Thyroid®

The cytotoxic T-lymphocyte-associated-4 (CTLA-4) molecule plays an important role in immune regulation by downregulating activation of T cells by antigen-presenting cells. Polymorphisms of the CTLA-4 gene have been shown to be associated with susceptibility to a number of autoimmune diseases. Some, but not all, studies suggest association between the CTLA-4 gene and autoimmune hypothyroidism. The aim of this study was to determine whether allelic association was present between the A-G single nucleotide polymorphism (SNP) at position 49 in exon 1 of the CTLA-4 gene and autoimmune hypothyroidism. The study was performed in 158 patients with autoimmune hypothyroidism and 384 control subjects. All subjects were white Caucasians from the United Kingdom. Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using the restriction enzyme Bbv1. There was a significant excess of the G allele in patients with autoimmune hypothyroidism compared with controls (43% vs. 32% respectively; χ ² = 10.7, p = 0.001; odds ratio 1.57). The GG and the AG genotypes were found to be more frequent in patients with autoimmune hypothyroidism than controls (17% vs. 8.8% and 50% vs. 46% respectively; χ ² = 11.7, p = 0.003). These results suggest that the CTLA-4 gene region on chromosome 2q33 is a susceptibility locus for autoimmune hypothyroidism in the United Kingdom.

Undifferentiated thyroid carcinoma (UTC) lacks an effective treatment. Boron neutron capture therapy (BNCT) is based on the selective uptake of ¹⁰B-boronated compounds by some tumors, followed by irradiation with an appropriate neutron beam. The radioactive boron originated (¹¹B) decays releasing ⁷Li, gamma rays and alpha particles, and these latter will destroy the tumor. In order to explore the possibility of applying BNCT to UTC we have studied the biodistribution of BPA. In in vitro studies, the uptake of p-¹⁰borophenylalanine (BPA) by the UTC cell line ARO, primary cultures of normal bovine thyroid cells (BT), and human follicular adenoma (FA) thyroid was studied. No difference in BPA uptake was observed between proliferating and quiescent ARO cells. The uptake by quiescent ARO, BT, and FA showed that the ARO/BT and ARO/FA ratios were 4 and 5, respectively (p < 0.001). In in vivo studies, ARO cells were transplanted into the scapular region of NIH nude mice, and after 2 weeks BPA (350 or 600 mg/kg body weight) was injected intraperitoneally. The animals were sacrificed between 30 and 150 minutes after the injection. With 350 mg, tumor uptake was highest after 60 minutes and the tumor/normal thyroid and tumor/blood ratios were 3 and 5, respectively. When 600 mg/kg body weight BPA were administered, after 90 minutes the tumor/blood, tumor/normal thyroid, and tumor/distal skin ratios for ¹⁰B concentrations per gram of tissue were approximately 3, showing a selective uptake by the tumor. The present experimental results open the possibility of applying BNCT for the treatment of UTC.

The effects of neonatal hypothyroidism on the number of Leydig cells were studied in neonatal Wistar rats. Moderate or severe hypothyroidism were induced during neonatal life by giving different amounts of methimazole (MMI; 0.05% or 0.1%) in the drinking water of pregnant and lactating dams. Rats were sacrificed on day 21 of postnatal life. Severely hypothyroid rats had approximately 45-fold higher serum thyrotropin (TSH) values and demonstrated approximately a 65% decrease in testes weight (p < 0.05) and the number of Leydig cells. However, in moderately hypothyroid rats, in which serum TSH was only approximately 16-fold higher, testicular weight was normal and the number of Leydig cells almost doubled (p < 0.01). There were no significant differences between the serum-free testosterone levels of the moderately and severely hypothyroid rats versus controls. Serum levels of 3α-androstanediol glucuronide, although decreased to less than 10% in severely hypothyroid rats (p< 0.01), were not changed by mild hypothyroidism. The number of Sertoli cells was increased in moderately hypothyroid rats versus controls (p < 0.05) and even further increased in severely hypothyroid rats (p < 0.05). We conclude that (1) severe neonatal hypothyroidism impairs the development and function of the testes and (2) moderate neonatal hypothyroidism stimulates the proliferation of Leydig cells.

