Value of color-coded Doppler sonography in the differential diagnosis of nodular thyroid gland changes

AIM: The incidence of functional autonomous adenomas, detected in every second nodular goiter by scintigraphic methods is very high in an area of iodine deficiency. The color-coded Doppler sonography (CCDS) as a diagnostic tool in differentiating thyroid nodules is discussed controversially. METHODS: In this prospective study we investigated the value of CCDS in 200 patients with nodular thyroid alterations compared with 99m-Technetium (Tc) scintigraphy. RESULTS: Focal maximas of Tc-uptake were detected in 22.5% of all patients, and 44.5% of the thyroid nodules showed increased vascularity. There was no correlation between nodular vascularity and thyroid 99m-Tc uptake (TcTU). In contrast to this we could demonstrate a significant relation between vascularity and the diameter of the nodule (p < 0.0001). The results are discussed in the context of method specific limitations of ultrasound examinations. CONCLUSION: Our results confirm that CCDS has no great importance in the differentiation of thyroid nodules. Scintigraphy remains the diagnostic method of choice to assess the topographic thyroid function.     

Scintigraphic discordances between technetium 99m and iodine 131 in the study of thyroid nodules

Eighty thyroid nodules found to be hyperfixating, isofixating or heterogeneous after an initial scintigraphy with Technetium 99m were studied comparatively using iodine 131. Differences in the apparent activity of the nodule and the extra-nodular parenchyma were found in one third of cases. A "cold nodule" appearance, not seen with techneitum was found in 8 cases at the time of the examination using iodine. Five of these patients underwent operation, the diagnosis being a carcinoma in one.     

Transition from cold to hot thyroid nodules

We report three cases of autonomously functioning thyroid nodules (AFTNs) that appeared hypofunctioning at radioactive iodine (131I) thyroid scan carried out at initial observation. Since at that time thyroid hormones and thyrotropin (TSH) were also normal, they were initially classified as "cold" nodules and treated with levothyroxine (LT4). The correct diagnosis of AFTN was made years later when a thyroid scintigraphy was repeated. In two of these patients, re-evaluation of the nodule was done because of the development of LT4 intolerance. A possible explanation is that these AFTNs had undergone hemorrhagic/cystic degeneration when they were first studied, but in subsequent years, proliferation of residual AFTN tissue caused the recurrence of a typical functioning nodule.     

Isolated thyroid nodule. Comparative value of cyto-puncture and scintigraphy

OBJECTIVES: Nodular thyroid disease, indicated by the presence of single or multiple nodules within the thyroid gland is a common clinical problem, the main question remains the malignancy. Radionuclide scanning, ultrasonography and fine needle aspiration biopsy have been helpful to distinguish benign from malignant nodules and to select patients for surgery. METHODS: We performed a prospective study to assess the comparative value of fine needle nonaspiration biopsy and thyroid scinti scan in the management of 412 patients operated for solitary thyroid nodule. RESULTS: Sensitivity and negative predictive values were the same for both methods, but specificity of cytology was greater than that of thyroid scinti scan (80.53% vs. 10.47%, p < 0.001). DISCUSSION: Thyroid radionuclide scanning remains valuable in the evaluation of a cytological benign solitary thyroid nodule when TSH value is low, in order to distinguish toxic adenoma from cold nodule in Graves' disease.     

Levothyroxine suppressive therapy for solitary thyroid nodule

In order to evaluate the efficacy of a TSH suppressive dose of levothyroxine to reduce the volume of a single thyroid nodule we studied 55 euthyroid patient: 45 (group A) were suppressed with LT4 (mean 1.7 +/- 0.9 micrograms/Kg/day) for 21.3 +/- 5.3 months, and 10 patients (group B) served as controls. All the nodules were "cold" at scintiscanning, solid at ultrasonography and benign by fine-needle aspiration cytology. As responders were assumed the nodules shrinked at the end of treatment of 50% in volume. Thyroid function values (TSH, T4, FT4, T3, FT3, thyroid peroxidase and thyroglobulin antibodies), clinical and ultrasonographic findings were evaluated initially and at the end of the study. A significant nodular volume decrease occurred in 8 treated patients (17.8%) while 37 (82.2%) amongst the group suppressed and all controls showed no change (A vs B = NS). In two untreated patients new nodules were noted; no new nodules were discovered in the treated group (A vs B p < 005). No side effects occurred in any treated patient, even if at the end of treatment a significant T4 and FT4 (p < 0.01) increase was observed. No one onset parameter can predict the response to the therapy. These results suggest that only a small group of patients affected by a single thyroid nodule seems to respond to a TSH suppressive therapy.     

