Thyroid®

The influence of thyroid hormones on the immune system is controversial. We analyzed the cytokine expression pattern of T lymphocytes in patients with severe nonimmune hypothyroidism in order to establish the role of thyroid hormones on the immune system. The study comprised 7 patients(1 male and 6 females) 20 to 76 years of age (mean age, 53 years), without signs of chronic thyroiditis, verified by histology and laboratory data. The patients were studied 5 weeks after total thyroidectomy. Peripheral blood mononuclear cell (PBMC) cultures and intracellular cytokine detection by flow cytometry before and after thyroid hormone replacement therapy were performed (free thyroxine [FT₄] 0.030 ± 0.034 ng/dL, versus FT₄: 2.16 ± 0.68 ng/dL). The control group consisted of 7 healthy subjects (FT₄: 1.20 ± 0.21 ng/dL). We found no significant differences in the cytokine pattern (interferon [IFN]-γ, IL-2, interleukin [IL]-4, IL-5, IL-6, IL-10, IL-13, tumor necrosis factor [TNF]-α, TNF-β) of CD4⁺ and CD8⁺ between the matched groups (hypothyroid subjects versus controls, levothyroxine treated subjects versus controls). Our data show no change in the type 1/type 2 balance of peripheral CD4⁺ and CD8⁺ T lymphocytes from patients with nonimmune hypothyroidism. According to our results, the hypothyreotic state does not contribute to the reported changes in cytokine production patterns in Hashimoto's thyroiditis.

In animal models the function of the sodium pump (sodium/potassium-adenosine triphosphatase [Na⁺/K⁺-ATPase]) is enhanced by 3,5,3′-triiodothyronine (T₃) and inhibited by the antiarrhythmic agent amio. However, it is still unclear whether the effect of the drug on Na⁺/K⁺-ATPase depends on the interference with thyroid hormone action. We evaluated the interaction of T₃ with amiodarone on Na⁺/K⁺-ATPase activity and site number in human myocardium. Right atrial slices were cultured with(T₃ ⁺) and without (T₃ ^-) 3 nM T₃ in presence and absence of amiodarone at therapeutical dose (1.5 μM). When compared to T₃ ⁺, T₃ ^- preparations showed decreased ³H-ouabain binding(p < 0.004) and lower 20-minute and 45-minute ⁸⁶Rb-uptake (p ≤ 0.004). Amiodarone caused an average 49% reduction of the T₃-dependent ³H-ouabain binding and decreased the Western blot signal for the Na⁺/K⁺-ATPase α ₁ subunit. The drug also inhibited T₃-dependent increase in ⁸⁶Rb-influx at 20 and 45 minutes by 66% and 42%, respectively, without affecting the affinity of the pump for K⁺. No differences were found in the ³H-ouabain binding and ⁸⁶Rb-uptake of T₃ ^-, T₃ ^- amio and T₃ ⁺-amio. In conclusion, T₃ stimulates the Na⁺/K⁺-ATPase in human atrial myocardium by increasing the number of ouabain-binding sites, whereas amiodarone decreases the sodium pump function secondarily to the antagonism with thyroid hormone.

Serial analysis of gene expression (SAGE) was applied to compare expression profiles of normal thyroid tissue and papillary thyroid carcinoma (PTC). A SAGE tag corresponding to the partial cDNA for the small protein 31 (SMAP31) is upregulated approximately 13-fold in papillary thyroid cancer (PTC) and was selected for further research. BLAST-searching the human genome database reveals that the SMAP31 gene is located on chromosome 4q11–12 and contains 6 exons. Alternative splicing results in seven transcripts encoding 2 possible open reading frames (ORF) of 73 and 95 amino acids. Database searching in GenBank's dbEST shows that SMAP31 transcripts are expressed mainly in brain, heart, gingiva, and lung tissue. Thyroid tissue contains three transcripts caused by alternatively splicing in the 5′ untranslated region (UTR), which all encode an identical ORF of 73 amino acids. Homology search shows that this protein contains a homeobox domain. Thyroid and/or thyroid carcinoma-specific expression of SMAP31 is studied using Northern blot and reverse transcriptase-polymerase chain reaction (RT-PCR) on a multiple tissue panel. RT-PCR experiments on a cDNA panel containing samples from different normal and tumor tissues shows expression of SMAP31 mRNA in brain, placenta, lung, heart, thyroid and thyroid carcinoma. SMAP31 expression is elevated in 4 of 6 PTC tumor samples compared to 4 normal thyroid controls.

