Presence of human T-lymphotropic virus type II-related genes in DNA of peripheral leukocytes from patients with autoimmune thyroid diseases

No etiologic role of human T-lymphotropic virus type II (HTLV-II) in any disease is yet known. The present study showed a high incidence of HTLV-II proviral DNA fragments in DNA of peripheral blood leukocytes from patients with autoimmune thyroid diseases. Using primers for the pol and tax regions of HTLV-II proviral DNA, amplified DNA fragments were demonstrated in 51.5% of the patients with Hashimoto's thyroiditis and in 11.8% of those with Graves' disease examined, but in only 1.9% of the disease controls and 1.0% of healthy individuals. These amplified DNA fragments hybridized with each of the inner probes. The nucleotide sequences of the DNA fragments of the pol and tax regions showed high homology with those of the prototype of HTLV-II. No antibodies for HTLV-II could, however, be detected in the patients examined. Because of the absence of its antibody, HTLV-II infection was not confirmed in these patients, but the presence of HTLV-II proviral DNA or its related DNA at high frequency suggests a relationship of HTLV-II with the development of autoimmune thyroid diseases. © 1995 Wiley-Liss, Inc.     

HTLV-I infection in patients with autoimmune thyroiditis (Hashimoto's thyroiditis).

To investigate the possible relationship of HTLV-I virus infection to autoimmune thyroid disease, we examined, firstly, the frequency of HTLV-I seropositivity among patients with Hashimoto's thyroiditis and, secondly, the frequency of Hashimoto's thyroiditis in patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP). Of 144 patients with Hashimoto's thyroiditis in the Tokushima and Kochi Prefectures, Japan, 9 (6.3%) were positive for serum HTLV-I virus antibody 2 of whom were confirmed histologically to have Hashimoto's thyroiditis. This percentage is significantly higher (P < 0.01) than the estimated prevalence (2.2%) of HTLV-I carriers among the general population in this region. Of 9 patients with HAM/TSP, 3 (33.3%), including 2 biopsy-proven cases, had evidence of Hashimoto's thyroiditis. This proportion is apparently much higher than the prevalence (1.7%) of Hashimoto's thyroiditis in the general population. These findings suggest that HTLV-I virus may be related to the development of Hashimoto's thyroiditis.     

Serum CXCL10 levels and neuromuscular manifestations in patients with autoimmune thyroid diseases

Objective: Serum C-X-C motif chemokine 10 (CXCL10) levels have been shown to be elevated in autoimmune thyroid diseases (AITD). This study sought to determine whether newly diagnosed AITD patients with neuromuscular findings had higher levels of CXCL10 than those without neuromuscular manifestations.

Design: A total of 80 patients were recruited to the study, which included treatment-naive hypothyroid Hashimoto's thyroiditis (n = 19) and hyperthyroid Graves' disease (GD; n = 21), euthyroid thyroid autoantibody-positive (n = 20) and -negative (n = 20) patients.

Methods: All patients underwent a thorough sensorimotor and neuromuscular examination. Serum samples were kept in ? 20°C for further CXCL10 measurements with ELISA.

Results: There was a significant difference with regard to serum CXCL10 levels only between GD and euthyroid thyroid autoantibody-negative patient groups [187(12-418) vs. 37.5(2-542) pg/ml, p < 0.05]. However, a comparison of newly diagnosed AITD patients with and without neuromuscular manifestations in terms of serum CXCL10 levels yielded no significant difference. When a correlation of existence of a neuromuscular manifestation and serum CXCL10 levels was evaluated, a significantly positive correlation was noted between carpal tunnel syndrome (CTS) and serum CXCL10 levels [207 (95-748) pg/ml in CTS-positive vs. 117 (2-977) pg/ml in CTS-negative patients, p < 0.05].

Conclusions: In this study, from a number of neuromuscular manifestations, only the existence of CTS correlated with significantly higher CXCL10 levels in the whole study group. Further studies with larger numbers of patients with autoimmune-based hyper- and hypothyroidism may better clarify the hypothesis regarding a relationship between serum CXCL10 levels and neuromuscular manifestations of AITD.     

In vitro production of interferon-gamma by peripheral blood from patients with Graves'' disease, Hashimoto''s thyroiditis and rheumatoid arthritis.