Medical treatment of multinodular goiter

Thyroid nodules are among the most common clinical problems in endocrinology. Among several factors responsible for the development of goiter, circulating TSH plays a major role because of its direct growth-promoting effects on the thyroid cells; moreover TSH may enhance the effects of other local growth factors which act in a paracrine mode in the thyroid gland. In addition, autoimmune thyroiditis can clinically appear as thyroid nodules frequently with the functional aspect of a subclinical hypothyroidism. For these reasons a therapeutical approach based on the thyroxine suppression of TSH secretion has become largely used by 1970s and is correctly employed in 75% of the patients with thyroid nodules whose biopsies result benign.     

Refined use of scintigraphy in the evaluation of nodular thyroid disease

BACKGROUND: Scintigraphy has been advocated in patients with a thyroid nodule when fine needle aspiration biopsy (FNAB) is not definitive. The purpose of this study was to determine the incidence of hyperfunctioning nodules in patients without a definitive FNAB, the correlation of serum thyrotropin (TSH) levels with the functional status of a nodule, and whether a sensitive TSH assay can be used in lieu of scintigraphy. METHODS: From 1990 to 1996, patients with a thyroid nodule were evaluated with FNAB and serum TSH measurement. Iodine-123 scintigraphy was reserved for patients without a definitive FNAB and was correlated with TSH levels. RESULTS: Of 356 patients with a thyroid nodule, 102 did not have a definitive FNAB. A hyperfunctioning nodule was diagnosed in 14 of the 102 patients. A low TSH level was detected in 12 (86%) of 14 patients with a hyperfunctioning nodule (mean = 0.04 +/- 0.38 microIU/mL) and only 20 (23%) of 88 patients with a hypofunctioning nodule (mean = 0.87 +/- 4.11 microIU/mL) (P < .05). Only 2 of 70 (2.8%) patients with a normal or increased TSH level had a hyperfunctioning nodule. CONCLUSIONS: A 14% incidence of hyperfunctioning nodules in patients without a definitive FNAB warrants the use of scintigraphy but only when serum TSH levels are low, thus avoiding unnecessary scans in 91% of patients with a thyroid nodule.     

Infantile and juvenile hypothyroidism with the gland in place and low radio-iodide uptake

27 hypothyroid infants of children, with a low iodine uptake in spite of a thyroid gland or thyroid tissue in normal pretracheal place, have been studied. 21 cases are related to primary thyroid involvement leading to vanishing iodine or technetium uptake. In 8 of these cases, clinical onset in late childhood, high frequency of antithyroid antibodies and of familial thyroid dysfunction were similar to those found in childhood's thyroiditis. 8 other cases had a precocious onset (first months in 6, first year in 1, second year in 1) with some pretracheal iodine uptake when first studied and no uptake at further examinations, 1 patient having received no treatment from first to second study, the others being without treatment from more than two months and certain of them receiving injections of TSH. The last 5 cases of this group were those of children born to 2 mothers with treated hypothyroidism, with low iodine uptake in pretracheal place. The role of genetic factors and auto-immunity in theses cases is discussed. The 6 other patients had clinically isolated hypothyroidism secondary to TSH deficiency, eventually associated to clinically inapparent GH or ACTH deficiencies, most of them by hypothalamic defect with normal response to TRH.     

Thyroid nodules: malignant or benign?

Palpation of a thyroid nodule should initiate a workup to exclude the rare but dangerous possibility of malignancy or autonomous function. Clinical evaluation will at times provide clues to malignancy, but the diagnostic cornerstone is fine-needle aspiration biopsy. Treatment may include observation, surgery, levothyroxine, or radioactive iodine.     