Radioactive iodine (¹³¹I) is routinely used for the treatment of differentiated thyroid cancers. Attempts have been made to enlarge this therapeutic strategy to nonthyroid tumors by coupling radioactive iodide administration with transfer of the sodium iodide symporter (NIS) gene into target cells, for example with an adenoviral vector (AdNIS). Although efficient iodide uptake was achieved in the tumors treated with AdNIS, no therapeutic effect could be observed with ¹³¹I, most probably because the iodide retention time in the target cells was short. To circumvent this problem, we propose to organify the iodide taken up, as it occurs in the thyroid. We constructed a recombinant adenovirus encoding the human thyroperoxidase (TPO) gene under the control of the cytomegalovirus early promoter (AdTPO). Infection of nonthyroid tumor cells with this virus led to production of an enzymatically active protein. A significant increase in iodide organification could be observed in cells coinfected with both AdNIS and AdTPO in the presence of exogenous hydrogen peroxide. However, the levels of iodide organification obtained were too low to significantly increase the iodide retention time in the target cells.

Apoptosis is an active biologic process that represents a form of programmed cellular suicide, activated either by genetic factors or by cellular lesions caused by various extracellular traumatic agents. The alterations of its functional mechanisms control cellular homeostasis are involved in the genesis of many illnesses. There are different control systems that can both stimulate and inhibit apoptosis, such as the p53 and Bcl-2 proteins. Different injuries may cause a rapid increase in the levels of p53 and the activation of the complex mechanism which leads either to damage repair or cellular apoptosis. The concept of tumor growth as a dynamic balance between cellular development and death is well applicable to differentiated thyroid carcinomas, which are generally not highly invasive and present excellent prognosis. On the contrary, in aggressive anaplastic thyroid carcinoma there is an increase in p53, whereas in normal thyroid cells there is a high expression of Bcl-2, so as to interfere with apoptosis when physiologic hormone levels are normal. However, only some of the biomolecular mechanisms behind the genesis of thyroid tumors have been explained, and the role of apoptosis in thyroid diseases has not been well defined. This review provides information about relationship between apoptosis and thyroid diseases.

Sensitive monitoring for thyroid cancer recurrence or persistence includes whole-body radioiodine scanning (WBS) and measurement of serum thyroglobulin (Tg) after endogenous or exogenous thyrotropin (TSH) stimulation. We reviewed our experience using recombinant human thyrotropin (rhTSH) in 83 patients to compare the clinical relevance of a positive WBS and/or Tg. Ten patients had a positive WBS; eight of these patients had activity limited to the thyroid bed. rhTSH-stimulated Tg was 2 ng/mL or more in 25 and 5 ng/mL or more in 13 patients. Of the patients with a negative WBS, 11 of 20 patients with a Tg 2 ng/mL or more and 7 of 9 patients with a Tg 5 ng/mL or more received therapy or further evaluation based on the Tg alone. Conversely, only 1 of 5 patients with a serum Tg less than 2 ng/mL received therapy or further evaluation based on a positive WBS alone. Three of the patients who did not receive therapy or further evaluation, had subsequent negative WBS 10–12 months later, suggesting lack of clinically significant disease. Twenty patients had a negative WBS and serum Tg 2 ng/mL or more. Eleven of 20 patients had a Tg less than 5 ng/mL and 4 of these patients had further evaluation with a neck ultrasound. One patient had a biopsy-proven recurrence (rhTSH-stimulated Tg 4 ng/mL). Subsequent evaluations (≥ 6 months later) have been negative for 8 patients. Of the nine patients with a Tg 5 ng/mL or more and a negative WBS, 7 had further evaluation and 6 of 7 had identified disease. In summary, rhTSH-stimulated WBS and Tg are complementary, but Tg is a more sensitive indicator of disease recurrence or persistence. In our practice, an rhTSH-stimulated Tg greater than 4–5 ng/mL often resulted in further evaluation, while a Tg less than 4 ng/mL rarely resulted in further immediate evaluation.