The production of interferon-gamma (IFN-gamma) by peripheral blood mononuclear cells (PBMC), CD4 cells, or CD8 cells in response to interleukin-2 (IL-2) stimulation has been studied; the samples were obtained from 12 healthy control subjects, 19 patients with Graves' disease (10 hyperthyroid and nine euthyroid), 13 patients with Hashimoto's thyroiditis (four hypothyroid and nine euthyroid), and 15 patients with rheumatoid arthritis (11 active and four inactive). A dose of IL-2 (25 U/ml) was utilized to induce IFN-gamma by PBMC from all four groups. The incremental increase in IFN-gamma values (with IL-2 stimulation minus without stimulation) was significantly less in PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis than that in PBMC from control subjects. The values from PBMC in patients with Graves' disease in a euthyroid state were below normal but greater than those from patients with Graves' disease in a hyperthyroid state. The incremental increase in IFN-gamma values from Graves' disease PBMC correlated with the serum TSH values (r = 0.622, P less than 0.01), but not with thyroid autoantibodies (anti-thyroid microsomal antibodies, anti-thyroid microsomal antibodies, nor TSH-binding inhibitory immunoglobulin activities). The incremental increase in IFN-gamma from PBMC from both control subjects and Graves' disease was correlated with that from CD4 cells (r = 0.711, P less than 0.01), but not with that from CD8 cells. The production of IFN-gamma in response to IL-2 from PBMC in Graves' disease correlated inversely with thyroid function, appearing to reflect the very effect of hyperthyroidism in this process. The precise explanation of these phenomena remains unclear. The decreased response of IFN-gamma to IL-2 stimulation by PBMC from patients with Graves' disease, Hashimoto's thyroiditis, and rheumatoid arthritis seems to be a non-specific phenomenon occurring in both organ specific autoimmune disease and systemic autoimmune disease. It may be due to a down-regulation in autoimmune disease of CD4 cells in response to IL-2, a decreased level of IL-2 cellular receptors or a decreased receptor affinity, associated increased soluble IL-2 receptors, or a defect of the intra-CD4 cellular IL-2 signal to produce or release IFN-gamma in the conditions studied.     

Autoantibodies against complement C1q correlate with the thyroid function in patients with autoimmune thyroid disease

Autoantibodies against complement C1q (anti-C1q) have been well described in patients with systemic lupus erythematosus, where they correlate with the occurrence of severe lupus nephritis. However, data on anti-C1q in organ-specific autoimmune diseases are scarce. In order to determine the prevalence of anti-C1q in patients with autoimmune thyroid disorders (AITD) and a possible association with thyroid function, we measured prospectively anti-C1q in 23 patients with Graves' disease (GD) and 52 patients with Hashimoto's thyroiditis (HT). Anti-C1q levels were correlated with parameters of thyroid function and autoantibodies against thyroperoxidase, thyroglobulin and thyroid stimulating hormone (TSH) receptor. Twenty-one patients with multi-nodular goitre and 72 normal blood donors served as controls. We found elevated concentrations of anti-C1q more frequently in patients with AITD than in controls: seven of 23 (30%) patients with GD and 11 of 52 (21%) patients with HT, compared with one of 21 (5%) patients with multi-nodular goitre and six of 72 (8%) normal controls. Anti-C1q levels did not correlate with thyroid autoantibodies. However, in GD absolute levels of anti-C1q correlated negatively with TSH and positively with free thyroxine (FT4) and triiodothyronine (FT3). In contrast, in HT, anti-C1q correlated positively with TSH levels. No correlation between TSH and thyroid autoantibodies was found. In conclusion, we found an increased prevalence of anti-C1q in patients with AITD and their levels correlated with the thyroid function in both GD and HT. This correlation seems to be independent of thyroid autoantibodies. Therefore, anti-C1q might point to a pathogenic mechanism involved in the development of AITD that is independent of classical thyroid autoantibodies.     