Running economy: comparison of body mass adjustment methods

Iodine plays a central role in thyroid physiology, being both a major constituent of thyroid hormones (THS) and a regulator of thyroid gland function. This review concerns those aspects of thyroid physiology in which significant advances have been made in recent years. We have known for decades that the thyroid gland concentrates iodine (I-) against an electrochemical gradient by a carrier-mediated mechanism driven by ATP. A similar I- uptake mechanism is found in other organs, including salivary glands, stomach, choroid plexus, and mammary glands, but only in the thyroid does TSH regulate the process. This past year saw a major advance with the cloning of the thyroid I- transporter. This development opens the way to an elucidation of the regulation of I- transport in the normal gland and in thyroid neoplasms that lack this property ("cold" nodules). All of the subsequent steps in TH biosynthesis, from oxidation and organification of iodide to the secretion of T4 and T3 into the circulation, are stimulated by TSH and inhibited by excess iodine. Recently, some of the regulatory mechanisms have been clarified. The function of the major TH-binding proteins in plasma is to maintain an equilibrium between extracellular and cellular hormone pools. Transthyretin, the principal T4-binding protein in cerebrospinal fluid, may play a similar role in the central nervous system. Although it generally is agreed that cellular uptake of TH is a function of the unbound (free) form of the hormone, there is evidence that certain TH-binding plasma proteins (i.e., apolipoproteins) may serve specific transport functions. The intracellular concentration of T3, the active TH, is determined by the rates of cellular uptake of T4 and T3, the rates of metabolic transformation, including conversion of T4 to T3, and the rate of T3 efflux. The latter has been assumed to be a passive process. However, recent studies by our group in San Francisco have shown that T3 is transported out of cells by a specific, saturable, verapamil-inhibitable mechanism. This T3 efflux system is widespread among cells from many tissues, and, at least in liver, modulates intracellular and nuclear concentration of the hormone and thereby influences TH action.     

Neonatal transient hypothyroidism: aetiological study. Italian Collaborative Study on Transient Hypothyroidism

AIMS: To define the aetiology of neonatal transient hypothyroidism (NTH) and recommend preventive measures. METHODS: Maternal and perinatal clinical data on the use of antiseptics, drugs, and contrast agents containing iodine were collected from 40 subjects. Thyroid stimulating hormone (TSH), free thyroxine (FT4), thyroxine (T4), thyroglobulin (TG), TSH receptor antibodies, thyroid peroxidase antibodies and urinary iodine were measured in random neonatal samples. In the mothers with known or suspected thyroid disorders, TSH, FT4, TSH receptor antibodies and thyroid peroxidase antibodies were also measured. RESULTS: The NTH aetiology was identified in 85% of cases. More than 50% of the babies with transient hypothyroidism had been exposed to iodine; maternal transfer of antibodies had occurred in a third of them. CONCLUSIONS: It is suggested that the practice of using iodine containing disinfectants should be withdrawn, and chlorhexidine substituted instead; that pregnant women should be advised of the adverse effects of using iodine products; and that thyroid function should be monitored whenever iodine is used.     

Hyperthyroidism induced by iodine in an apparently normal thyroid gland. A new iatrogenic disease

Iodine-induced thyrotoxicosis was reported to occur in patients with previously altered thyroid gland. Evidence is presented here from 23 cases that iodine-induced thyrotoxicosis may also occur in patients with no prior thyroid desorder and is characterized by: a) an almost undetectable 131I uptake, wich can be activated by TSH; b) a spontaneous improvement within a few weeks or months after withdrawing the high intake of iodine; c) the absence of any detectable thyroid abnormality after recovery.     

Thyroxine suppressive therapy in patients with nodular thyroid disease

PURPOSE: To review evidence about thyroxine suppressive therapy in patients with thyroid nodules, including the clinical importance and natural history of nodules and the effects and potential side effects of thyroxine therapy. DATA SOURCES: English-language articles published from 1986 to December 1996 were identified through searches of the MEDLINE database, selected bibliographies, and personal files. DATA EXTRACTION: Randomized, controlled trials and nonrandomized trials of thyroxine suppressive therapy for solitary and predominantly solid thyroid nodules were reviewed. In most studies, nodule cytology was evaluated by fine-needle aspiration biopsy. Therapy was considered suppressive if suppression was documented by thyroid-stimulating hormone-releasing hormone tests or sensitive thyroid-stimulating hormone assays. Response was defined as a decrease of 50% or more in nodule size or volume; most recent studies measured nodule size by ultrasonography. DATA SYNTHESIS: The evidence suggests that thyroxine suppressive therapy fails to shrink most nodules: Only 10% to 20% of nodules responded to this treatment. Fine-needle aspiration biopsy is more reliable in distinguishing benign from malignant nodules. Recent studies suggest that spontaneous decrease in size with complete disappearance of thyroid nodules is not uncommon. No data show that thyroxine therapy arrests further growth in most existing nodules or prevents the emergence of new nodules. Postoperative thyroxine therapy does not seem to prevent recurrence of thyroid nodules except in patients with a history of radiation therapy. Potential adverse effects of long-term suppressive therapy include osteoporosis and heart disease. CONCLUSIONS: Patients with cytologically benign nodules are best followed without thyroxine treatment. Most benign nodules remain stable in size and remain benign when monitored for a long time. For nodules that increase in size, biopsy should be done again or surgery should be performed.     