To evaluate the effect of different initial levothyroxine (LT₄) replacement doses on growth and intellectual outcome in patients with congenital hypothyroidism (CH) detected by neonatal screening program, the longitudinal growth and intelligence quotient (IQ) were assessed and compared at 4 years of age in 83 patients with CH. The patients were divided into three groups according to the initial LT₄ dose used: (1) group 1 (n = 42) received the previously recommended dose of 6.0-8.0 μg/kg per day; (2) group 2 (n = 21) received a dose of 8.1-10.0 μg/kg per day; (3) Group 3 (n = 20) a dose of 10.1-15.0 μg/kg per day. The IQ, evaluated by the Wechsler Preschool and Primary Scale of Intelligence test at 4 years of age, was significantly higher in group 3 (IQ 98 ± 9) compared to group 1 (IQ 88 ± 13; p < 0.05) but not compared to group 2 (IQ 94 ± 13). However, the IQs were below the normal range (< 85) in six patients from group 2 (28%), but in none of the patients from group 3 (p = 0.03). Patients from group 3, with severe CH at diagnosis, had an IQ (97 ± 9) at 4 years of age, which was not different from that of patients from the same group with moderate CH at diagnosis (IQ 99 ± 9). Similar results were also observed in patients from group 2 however, mean IQ scores in these patients(93 ± 12) were several points lower than those observed in patients from group 3 (95 ± 15). After the first month of treatment, optimal serum levels of thyroxine (T4) and free thyroxine (FT₄) were achieved in all groups, however, only patients from group 3 were able to normalize thyrotropin (TSH) (group 1, 16.0 ± 12.0; group 2, 9.2 ± 10.0; and group 3, 2.4 ± 3.3 mU/L; p< 0.0001). Twelve patients from group 2 treated with an initial LT₄ dose above 9 μg/kg per day were able to normalize TSH levels within the first 3 months of life and this resulted in a better IQ (97 ± 16) compared to the remaining patients from the same group (IQ 90 ± 9). In the whole group of 83 patients the IQ at 4 years of age was positively correlated to both initial LT₄ dosage (r = 0.27, p < 0.02) and FT₄ concentrations after the first month of treatment (r = 0.29, p < 0.02), and negatively correlated to TSH concentrations after the first month of treatment (r = -0.27, p < 0.02). No significant differences were observed in height, weight, head circumference, and bone age maturation among the three groups of patients. No clinical signs or symptoms of overtreatment were observed during follow-up in patients receiving the higher LT₄ dosage. Our results indicate that high LT₄ starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age, even in patients with severe CH at diagnosis. Growth and bone age maturation are not affected by such a high dose.

