Pituitary tumours: TSH-secreting adenomas.

Thyrotropin-secreting pituitary adenomas (TSHomas) are a rare cause of hyperthyroidism and account for less than 2% of all pituitary adenomas. In the last years, the diagnosis has been facilitated by the routine use of ultra-sensitive TSH immunometric assays. Failure to recognise the presence of a TSHoma may result in dramatic consequences, such as improper thyroid ablation that may cause the pituitary tumour volume to further expand. The diagnosis mainly rests on dynamic testing, such as T3 suppression tests and TRH, which are useful in differentiating TSHomas from the syndromes of thyroid hormone resistance. The first therapeutical approach to TSHomas is the pituitary neurosurgery. The medical treatment of TSHomas mainly rests on the administration of somatostatin analogues, such as octreotide and lanreotide, which are effective in reducing TSH secretion in more than 90% of patients with consequent normalisation of FT4 and FT3 levels and restoration of the euthyroid state.

Impact of resistance to thyroid hormone on the cardiovascular system in adults.

BACKGROUND: The clinical manifestations of resistance to thyroid hormone (RTH) are highly variable, and the impact of RTH on the cardiovascular system has been poorly investigated. AIM: The objective of the study was to evaluate the cardiovascular characteristics of 16 untreated and asymptomatic patients with RTH compared with 16 euthyroid healthy controls to define the cardiovascular involvement in RTH syndrome. PATIENTS AND METHODS: Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 +/- 12 yr, range 21-45 yr) and 16 controls (nine males; aged 33 +/- 5 yr, range 24-42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded. RESULTS: Heart rate was comparable with that of controls, whereas arterial pressure was higher than controls. Mean interventricular septum diastolic thickness and mean left ventricular (LV) posterior wall diastolic thickness were significantly lower in RTH patients than controls with a consequent significant decrease of the mean LV mass and LV mass indexed by body surface area. Patients also had abnormalities of myocardial relaxation as indicated by a significant increase of peak A and consequent reduction of the early to late ratio. Finally, systemic vascular resistance was significantly higher in RTH patients than controls. CONCLUSIONS: Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patients.

A novel tyrosine-kinase selective inhibitor, sunitinib, induces transient hypothyroidism by blocking iodine uptake.

CONTEXT: Sunitinib (sunitinib malate; SU11248; Sutent; Pfizer Inc., New York, NY) is a multitarget inhibitor of tyrosine kinases for the treatment of some human cancers. A myxedematous coma in a patient treated with sunitinib for a gastrointestinal stromal tumor was unexpectedly observed. OBJECTIVE: Our objective was to evaluate the effect of sunitinib on thyroid function in 24 patients with gastrointestinal stromal tumors. DESIGN: This was a prospective, observational cohort study. SETTING: The study was performed at two tertiary care hospitals. PATIENTS: A total of 24 patients receiving the following cycles of therapy were included in the study: 4-wk daily treatment at the dose of 50 mg orally (ON) and 2-wk withdrawal (OFF). INTERVENTIONS: Thyroid function tests, ultrasonography, and iodine-123 ((123)I) thyroidal uptake were performed at the end of several ON and OFF periods. RESULTS: After one to six cycles of treatment, 46% of patients developed hypothyroidism. Initially, TSH levels were elevated at the end of ON periods and normalized at the end of OFF periods, but a worsening in following cycles was always observed. Neither echographic alterations nor variations in thyroglobulin and antithyroid autoantibodies were found during the ON and OFF periods. On the contrary, (123)I uptake was significantly reduced at the end of ON periods, with partial or total normalization at the end of OFF periods. CONCLUSIONS: A high prevalence of hypothyroidism, very severe in some cases, was observed during sunitinib. Significant variations in (123)I uptake strongly suggest that the underlying mechanism is an impaired iodine uptake. The absence of thyroid autoimmunity, the lack of a preceding transient hyperthyroidism, and the normal echographic pattern exclude autoimmune and/or destructive mechanisms. Patients on sunitinib should be strictly monitored for the appearance of hypothyroidism and promptly treated.

Thyroid scintigraphy and perchlorate test after recombinant human TSH: a new tool for the differential diagnosis of congenital hypothyroidism during infancy.