Analysis of susceptibility of NOD mice to spontaneous and experimentally induced thyroiditis

Beside diabetes, non-obese diabetic (NOD) mice develop sporadic lymphoid infiltration of the thyroid gland, mimicking Hashimoto's thyroiditis. We have examined the prevalence of those manifestations in NOD mice, the influence of the major histocompatibility complex (MHC) and the association with autoantibodies. The incidence at 1 year is of 14.3% in wild-type NOD mice versus 19.6% in congenic NOD.H2^k mice. The moderate, but statistically significant difference, based on the analysis of 161 NOD and 169 NOD.H2^k mice, suggests that MHC genes partially control spontaneous NOD thyroiditis. Autoantibodies against thyroglobulin (Tg) are mouse specific and their presence correlates closely with thyroiditis. The strong correlation between cellular and humoral anomalies therefore resembles Hashimoto's thyroiditis. NOD and NOD.H2^k mice actively immunized against Tg develop severe chronic lesions with epithelium necrosis and interstitial tissue fibrosis. Most interestingly, those lesions do not regress spontaneously as in CBA/J mice. Paradoxically, the response to Tg of lymph node cells from NOD mice is weaker both in proliferation and cytokine production. The defect is most evident for interferon-γ-producing T cells and is reflected in the marked deficit in IgG2a antibodies. Thus a moderate anti-Tg response seems to favor chronicity of thyroiditis. In conclusion, NOD and NOD.H2^k mice offer a unique opportunity of analyzing the factors leading to immune chronicity in a genetic context which promotes autoimmune endocrinopathies.     

Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves' disease.

Autoantibodies directed against human CD38 (an enzyme catalysing the interconversion of NAD(+) and cyclic ADP-ribose) have been demonstrated recently in patients with type 2 diabetes. We tested 220 consecutive Caucasian patients with autoimmune chronic thyroiditis, 104 patients with Graves' disease, 220 subjects from the general population (control I) and 78 healthy control subjects not affected by thyroid autoimmune disorders (control II) for the presence of anti-CD38 autoimmunity. Using Western blot analysis and optical densitometry, a specific band corresponding to human recombinant CD38 was identified in the serum of several subjects. By defining anti-CD38 positivity as a standardized optical reading > 3 s.d. higher than the mean value of control I, 10.4% of patients with thyroiditis and 7.7% of Graves' patients were anti-CD38 positive (P = 0.0009 versus 1.8% of control I). Similarly, 13.1% of patients with thyroiditis and 10.5% of Graves' patients had a standardized optical reading > 3 s.d. higher than the mean value of the subjects not affected by thyroid autoimmune disorders (P = 0.002 versus 1.2% of control II). Anti-CD38 autoimmunity did not differ between euthyroid, hyperthyroid or hypothyroid patients or between patients with or without thyroid hypoechogenicity. Anti-CD38 autoantibodies were associated with higher levels of circulating antithyroid-peroxidase antibodies (P = 0.03) and they were more frequent in Graves' patients with ophthalmopathy (P < 0.05). Anti-CD38 autoantibodies are a new autoimmune marker in chronic autoimmune thyroiditis and Graves' disease. The specific role of CD38 and its autoantibodies in the modulation of thyroid cell function or growth remains to be investigated.     

Association studies of the IL-23R gene in autoimmune thyroid disease in the Japanese population

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are caused by interplays of genetic factors and environmental triggers. Interleukin-23 and its receptor (IL-23R) guide T cells towards the Th17 phenotype. IL-23R single nucleotide polymorphisms (SNPs) have been shown to be associated with several autoimmune diseases, including Crohn's disease and rheumatoid arthritis, and Graves' ophthalmopathy (GO) in Caucasians. To determine whether variants in the IL-23R gene are associated with AITDs in Japanese, 464 Japanese AITD patients (290 with GD, 174 with HT) and 179 matched Japanese control subjects were genotyped for four SNPs spanning the IL-23R gene. SNPs rs11209026 and rs7530511 were genotyped using TaqMan allelic discrimination assays and SNPs rs2201841 and rs10889677 were genotyped using a fluorescent-based restriction fragment length polymorphism method. Case-control association studies were performed using the χ² and Fisher's exact tests with Yates correction. Of the four SNPs rs11209026 was non-polymorphic in our dataset. The other three SNPs were not associated with GD or GO or HT in our Japanese population. These results suggest that the IL-23R gene is associated with AITDs only in a specific ethnic group.     

Expression of intercellular adhesion molecule-1 (ICAM-1) on thyroid epithelial cells in Hashimoto's thyroiditis but not in Graves' disease or papillary thyroid cancer.

