patients affected by solitary nodular disease of the thyroid or multinodular goiter had a different clinical outcome when treated with suppressive levo-thyroxine (L-T4) therapy rather than replacement L-T4 therapy. We evaluated, by a retrospective analysis, 36 patients who had received TSH-suppressive L-T4 therapy according to TSH value and 55 who had received replacement L-T4 therapy. Fine needle aspiration cytology and thyroid scan after 131I were evaluated before L-T4 administration, while echographic monitoring of number and dimensions of nodules was recorded prior to and during L-T4 treatment. No difference in duration of L-T4 treatment (about 3 years) was registered between the TSH-suppressive therapy group and replacement therapy group. L-T4 administration in a TSH-suppressive or replacement manner did not induce a numerical or volumetric significant decrease of the main nodule or of the total nodule volume. Our data show that chronic TSH-suppressive therapy does not seem to be better than replacement therapy. Moreover, TSH-suppressive therapy presented a higher risk of adverse events than replacement therapy, thus requiring a more careful check with a higher cost of care.

Adolescent↗
PubMed2005

Application of mouse monoclonal antibodies for identification of antigen regions of human thyroid peroxidase in adolescents with Graves' disease and non-toxic multinodular goiter by flow cytometry.

Thyroid peroxidase (TPO) is the major thyroid autoantigen recognized by serum autoantibodies from patients with Graves' disease (GD) or Hashimoto's thyroiditis directed to two immunodominant conformational regions termed A and B. The epitopes of human TPO have been defined using a panel of mouse monoclonal antibodies (mAbs). The aim of this study was to estimate the expression of chosen surface antigen regions of TPO (1, 18, 30, 64 epitopes) on thyroid cells in 15 patients with non-toxic multinodular goiter (NTMG) and 15 patients with GD. The thyrocytes were identified by indirect method: in the first stage we added mouse monoclonal autoantibodies specific for TPO regions and in the second stage we conjugated this complex with rabbit anti-mouse antibodies IgG (Fab')(2) with FITC. All investigations were performed by flow cytometry using Coulter EPICS XL apparatus. The percentages of thyrocytes with expression of epitopes 1, 18, 30, 64 TPO were measured in relation to the respective anti-TPO concentrations: 50-1600 microg/ml. The analysis of epitopes located in immunodominant regions (IDR) of TPO revealed higher percentages of thyrocytes in cases with GD in comparison to NTNG. The most predominant difference was observed for mAb 64 epitope (48 vs 7%, p < 0.019; 39 vs 5%, p < 0.017) at the concentration of 100-200 microg/ml mAbs. The expression of 18 epitope on thyrocytes was also statistically higher in Graves' patients than in the NTMG (14 vs 6%, p < 0.025) at concentration of 400 microg/ml mAbs. However, this expression was much less pronounced. In all the cases, the percentages of thyrocytes with epitopes 1 and 30 were in low detection (8-15% of positive cells). In conclusion, our findings suggest that the elevated expression of TPO epitopes 18 and 64 in young patients with thyroid autoimmune diseases increase stimulation and activation of thyroid cells during inflammatory reaction within the thyroid gland. In addition, predominant expression of 64 TPO epitope that recognizes B domain in GD patients could be a useful marker of the immune process in the thyroid gland.

Adolescent↗
PubMed2004

Oxidation products and antioxidant markers in plasma of patients with Graves' disease and toxic multinodular goiter: effect of methimazole treatment.

Oxidative stress plays an important role in hyperthyroidism-induced tissue damage, as well as in development of autoimmune disorders. To clarify influence of thyroid metabolic status and autoimmune factors on blood extracellular indices of reactive oxygen species (ROS) generation and free radical scavenging in hyperthyroidism, we studied patients with newly diagnosed and untreated Graves' disease without infiltrative ophthalmopathy (17 female and 8 male, aged 41.8 +/- 8.9) and toxic multinodular goiter (15 female and 9 male, aged 48.4 +/- 10.1) under the same antithyroid treatment protocol. Initially and after achievement of stable euthyroidism with methimazole, plasma levels of hydrogen peroxide (H202), lipid hydroperoxides (ROOH) and ceruloplasmin (CP) and serum concentrations of thiobarbituric acid-reacting substances (TBARS) were determined. Similarly, activities of plasma superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were assayed. The results were compared to those of age- and sex-matched controls. Average duration of hyperthyroidism and treatment period were similar in both patients groups. H202, ROOH and TBARS concentrations were significantly higher in hyperthyroid patients compared to controls. Hyperthyroidism caused an evident increase in SOD and CAT activities and CP level, as well as a decrease in GPx and GR activities. Achievement of euthyroidism resulted in normalization of all analyzed parameters in both hyperthyroid patients groups. These findings suggest that the changes in blood extracellular indices of oxidative stress and free radical scavenging in hyperthyroid patients are influenced by thyroid metabolic status, and are not directly dependent on autoimmune factors present in Graves' disease.