The genetic basis for Graves' disease remains largely unknown, but significant linkage to microsatellite markers on 20q11 suggests that this region harbors a susceptibility gene. One obvious candidate gene at this 20q11 locus is CD40, which encodes a B-cell–surface receptor that is involved in T-cell to B-cell signaling and is implicated in control of T-cell autoreactivity. In addition, an allele of a single nucleotide polymorphism (SNP) in the Kozak consensus sequence of the 5′ untranslated region of CD40 exon 1 has been reported to show modest evidence for association with Graves' disease. We have investigated the role of this 5′ untranslated region (5′ UTR) in Graves' disease susceptibility in our cohort of 451 unrelated white subjects with Graves' disease and 446 healthy controls. The CD40 5′UTR SNP (C → T, position−1) was polymerase chain reaction (PCR)amplified and genotyped using the restriction enzyme NcoI. The frequency of the C allele was 74.8% in Graves' probands compared to 75.1% in controls (not significant [NS]). We find no evidence to support allelic association with Graves' disease at this CD40 SNP, despite the adequate power of the study. We are unable to confirm a role for CD40 in Graves' disease pathogenesis in our U.K. population, however, further studies involving larger patient cohorts and a saturated SNP marker map are required to resolve this issue.

Autoantibodies to thyroglobulin (TgAb) and thyroid peroxidase (TPOAb) are of immunoglobulin G (IgG) class and have high affinities for their respective autoantigens. Both autoantibodies are markers of thyroid autoimmunity and they can be measured by a variety of assays. From the clinical perspective, TgAb are less prevalent than TPOAb and less useful than TPOAb for prediction of thyroid dysfunction. Moreover, TgAb interfere with Tg measurements to monitor metastases in thyroid cancer. However, increasing evidence suggests that these TgAb provide a surrogate for Tg. In terms of disease pathogenesis, Tg has been suggested to play a role in Graves' ophthalmopathy. Pending further studies, TgAb epitopes could distinguish between individuals who are euthyroid or who have clinical disease. A final, intriguing reason for measuring and characterizing TgAb is the interest these autoantibodies have rekindled in their autoantigen. It is conceivable that Tg polymorphisms, combined with the explosive mix of iodine, TPO and H₂O₂ necessary for thyroid hormone synthesis, inadvertently provide the trigger for the autoimmune thyroid response.

Little is known about the reaction of normal thyroid glands to the iodine load given by x-ray dyes. We have therefore investigated the short-term effects of high doses of iodine on thyroid parameters in euthyroid patients. We measured free triiodothyronine (FT₃), free thyroxine (FT₄), and thyrotropin (TSH) serum concentrations before and daily for 1 week after parenteral application of x-ray dyes (coronary angiography: n = 16; computed tomography [CT] of either thorax or abdomen: n = 6; iodine dose range from 300–1221 mg of iodine per kilogram). Inclusion criteria were as follows: normal FT₄, normal TSH, negative thyroid antibodies, urinary iodine excretion below 30 μg/dL, no palpable goiter and no euthyroid sick syndrome. All but one patient reacted with a TSH increase. Mean TSH values increased significantly 3–5 days after the iodine load within the normal range. Four patients (18%) had a TSH increase above normal, the maximal observed value being 6.4 μU/mL. Basal TSH values of these four patients were above 2 μU/mL. The day peak TSH concentrations were reached varied from day 1 to day 7, the majority (32%) having the peak on day 3. Peak TSH was significantly correlated with basal TSH values (r = 0.794, p < 0.0001). FT₄ and FT₃ remained unchanged and there was no significant correlation between the dose of iodine and the TSH reaction. In conclusion, iodine-containing contrast media can induce transiently subclinical hypothyroidism even in euthyroid patients. The TSH reaction seems to depend on the preexisting state of thyroid function.

In order to assess the effect of propylthiouracil (PTU) or methimazole (MMI) pretreatment on patient outcome after radioiodine therapy, we examined 100 patients with Graves' disease 3, 6, 9, and 12 months after administration of a 10-mCi standard single dose of ¹³¹I. They were assigned to one of three groups: no drug (ND) treatment (30 cases); MMI (45 cases); and PTU (25 cases). Antithyroid drugs (ATD) were withdrawn 15 days before radioiodine administration. The groups were similar concerning age, gender, ATD pretreatment duration, goiter size, and initial serum triiodothyronine (T₃), thyroxine (T4), free thyroxine (FT₄), antithyroid autoantibody levels, 24-hour radioiodine uptake and ¹³¹I dose administered per gram of thyroid tissue. ND and MMI groups presented a similar rate of cure of 73.3% and 77.8% respectively(p = NS). In contrast, the PTU group showed a rate of cure of only 32% (p < 0.05). Logistic regression analysis indicated that PTU administration (p = 0.003) and thyroid size (p = 0.02) were the variables related to radioiodine therapy failure. Our data demonstrate that the chance of ¹³¹I treatment failure is higher in individuals using PTU than in patients using MMI or not using any ATD before radioiodine (odds ratio [OR] 5.84; 95% confidence interval [CI] 1.82–18.76) suggesting that PTU should be avoided in the treatment of patients with Graves' disease.