In order to study the possible role of antigen-independent adhesion systems in thyroid autoimmunity, we evaluated by indirect immunofluorescence the expression of lymphocyte functional antigen-1 (LFA-1) and its ligand ICAM-1 on mononuclear cell infiltrates (when present) and thyroid follicular cells of four patients with Hashimoto's thyroiditis, 30 with Graves' disease, five with papillary cancer, two with follicular adenoma, and two normal thyroid specimens. The expression of MHC class I and class II antigens was also evaluated. Most mononuclear infiltrates were LFA-1 positive, as expected. A positivity for ICAM-1 on follicular cells was observed in three out of four Hashimoto's thyroiditis specimens; such a phenomenon was totally absent in Graves' disease or any other pathological condition, or in normal tissue. MHC class II expression on thyrocytes was observed in all the patients with Hashimoto's thyroiditis, in 27 out of 30 with Graves' disease and in three out of five papillary cancer specimens.     

Thyroid cancer and thyroid autoimmune disease: A review of molecular aspects and clinical outcomes

Thyroid cancer (TC) is the most prevalent malignant neoplasm that affects the endocrine system. Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is the most common autoimmune thyroid disease (AITD) that, together with Graves' disease (GD), represent the main autoimmune diseases that affect the thyroid gland. Some studies suggest a greater risk of AITD and the development of TC, while others, investigate its relationship with TC progression and patient prognosis. In this review, we have analyzed published data on the molecular aspects related to the association between AITD and TC, addressing their influence on TC progression, diagnosis, and prognosis of the patients. MEDLINE database (PubMed) platform was used as a search engine and the original articles related to the topic were selected using the keywords combination “thyroid cancer and Hashimoto thyroiditis” or “thyroid carcinoma and thyroid autoimmune disease”. After the selection, we categorized the main findings of the papers into four topics: antitumor immunity, tumor progression, diagnosis, and prognosis. Although most of the studies have pointed out the presence of AITD as a factor that increases the risk of TC, few molecular mechanisms to support this conclusion have been described. Additionally, little information is available to explain, pathophysiologically, the effects of autoimmunity in TC diagnosis, progression, and prognosis.     

Lower proportions of CD4+CD25high and CD4+FoxP3, but not CD4+CD25+CD127low FoxP3+T cell levels in children with autoimmune thyroid diseases

The essence of autoimmune thyroid disease (AITD) is loss of tolerance of own tissues caused by malfunction of T lymphocytes, which affects the production of antibodies reacting with particular cell structures and tissues. Foxp3⁺ regulatory T cells (Tregs) take part in the regulation of immune response and play a leading role in developing immune tolerance through active suppression. The aim of the study was to estimate the expression of CD4+CD25^high, CD4+CD25+CD127^lowFoxP3⁺ and CD4+ FoxP3 T cells in patients with Graves' disease (GD) (n = 24, median age 15.5 years), in patients with Hashimoto's thyroiditis (HT) (n = 30, median age 15 years) in comparison with sex- and age-matched healthy control subjects (n = 30, median age 15 years). Polychromatic flow cytometry using a FACSCalibur (BD Biosciences) cytometer was applied to delineate T regulatory cell populations. In untreated patients with Graves' disease and HT we observed a significant decrease in CD4+FoxP3 (p < 0.001, p < 0.01) and CD4+CD25^high (p < 0.016, p < 0.048) T lymphocytes as compared to the healthy control subjects. After 6–12 months of L-thyroxine therapy in HT cases these phenotypes of Tregs were normalized, yet no such changes were observed during GD therapy. The analysis of CD4+CD25+CD127^lowFoxP3⁺T cells in the peripheral blood revealed comparable percentages of these cells in patients with thyroid autoimmune diseases to the controls. We conclude that the reduction number of Tregs with CD4+CD25^high and CD4+FoxP3 phenotype suggests their role in initiation and development of autoimmune process in thyroid disorders.     

Correlation of number of intrathyroid lymphocytes with antimicrosomal antibody titer in Hashimoto's thyroiditis

The variants of Hashimoto's thyroiditis (classic, florid, and fibrotic types) differ in clinical manifestations, laboratory tests, and morphology. The titers of autoantibodies correlate with the degree of thyroidal lymphocytic infiltration (Wislon et al., 1998(5)) It appears that the density of lymphocytes is inversely proportional to antimicrosomal antibody (AMA) titer. The aim of the present study is to determine the precise relationship between the number of lymphocytes and AMA titer. It may be useful to predict the onset of the disease in subclinically hypothyroid patients. In 62 cases of cytologically confirmed Hashimoto's thyroiditis, the number of lymphocytes per high-power field was counted and correlated with AMA titer. The grading of lymphocytes was done as 1 (<10/HPF), 2 (11-20/HPF), and 3 (>/=21/HPF). The results showed no correlation between lymphocyte number and AMA titer.     