Adult↗
PubMed1996

An endoplasmic reticulum storage disease causing congenital goiter with hypothyroidism.

In humans, deficient thyroglobulin (Tg, the thyroid prohormone) is an important cause of congenital hypothyroid goiter; further, homozygous mice expressing two cog/cog alleles (linked to the Tg locus) exhibit the same phenotype. Tg mutations might affect multiple different steps in thyroid hormone synthesis; however, the microscopic and biochemical phenotype tends to involve enlargement of the thyroid ER and accumulation of protein bands of M(r) < 100. To explore further the cell biology of this autosomal recessive illness, we have examined the folding and intracellular transport of newly synthesized Tg in cog/cog thyroid tissue. We find that mutant mice synthesize a full-length Tg, which appears to undergo normal N-linked glycosylation and glucose trimming. Nevertheless, in the mutant, Tg is deficient in the folding that leads to homodimerization, and there is a deficiency in the quantity of intracellular Tg transported to the distal portion of the secretory pathway. Indeed, we find that the underlying disorder in cog/cog mice is a thyroid ER storage disease, in which a temperature-sensitive Tg folding defect, in conjunction with normal ER quality control mechanisms, leads to defective Tg export. In relation to quality control, we find that the physiological response in this illness includes the specific induction of five molecular chaperones in the thyroid ER. Based on the pattern of chaperone binding, different potential roles for individual chaperones are suggested in glycoprotein folding, retention, and degradation in this ER storage disease.

Animals↗
PubMed2003

Acute increase in goiter size during a normal pregnancy: an exceptional case report.

This case report illustrates an exceptional clinical situation in which a pregnant woman abruptly presented, at 5 months' gestation, with major swelling of the thyroid gland that led to respiratory symptoms and emergency hospitalization. The medical condition was shown to be caused by acute intrathyroidal hemorrhage within a preexisting-albeit until then unnoticed-multinodular goiter. The cause of the intrathyroidal hemorrhage could not be firmly delineated, although it remains possible that an unusual extraneous cause constituted a "trauma" that triggered this rare medical condition.

Acute Disease↗
PubMed2003

Ultrasound-guided laser thermal ablation in the treatment of autonomous hyperfunctioning thyroid nodules and compressive nontoxic nodular goiter.

OBJECTIVE: Percutaneous laser thermal ablation (LTA) has been applied in several tumors. In this study we evaluated the safety and long-term efficacy of LTA in the treatment of benign thyroid nodules. DESIGN AND PATIENTS: Seven patients with autonomous hyperfunctioning thyroid nodule (group A) and five patients with compressive nodular goiter (group B) were treated with LTA. Up to three needles were positioned centrally in the thyroid nodule and laser fiber was placed in the lumen of the needle. Laser illumination was performed reaching a maximal energy deposition of 1800 J per fiber. MEASUREMENTS: Thyroid nodule volume, endocrinologic, and clinical evaluation were performed at baseline, 3, and 12 months after the treatment. Scintigraphy was performed at diagnosis and 12 months after the first session in group A. RESULTS: In group A, mean thyroid volume decreased from 3.15 +/- 1.26 mL to 0.83 +/- 0.49 mL (p < 0.001) after 12 months. The treatment induced disappearance of clinical signs and symptoms related to hyperthyroidism; normalization of free triiodothyronine (FT(3)), free thyroxine (FT(4)), and thyrotropin (TSH) serum levels and recovery of extranodular uptake at scintiscan. In group B, mean thyroid volume decreased from 11.14 +/- 4.99 mL to 3.73 +/- 1.47 mL (p < 0.01) after 12 months. Pressure symptoms in the neck, difficulty in swallowing and tracheal displacement improved in all patients. The treatment was well tolerated in both groups of patients. CONCLUSIONS: LTA appears to be a valid and safe alternative approach in the treatment of benign thyroid nodules.

Adult↗
PubMed2004

Utility of frozen-section examination for diagnosis of malignancy associated with multinodular goiter.

BACKGROUND: Frozen-section examination (FSE) has traditionally been used for the intraoperative diagnosis of thyroid cancer. However, the utility of the technique is now controversial, especially in multinodular goiter (MNG), on which there are few studies. The aim of this study was to analyze the utility of FSE for ruling out malignancy in patients undergoing surgery for MNG. PATIENTS AND METHODS: FSE was performed in 197 patients with MNGs undergoing surgery for suspected malignancy, either preoperatively (n = 145; 74%) or intraoperatively (n = 52; 26%), and where the preoperatively planned surgical technique was partial resectional surgery. The FSE diagnosis was classified as benign, suggestive of malignancy, or malignant. The following FSE parameters were calculated for diagnosing MNG-associated carcinoma: true- and false-positives and true- and false-negatives, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy. The chi2 and Student's t tests were applied. RESULTS: The FSE revealed benignity in 191 cases (97%), suggested malignancy in 3 (1.5%), and were malignant in the remaining 3. The final histology revealed 16 carcinomas (8%), of which only 3 were detected by FSE. Only tumor size was a factor significantly associated with FSE carcinoma detection (p = 0.0012). The sensitivity of the technique for detecting carcinoma was 19%, specificity, 100%; positive predictive value, 100%; negative predictive value, 93%; and diagnostic accuracy, 93%. CONCLUSIONS: FSE should not be used routinely in the management of MNG, and considering its low rate of sensitivity for detecting malignancy, the decision on the extent of the thyroidectomy should be based on other factors and explorations.