The necessity of iodine restriction before radioiodine uptake (RAIU) testing for differentiation of thyrotoxicosis is controversial. The present study was undertaken to investigate the effects of iodine restriction on the RAIU value, and the necessity of iodine restriction in differentiating between Graves' disease (GD) and silent thyroiditis (ST). We investigated 415 patients, 277 of whom were patients with GD who had undergone iodine restriction before RAIU [GD(+)], 66 were patients with GD who did not undergo iodine restriction [GD(-)], 61 were patients with ST who had undergone iodine restriction [ST(+)], and the remaining 11 were patients with ST who did not undergo iodine restriction [ST(-)]. The RAIU value of the GD(+) group, 47.6% ±14.4% (mean ±standard deviation [SD]), was significantly higher than that of the GD(-) group, 42.4% ± 17.6%(p = 0.03). However, the areas under the curves from the receiver operator characteristics analyses for the comparison between groups GD(+)/ST(+), GD(+)/ST(-), GD(-)/ST(+) and GD(-)/ST(-) were 0.99967, 0.99967, 0.98436, and 0.98485, and very high, respectively. High diagnostic value of the RAIU test was confirmed, but not affected by the presence of iodine restriction in the differentiation between GD and ST, therefore, iodine restriction before the RAIU test was unnecessary.

The use of thyroid ultrasonography for determination of thyroid volume requires reliable reference criteria. The current World Health Organization/International Council for the Control of Iodine Deficiency Disorders (WHO/ICCIDD) reference has been questioned since iodine-sufficient children have been found throughout the world with distinctly smaller thyroid volumes. A difference in part explained by a systematic bias when generating the WHO/ICCIDD reference data. The objective with this study was to evaluate normative thyroid volumes in our region and, if possible, develop a multivariate model for their interpretation. Thyroid ultrasonography was performed and anthropometrical measurements were taken in 561 children and adolescents. The best predictor for thyroid volume in both girls and boys was body surface area (BSA), followed by age, weight, and height. References for normative thyroid volumes were calculated for each of the predictors. When these references were compared with other references throughout the world, the age-specific references were in good accord, but distinct differences were found between our BSA-specific references and other references based on a majority of children younger than ours. Using multivariate analyses, BSA and age were found to significantly influence thyroid volume, independently of each other. Multiple regression models by gender using BSA and age as predictors for thyroid volume were constructed. Using these models the difference between the BSA-specific references could be markedly reduced. To interpret thyroid volume accurately we propose the use of a multivariate model using age and BSA as predictors of thyroid volume.

Subacute thyroiditis (SAT) is a spontaneously remitting inflammatory disorder of the thyroid, associated with human leukocyte antigen (HLA)-B35, and may be virally induced in genetically predisposed individuals. A 57-year-old Caucasian man presented with symptoms of hyperthyroidism as well as enlargement and tenderness of the thyroid. The patient had an elevated erythrocyte sedimentation rate, low thyrotropin (TSH) and elevated thyroxine and triiodothyroinine levels with suppressed ¹³¹I thyroidal uptake. He was diagnosed to have SAT. In the patient's family three sisters and one brother also had had SAT, as probably did the deceased father. Because of the familial occurrence HLA-typing was performed. All affected family members were heterozygous for HLA-B35. The family members lived more than 50 miles apart in different regions of The Netherlands and had SAT at different time points between 1986 and 2002, which in combination with HLA-B35 seems to highlight the importance of genetic influences as a risk factor for the development of SAT in this family. In conclusion, the case described here represents the second familial incidence and largest family reported so far with occurrence of SAT in association with HLA-B35.

A 59-year-old African American male with a remote history of Graves' disease presented with a 13-cm sacrococcygeal mass that was resected. Pathologic examination revealed this to be papillary thyroid carcinoma with large areas of hemorrhage and necrosis. No other teratomatous elements were identified. The patient underwent extensive evaluation of the thyroid gland with ultrasound, computed tomography (CT) scan, and laboratory studies without any evidence of thyroid mass or malignancy. In addition, further evaluations with chest/abdominal/pelvic CT as well as a bone scan failed to reveal any evidence of metastatic disease. At 1-year follow-up, the patient has remained euthyroid and without evidence of recurrence. We believe that our patient may represent the first reported case of malignant transformation of mature thyroid tissue in a sacrococcygeal teratoma. The impact of his diagnosis on the decision-making for performing a total thyroidectomy is discussed.