Experimental autoimmune thyroiditis in human parvovirus B19 transgenic mice

Viral infection is implicated as a cause of autoimmune diseases. Whereas its role in Hashimoto's thyroiditis (HT) remains undefined, recent studies suggested a link between human parvovirus B19 (B19) infection and HT. We tested such possibility by using B19 nonstructural protein 1 (NS1) transgenic C57BL/6 mice, which harbor nonpermissive genetic background (H-2^b). Mice were immunized with either thyroglobulin (Tg) or saline. No thyroiditis developed in saline-treated mice and Tg-immunized males regardless of the presence or absence of NS1. In contrast, thyroiditis was induced by Tg immunization in 25% of transgenic females, but not in wild-type females. However, the thyroiditis incidence in the former did not differ significantly from that of the latter. In addition, intrathyroidal T-cell receptor gene expression was not augmented in Tg-immunized transgenic females. Immunization with Tg led to a comparable increase in serum anti-Tg antibody levels in the wild-type and transgenic mice. Our results indicate that the introduction of B19 NS1 gene into C57BL/6 mice is insufficient to promote the development of autoimmune thyroiditis. Further studies are required, however, before concluding that B19 infection is not involved in HT induction.     

The production of mannan-binding lectin is dependent upon thyroid hormones regardless of the genotype: A cohort study of 95 patients with autoimmune thyroid disorders

Complement mannan-binding lectin (MBL) deficiency is associated with increased susceptibility to infections and autoimmune diseases. Previous studies suggested that the production of MBL is stimulated by thyroid hormones. The aim of our study was to investigate this association in patients with autoimmune thyroid diseases (AITD). Serum levels of MBL and parameters of the thyroid function were determined in 62 patients with Hashimoto's thyroiditis, 33 with Graves' disease and 47 blood donors. Follow-up measurements were performed after 6 to 24 months. MBL2 genotypes were determined using multiplex PCR and compared to 359 healthy Czech individuals. Serum levels of MBL tightly correlated with thyroid hormones, leading to strongly increased MBL levels in hyperthyroidism and decreased levels in hypothyroidism. With normalization of the thyroid function during follow-up, MBL levels decreased or increased respectively. The observed correlations were not due to MBL polymorphisms since the frequency of MBL2 polymorphisms in AITD patients was not different from the general population. We conclude that AITD are not associated with MBL polymorphisms. However, the MBL production is strongly dependent on thyroid function, regardless of the genotype.     

Inclusion of ALKBH5 as a candidate gene for the susceptibility of autoimmune thyroid disease

PurposeRNA demethylase AlkB homolog 5 (ALKBH5) gene is pivotal in N6-methyladenosine (m6A) modification. Therefore, this study aimed to explore the potential relationship between polymorphisms of ALKBH5 gene and the development of autoimmune thyroid disease (AITD).Material and methodsA case-control study of 979 AITD patients, including 620 Graves' disease (GD) and 359 Hashimoto's thyroiditis (HT), and 732 normal controls of the Chinese Han population was performed using high-throughput sequencing (HiSeq) genotyping method for detecting 5 variants in ALKBH5 gene (rs12936694, rs2124370, rs4925144, rs8068517, and rs9913266). In addition, the associations between ALKBH5 single nucleotide polymorphisms (SNPs) and clinical phenotypes of AITD were investigated.ResultsCompared to normal controls, rs9913266 displayed significant differences in allele and genotype distributions in AITD and GD. rs12936694 also showed significantly different frequencies of alleles in AITD and GD. The link of these 2 loci polymorprhisms to AITD and GD also existed after adjusting for age and gender. When stratified by sex, the minor allele of rs9913266 was associated with the risk of female AITD and HT development before and after adjusting for age and gender. There was a significant association between rs8068517 locus and GD in females after adjusting for the confounders. Finally, we observed significant correlations of haplotypes CGACA and CAGCG to the susceptibility of AITD and GD.ConclusionsOur results provided evidence of association of polymorphisms in ALKBH5 gene with AITD, GD, and HT patients, and hence ALKBH5 might be the candidate gene for susceptibility to AITD.     