Hürthle cell tumor dwelling in hot thyroid nodules: preoperative detection with technetium-99m-MIBI dual-phase scintigraphy

Single injection dual-phase scintigraphy (early and late acquisitions) with 99mTc-MIBI was used to differentiate benign and malignant hot thyroid nodules. METHODS: Thirteen euthyroid and two hyperthyroid patients displaying a hot thyroid nodule on the 99mTc scan due to an autonomously functioning thyroid nodule (AFTN) underwent early (15-30 min) and late (3-4 hr) thyroid scintigraphy after the administration of 740-1000 MBq 99mTc-MIBI. Visual scoring was done to assess nodular tracer uptake and retention. In addition, the nodular-to-thyroid (N/T) uptake ratio in the early and late image and the washout rates (WO) from the nodule and thyroidal tissue were measured. All patients underwent thyroid surgery. RESULTS: Histopathology revealed a Hürthle cell tumor in three nodules, a benign adenoma with oxyphilic metaplasia in two nodules and a benign adenoma without oxyphilic cells in the remaining 10 nodules. The Hürthle cell tumor nodules displayed intense and persistent uptake of 99mTc-MIBI (N/T was 2.81 +/- 0.52 and 5.53 +/- 1.06 in early and late images, respectively; WO from the nodule was 12.33 +/- 0.47, WO from the thyroidal tissue was 22.00 +/- 3.56). The benign nodules showed intense uptake in the early image and intense uptake to absent retention in the late image (N/T was 2.94 +/- 1.31 and 1.62 +/- 0.50 in the early and late images, respectively; WO from the nodule was 20.25 +/- 2.92, WO from the thyroidal tissue was 20.33 +/- 2.92). CONCLUSION: Single injection dual-phase 99mTc-MIBI scintigraphy of the thyroid with AFTN can identify nodules as a result of the activity of a Hürthle cell tumor, since these tumors cause intense and persistent tracer uptake in contrast with a benign AFTN.     

TSH receptor and Gs-alpha gene mutations in the pathogenesis of toxic thyroid adenomas--a note of caution

The detection of a constitutive activation of the AC cascade by TSH-R and Gs alpha mutations in a number of TTAs should not distract from the large gap in our understanding of the pathogenesis of thyroid tumors. TTAs form only a minor fraction of all thyroid nodules, and even within this small subgroup, activating mutations have been found regionally with a highly variable incidence. If activating mutations were the sole and only cause of TTAs, a homogeneous functional and morphological response of all thyrocytes would ensue. This, however, is not the case. Rather, severe disturbances of the Gs protein-AC cascade regularly occur in TTAs. Even within thyroids affected by activating TSH-R germline mutations, some cell clones proliferate at a faster rate than others, causing nodular growth with time. Moreover, not only functional, but also morphological heterogeneity very frequently evolves even in clonal adenomas. The natural heterogeneity among individual thyrocytes may account for a different functional and proliferative response among cells affected by identical mutations or any other gain-of-function event. The recent findings in toxic adenomas must be taken together with the fact that, in the large majority of all thyroid nodules, iodine metabolism is by no means enhanced, but diminished or absent and that, in this type of tumor, no consistent pattern of growth-stimulating mutational events has yet been identified. The nature, the precise temporal sequence and interaction of the genetic, cytogenetic, and environmental events that cause the very common and often autonomous nodular growth of only a few distinct cell populations within the human thyroid gland remain largely unknown.     

Morphological and functional polymorphism within clonal thyroid nodules

Thirty-nine thyroid nodules, removed because of recent growth, were analyzed morphologically by serial histological sections for the classical histomorphological hallmarks of follicular cell replication and for immunohistochemically demonstrable overexpression of the growth-associated ras-gene product p21ras. Clonal analysis was performed using the highly informative probe M27 beta that detects polymorphisms on the locus DXS255 of the X-chromosome. Twenty-four nodules were of clonal and 15 nodules were of poly-clonal origin. Only 3 out of the 24 clonal nodules were histomorphologically uniform. In all others, the structural hallmarks of active growth and the P21ras growth-marker expression were remarkably heterogeneous throughout the tumors. There were no histomorphological characteristics distinguishing these clonal tumors from polyclonal nodules. Even if a clonal thyroid tumor may be originally homogeneous in respect to the parameters studied here, mechanisms must exist that create wide heterogeneity of growth and of morphogenetic potential among the individual follicular cells during further expansion of the nodule. Thus, clonal nodules are much more common in nodular goiters than hitherto assumed on grounds of the classical morphological criteria. The diagnosis of a true monoclonal nodule can no longer rely on morphological and functional criteria alone but requires molecular or cytogenetic analysis of clonality.     