False Negative Reactions↗
PubMed2004

Anaplastic thyroid carcinoma with destructive thyrotoxicosis in a patient with preexisting multinodular goiter.

Presentation of anaplastic thyroid carcinoma with thyrotoxicosis is extremely rare and its occurrence in a patient with Wegener's granulomatosis has not been reported previously. We describe an elderly lady with Wegener's granulomatosis who developed a rapidly growing anaplastic thyroid carcinoma in a preexisting multinodular goiter and discuss the mechanism of thyrotoxicosis in this patient.

Aged↗
PubMed1992

Low-molecular-weight iodoproteins in the congenital goiters of cog/cog mice.

Previously we described sedimentation and immunologic abnormalities of thyroglobulin (Tg) in a strain of mice with inherited congenital goiter and hypothyroidism (cog/cog). The goals of the present study were to determine the extent to which thyroid gland stimulation by TSH accounts for the abnormal properties of cog/cog Tg and to characterize further the abnormally small iodoproteins found in cog/cog mice. Cog/cog and control +/cog and BALB/c mice were fed with either normal or thyroid-hormone-containing diets and were injected with Na125I. Sucrose density gradient centrifugation of labeled thyroid extracts from cog/cog mice on normal diet showed that 82% of the iodine was in iodoproteins smaller than Tg, with sedimentation rates of 3-8S. No 12S and 19S peaks, characteristic of normal Tg, were present, but distinct and stable 12S and 19S peaks emerged after recentrifugation of the 12S and 19S areas. In contrast, in cog/cog mice treated with T4, a smaller (55%) amount of 3-8S iodoproteins and distinct 12S and 19S peaks were present. In both groups of mice, the labeled 3-8S iodoproteins were composed of three fractions: 15% precipitated by antirat Tg serum, 38% precipitated by antimouse albumin serum, and 47% not precipitated by either serum. The 3-8S iodoproteins contained labeled MIT and DIT and no T4. On sodium dodecyl sulfate polyacrylamide gel electrophoresis the 3-8S iodoprotein fraction that reacted with anti-Tg serum contained a distinct electrophoretic band at 49K. The 3-8S nonreactive iodoproteins resolved into several bands of lower molecular weight. We conclude that the 3-8S iodoproteins in cog/cog mice are heterogeneous and that TSH stimulation contributes to the production of these low-molecular-weight iodoproteins.

Amino Acids↗
PubMed1993

Antithyroid and goitrogenic effects of coal-water extracts from iodine-sufficient goiter areas.

Goiter in iodine-sufficient areas has been linked to water-borne goitrogens in watersheds and aquifers rich in coal and shale. In the present study, the potential antithyroid and goitrogenic effects of coal-water extracts (CWE) were investigated in vivo in rats after chronic and acute oral administration of CWE, and in vitro by a thyroid peroxidase (TPO) enzyme system. CWE was prepared by continuous extraction of ground (40 mesh) Appalachian coal with goitrogen-free water (GFW). Female Buffalo rats fed on Purina iodine-rich diet (12 micrograms I-/day/rat), were given ad lib CWE (50 mg/ml; approximately 20 mL/day/rat) or GFW (controls) for 2 months. At the end of the experiment, 125I 1 microCi, was injected i.p. and 4 h later the thyroid glands were removed, weighed, and analyzed histologically and for total 125I and 125I-labeled compounds. Rats on CWE had larger thyroid glands [7.2 +/- 0.3 mg/100 g (mean +/- SE) vs 5.0 +/- 0.5 controls; p < 0.005] with distinct histological changes of smaller thyroid follicles, some with columnar epithelium, and with more dense colloid than in controls, and had significant inhibition of the coupling mechanism for production of thyroid hormones [125MIT + DIT/125T3 + T4: 5.1 +/- 0.2 vs 3.9 +/- 0.1 controls, p < 0.005; and 125T3 + T4 (%): 10.6 +/- 0.3 vs 12.6 +/- 0.4 controls, p < 0.005]. Female Sprague-Dawley rats under the same conditions as Buffalo rats were given acutely by GI tube 2 mL of CWE (5 g/mL) or GFW (controls).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