Vitamin D and autoimmune thyroid diseases

The role of vitamin D as an immune modulator has been emphasized in recent years, and low levels of the hormone were observed in several autoimmune diseases including multiple sclerosis and systemic lupus erythematosus. Vitamin D mediates its effect though binding to vitamin D receptor (VDR), and activation of VDR-responsive genes. While VDR gene polymorphism was found to associate with autoimmune thyroid diseases (AITDs), few studies examined levels of vitamin D in these patients and those that did yielded conflicting results. We therefore undertook to evaluate the levels of vitamin D in patients with AITDs compared to patients with non-AITDs and healthy controls. Serum vitamin D (25-OH) levels were measured in 50 patients with AITDs, 42 patients with non-AITDs and 98 healthy subjects, utilizing the LIAISON chemiluminescence immunoassay (DiaSorin, Saluggia, Italy). Vitamin D deficiency was designated at levels lower than 10 ng/ml. Antithyroid antibodies, thyroid functions and demographic parameters were evaluated in all patients. The prevalence of vitamin D deficiency was significantly higher in patients with AITDs compared with healthy individuals (72% versus 30.6% P<0.001), as well as in patients with Hashimoto''s thyroiditis compared to patients with non-AITDs (79% versus 52% P<0.05). Vitamin D deficiency also correlated to the presence of antithyroid antibodies (P=0.01) and abnormal thyroid function tests (P=0.059). Significantly low levels of vitamin D were documented in patients with AITDs that were related to the presence of anti thyroid antibodies and abnormal thyroid function tests, suggesting the involvement of vitamin D in the pathogenesis of AITDs and the advisability of supplementation.     

Avidity of thyroglobulin antibody in sera from patients with Hashimoto's thyroiditis with different thyroid functional status

The mechanism of disease progression in Hashimoto's thyroiditis (HT) is still unclear. Thyroglobulin antibody (TgAb) is a diagnostic hallmark of HT. The aim of our study was to evaluate the avidity of TgAb in sera from HT patients with different thyroid functional status. Sera from 50 patients with newly diagnosed HT were collected and divided into three groups according to thyroid function: patients with hypothyroidism (H, n = 18), subclinical hypothyroidism (sH, n = 18) and euthyroidism (Eu, n = 14). Titres and avidity of TgAb were determined by enzyme‐linked immunosorbent assays (ELISAs). Avidity constant (aK) was determined as the reciprocal value of the thyroglobulin molar concentration in the liquid phase resulting in 50% inhibition of TgAb binding to thyroglobulin in solid‐phase ELISAs. The titres and aK of TgAb were performed using log‐transformation, and expressed as lgT and lgaK, respectively. Mean lgT of TgAb in sera was 4·19 ± 0·60 in H, 3·77 ± 0·63 in sH, and 3·29 ± 0·64 in Eu, respectively. The median avidity of TgAb was 2·30 × 10⁹ in H, 8·80 × 10⁸ in sH, 2·00 × 10⁷ in Eu, respectively. lgT and lgaK of TgAb were at significantly lower levels in Eu than in sH and H (P < 0·05). Correlation was found between lgT and lgaK (r = 0·594, P < 0·05). lgaK was also related to TSH (r=0·308, P < 0·05). Our study indicated that patients with high‐avidity TgAb might be at high risk of developing subclinical, even to overt, hypothyroidism.     

Fine-needle aspiration of subacute granulomatous thyroiditis (De Quervain's thyroiditis): A clinico-cytologic review of 36 cases

Although subacute granulomatous thyroiditis (SGT) is usually diagnosed clinically, there are other thyroid conditions that must be ruled out. This task is achieved by means of fine-needle aspiration (FNA). In retrospect, the clinical and cytologic findings seen in 36 SGT cases are reassessed with a view to deciding which findings are most reliable for reaching a confident cytologic diagnosis. These are: the simultaneous presence in the same aspirate of the following cells: 1) follicular cells with intravacuolar granules and/or plump transformed follicular cells; 2) epithelioid granulomas; 3) multinucleated giant cells; 4) an acute and chronic inflammatory dirty background; 5) the absence of the following cells: fire-flare cells, hypertrophic follicular cells, oncocytic cells, and transformed lymphocytes. The absence of one or more of these requirements does not exclude SGT but does increase the number of thyroid conditions that come into the differential diagnosis. In these cases, it is essential to review clinical data carefully and to submit the patient to a close clinical and FNA follow-up. Diagn. Cytopathol. 16:214–220, 1997. © 1997 Wiley-Liss, Inc.