Clinical significance of clonality in thyroid nodules

BACKGROUND: Many different neoplastic and hyperplastic thyroid diseases present with clinically apparent thyroid nodules. Clonality analysis indicates whether a nodule arises from the polyclonal proliferation of a group of cells or forms a clone from a genetically altered cell and thus provides objective information on the origin of the thyroid nodules. Clonality was studied in thyroid nodules using the polymerase chain reaction (PCR) assay in the X-linked human androgen receptor (HUMARA) gene by random X chromosome inactivation in women. METHODS: DNA samples were obtained from 28 nodules in 21 women. All nodules and non-tumour thyroid tissues were fractioned selectively under a cryostat. Genomic DNA was isolated and digested with HhaI. PCR amplification of the HUMARA locus was performed using PCR mixtures containing [alpha-32P]2'-deoxycytidine 5'-triphosphate. The PCR products were analysed by denaturing gel electrophoresis. RESULTS: The HUMARA alleles were heterogeneous in 18 of 21 patients. Among the 23 nodules from 18 patients, all of the eight papillary thyroid carcinomas were monoclonal. Two solitary nodules from follicular adenomas were monoclonal. Of the 13 follicular nodules from nodular goitres, ten were polyclonal and three were monoclonal. The monoclonal follicular nodules were larger in size (3.5 versus 2.0 cm, P< 0.05) and had a tendency towards more cystic changes than polyclonal nodules. CONCLUSION: PCR-based clonality study of thyroid nodules may help to distinguish hyperplastic from neoplastic nodules.     

Changes in radioiodine turnover in patients with autonomous thyroid adenoma treated with percutaneous ethanol injection

In 24 patients with autonomous thyroid adenoma, we studied the hormonal pattern (free thyroxine, free triiodothyronine and thyroid stimulating hormone) and markers of radioiodine turnover before and after nodule ablation with percutaneous ethanol injection. METHODS: The hormonal pattern was studied before treatment and at various intervals after nodule ablation. Changes in radioiodine turnover were studied measuring 131I protein-bound iodine and the biologic half-life of radioiodine in the thyroid (calculated from thyroid uptake at 24 and 48 hr) before and after ethanol treatment. RESULTS: The hormonal pattern was normalized by treatment in all patients and remained normal for the follow-up period. Before treatment, protein-bound 131I was elevated in all patients but 4; after treatment, it normalized in 15 patients with the disappearance of the adenoma on scintigraphy. In the remaining 9 patients with only partial nodule destruction on scintigraphy, protein-bound 131I remained elevated although markedly reduced. Biologic half-life was shortened in 18 of 24 patients before treatment; after treatment, it was normal in 18 of 24 patients (13 of 15 with complete nodule ablation and 5 of 9 with partial ablation). CONCLUSION: Ethanol treatment normalized the hormonal pattern in all patients. Measures of radioiodine turnover were better markers of residual disease in that they normalized in almost all patients with complete nodule ablation, whereas they remained abnormal in a high proportion of patients with incomplete ablation. Thyroid hormones remained normal over a follow-up period of 3-7 yr in all patients.     

Suppressive therapy with levothyroxine for solitary thyroid nodules: a double-blind controlled clinical study and cumulative meta-analyses

Levothyroxine suppressive treatment of solitary thyroid nodules is controversial. A 1-yr prospective randomized placebo-controlled trial was conducted to evaluate the effect of T4 on nodule volume and bone mineral density, and meta-analyses were performed to examine the quantitative synthesis of data from similar designed controlled trials. Forty-five euthyroid patients (42 females, age range: 19-73 yr) with single, colloid nodules were randomized to T4 (21 patients, 2.7 +/- 0.3 microg/kg, TSH < 0.3 microIU/mL) and placebo. Ultrasonography and densitometry were performed at baseline and repeated after treatment. Mean nodule volume or bone mineral density did not change. Nodule reduction more than 50% was observed in 6 of 21 treated patients and 2 of 24 placebo patients (P = 0.12). This study and another 6 prospective controlled trials (minimum 6 months, ultrasonographic nodule evaluation) were included in cumulative meta-analyses (risk-difference method). Nodule volume decreased more than 50% in a significantly higher percentage of patients in the T4 groups (risk difference, 16.7%; 95% confidence intervals, 5.8-27.6%). Four trials evaluated nodule growth with homogeneous results (Q = 0.42). Nodule volume increased more than 50% in a significantly smaller percentage of patients treated with T4 (risk difference, 9.7%; 95% confidence intervals, 2.0-17.4%). In conclusion, T4 treatment is associated with decreased nodule volume in 17% of patients and may inhibit growth in another 10%.