The surgical approach to primary hyperparathyroidism (HPT) is changing. In patients with a high probability to be affected by a solitary parathyroid adenoma (PA), a unilateral neck exploration (UNE) or a minimally invasive radio-guided surgery (MIRS) using the intraoperative gamma probe (IGP) technique have recently been proposed. We investigated the role of IGP in a group of 84 patients with primary HPT who were homogeneously evaluated before surgery by a single-day imaging protocol including ^99mTcO₄/MIBI subtraction scan and neck ultrasound (US) and then operated on by the same surgical team. Quick parathyroid hormone (QPTH) was intraoperatively measured in all cases to confirm successful parathyroidectomy. In 70 patients with scan/US evidence of a single enlarged parathyroid gland (EPG) and with a normal thyroid gland, MIRS was planned. In the other 14 patients, the IGP technique was utilized during a standard bilateral neck exploration (BNE) because of the presence of concomitant nodular goiter (11 cases) or multiglandular disease (MGD) (3 cases). The IGP technique consisted of the following: (1) in the operating room, a low ^99mTc-MIBI dose (37 MBq) was injected intravenously during anesthesia induction; (2) subsequently, the patient's neck was scanned with the probe by the surgeon to localize the cutaneous projection of the EPG; (3) in patients who underwent MIRS, the EPG was detected intraoperatively with the probe and removed through a small, 2 to 2.5 cm skin incision; (4) radioactivity was measured on the EPG both in vivo and ex vivo, the thyroid, the background and the parathyroid bed after EPG removal. In patients with concomitant nodular goiter, the radioactivity was also measured on the thyroid nodules. Surgical and pathologic findings were consistent with a single PA in 78 patients, parathyroid carcinoma in 2, and MGD in 4. MIRS was successfully performed in 67 of the 70 patients (97.7%) in whom this approach was planned. It must be pointed out that the IGP technique was particularly useful in detecting the PAs located in ectopic site (5 in the upper mediastinum, 2 at the carotid bifurcation) and deep in the neck (6 in the paratracheal/paraesophageal space). Moreover, MIRS was also successfully performed in the seven patients who had undergone previous parathyroid or thyroid surgery. In the other 3 of 70 patients (4.3%), a conversion to BNE was required because a parathyroid carcinoma (2 cases) and a MGD (1 case) were diagnosed during surgical intervention. It is worth noting that in this latter patient affected by MGD, in contrast with the other patients from our series, QPTH remained elevated after the removal of the preoperatively visualized EPG suggesting the persistence of occult hyperfunctioning parathyroid tissue, and another contralateral EPG was found at BNE. Regarding the group of patients in whom a BNE was planned, the IGP helped the surgeon to localize a supernumerary EPG ectopic in the thymus in a patient with MGD, and to localize a PA ectopic to the right carotid bifurcation in a patient with nodular goiter. However, it has to be pointed out that it was difficult for the surgeon to differentiate intraoperatively with the probe the radioactivity of the EPG from that of thyroid nodule(s) in the other 10 patients with HPT with a concomitant nodular goiter, particularly in 6 patients in whom ^99mTc-MIBI uptake was higher in thyroid nodule(s) than in EPG. On the basis of these data we can conclude that: (1) in patients with primary HPT with a high scan/US probability to be affected by a single PA and with a normal thyroid gland, IGP appears to be an useful technique with the aim of performing MIRS; (2) a ^99mTc-MIBI dose as low as 37 MBq appears to be adequate to successfully perform MIRS; (3) the measurement of QPTH is strongly recommended in patients with HPT selected for MIRS to confirm complete removal of hyperfunctioning parathyroid tissue; (4) MIRS can be useful also in patients with HPT who previously received parathyroid/thyroid surgery with the aim of limiting surgical trauma at reoperation and minimizing the related risk of complications; (5) with the exception of PA located in ectopic sites, IGP does not seem to be a recommendable technique in patients with HPT concomitant nodular goiter.

We studied the evolution of 150 pregnancies corresponding to 114 women (16-39 years old) with primary hypothyroidism. Fifty-one pregnancies (34%) were conceived under hypothyroidism: 16 overt (X ± standard deviation [SD], thyroxine [T₄]: 2.44 ± 0.7 μg/dL; thyrotropin [TSH]: 33.4 ± 8.82 mIU/L), and 35 subclinical hypothyroidism (T₄: 6.93 ± 1.88μg/dL; TSH: 12.87 ± 8.43 mIU/L); 99 pregnancies were conceived under euthyroidism while undergoing thyroid therapy. When treatment with levothyroxine was inadequate, the outcome of pregnancy was abortion in 60% of overtly hypothyroid patients and in 71.4% of subclinically hypothyroid patients, premature delivery in 20% and 7.2% respectively, and term delivery in 20% and 21.4%, respectively. When treatment was adequate, 100% of overtly hypothyroid patients and 90.5% of subclinically hypothyroid patients carried pregnancies to term; there were no abortions in any of the groups. Abortions, premature and term deliveries in patients who were euthyroid on levothyroxine at the time of conception were 4%, 11.1% and 84.9% respectively. Of the patients receiving levothyroxine therapy before conception, 69.5% had to increase the dose (mean increase 46.2 ± 29.6 μg/d). Of 126 evaluated newborns, 110 were delivered at term while 16 were premature. Eight newborns, 4 were premature, had congenital malformations (6.3%), and 4 died. Our results show that the evolution of pregnancies did not depend on whether the hypothyroidism was overt or subclinical but mainly on the treatment received. The adequate treatment of hypothyroidism during gestation minimizes risks and generally, makes it possible for pregnancies to be carried to term without complications.

To study the association between smoking and thyroid disease (Graves' disease [E05.0], nodular toxic goiter [E05.2], and autoimmune hypothyroidism [E03.9]) in a low-iodine intake area a case-control study was undertaken. A self-administered questionnaire was issued to 864 consecutive patients with hyperthyroidism and 628 patients with autoimmune hypothyroidism treated at five university or regional endocrinologic clinics in Denmark between January 1, 1990 and December 31, 1998. Each respondent was compared to an age- (± 5 years) and gender-matched normal control person randomly drawn from the background population. A total of 621 patients with hyperthyroidism (72%) and 411 patients with autoimmune hypothyroidism (66%) responded. Of these, 617 (542 females) and 408 (364 females) could be analyzed, respectively. There was an increased risk of both Graves' disease (odds ratio [OR] = 2.5, 95% confidence interval [CI]: 1.8–3.5), toxic nodular goiter (OR = 1.7, 95% CI: 1.1–2.5), and autoimmune hypothyroidism (OR = 1.5, 95% CI: 1.1–2.1) with ever smoking compared to never smoking in women, but not in men. With the high proportion of ever-smokers among women (56%), the attributable risk of smoking in women was 45% in Graves' disease, 28% in toxic nodular goiter, and 23% in autoimmune hypothyroidism. Ever use of oral contraceptives was associated with a slightly lower risk of Graves' disease in women, but not of toxic nodular goiter or autoimmune hypothyroidism. In conclusion, smoking is a powerful risk factor for thyroid disease, especially in populations with a high smoking frequency. Oral contraceptive use is associated with a slightly lower frequency of Graves' disease.

We describe a 23-year-old woman with a 3-week history of episodic leg weakness. The onset of weakness always occurred in the evening after dinner and the attacks resolved spontaneously by morning. Physical examination revealed a resting tachycardia and symmetrical, proximal weakness involving both arms and legs. Electrocardiogram (ECG) and electrolyte analysis showed a severe hypokalemia and thyroid function tests showed hyperthyroidism. The patient was diagnosed as having Graves' thyrotoxicosis and thyrotoxic periodic paralysis (TPP) and was initially treated with propranolol and subsequently carbimazole. No recurrence of the paralysis has been noted. TPP is most common in males of Asian extraction and is rare in women even in the Asian population. With increasing immigration, TPP is likely to occur more frequently in both Europe and North America and awareness of the condition is vital. Treatment of the underlying thyroid dysfunction cures the muscle symptoms.

Resistance to thyroid hormone (RTH) is a clinical syndrome characterized by elevated serum thyroid hormone (TH) levels, unsuppressed thyrotropin (TSH) levels, and tissue hyposensitivity to TH. In almost all cases, the genetic basis of RTH lies in mutation of one of the two TH receptor β (TRβ) alleles. Recently, patients from several families with phenotypic manifestations of RTH in the absence of TR mutations have been described. We report a case of a 31-year-old woman who presented with goiter, tachycardia, elevated TH levels, unsuppressed TSH, and "inappropriately normal" levels of peripheral TH action markers. In two separate clinical evaluations, the patient exhibited typical clinical and biochemical evidence for peripheral and pituitary RTH. Surprisingly, reverse transcriptase-polymerase chain reaction (RT-PCR) of full-length TRα and TRβ mRNAs, and genomic PCR using primers flanking exons encoding the carboxy-terminal region of TRβ failed to demonstrate mutations in the TRα or TRβ genes. It is likely that defects in the regulation of TR genes or mutations in transcriptional cofactors involved in TR signaling account for this patient's phenotype.