PURPOSE: Prompt initiation of L-thyroxine therapy in neonates with congenital hypothyroidism (CH) often prevents the performance of functional studies. Aetiological diagnosis is thus postponed until after infancy, when the required investigations are performed after L-thyroxine withdrawal. The aim of this study was to verify the efficacy and safety of new protocols for rhTSH (Thyrogen) testing during L-thyroxine replacement in the differential diagnosis of CH. METHODS: Ten CH patients (15-144 months old) were studied. Seven had neonatal evidence of gland in situ at the ultrasound examination performed at enrolment and received two rhTSH injections (4 microg/kg daily, i.m.) with 123I scintigraphy and perchlorate test on day 3. Three patients with an ultrasound diagnosis of thyroid dysgenesis received three rhTSH injections with 123I scintigraphy on days 3 and 4. TSH and thyroglobulin (Tg) determinations were performed on days 1, 3 and 4, and neck ultrasound on day 1. RESULTS: rhTSH stimulation caused Tg levels to increase in eight cases. Blunted Tg responses were seen in two patients with ectopia and hypoplasia. Interestingly, in two cases the association of different developmental defects was demonstrated. Perchlorate test revealed a total iodide organification defect in two patients, including one with a neonatal diagnosis of Pendred's syndrome, who were subsequently found to harbour TPO mutations. rhTSH did not cause notable side-effects. CONCLUSION: These new rhTSH protocols always resulted in accurate disease characterisation, allowing specific management and targeted genetic analyses. Thus, rhTSH represents a valid and safe alternative to L: -thyroxine withdrawal in the differential diagnosis of CH in paediatric patients.

Syndromes of hormone resistance in the hypothalamic-pituitary-thyroid axis.

Forty years have elapsed since the first description of a syndrome of resistance in the hypothalamic-pituitary-thyroid axis, i.e., resistance to thyroid hormone action. In the last two decades many other types of resistance have been discovered, including resistance to the action of thyrotropin-releasing hormone (TRH), of thyroid-stimulating hormone (TSH), and of thyroid hormones (THs); the latter can be due not only to thyroid hormone receptor defects but also to alteration in genes encoding TH-specific transporters or components involved in metabolic pathways of THs. Moreover, alteration in genes encoding for second messengers may cause forms of resistance other than those due to receptor mutations, the most important one being that of an inactivating mutation in the G-protein alpha-subunit leading to TSH resistance in the setting of pseudohypoparathyroidism type 1a. Recognition of these rare thyroid disorders is of great importance not only for informed genetic counselling but also for avoiding diagnostic mistakes that may lead to incorrect and potentially dangerous treatments.

TBG deficiency: description of two novel mutations associated with complete TBG deficiency and review of the literature.

Thyroxine-binding globulin (TBG) is the main thyroid hormone transport protein in serum. Inherited TBG defects lead to a complete (TBG-CD) or a partial (TBG-PD) deficiency and have a diagenic transmission, being clinically fully expressed only in hemizygous males and in homozygous females. In the present study, seven patients from two unrelated families with TBG-CD were studied and two novel TBG mutations were documented. In particular, a T insertion at the 5' donor splice site of exon 0, between nucleotides 2 and 3 at the beginning of intron 1 (g.IVS1+2_3insT) was found in one family and was named TBG-Milano. The other novel mutation is a T deletion at nucleotide 214 of exon 1, which leads to a frameshift at codon 50 with a premature stop codon at position 51 (c.214delT, P50fsX51) and was named TBG-Nikita. According to the X-linked transmission of the defect, females harboring the mutation showed a reduction in TBG levels with normal TSH and total thyroid hormone values at the lower limit of normal. Males harboring either TBG-Milano or TBG-Nikita, showed normal TSH values and low levels of total thyroid hormones and lacked TBG. In conclusion, we report two novel mutations of the TBG gene associated with a complete TBG defect. The first mutation lies at the 5' donor splice site of exon 0 and probably alters the start of translation, while the second is a single nucleotide deletion and leads to a premature stop codon.

Total iodide organification defect: clinical and molecular characterization of an Italian family.

Thyroid peroxidase (TPO) deficiency is frequently involved in total iodide organification defects (TIOD). According to the recessive mode of inheritance, mutations are found in homozygous or in compound heterozygous states. However, a single heterozygous TPO mutation is reported in a high percentage (approximately 20%) of patients with typical TIOD phenotype. In the present study, the genetic and clinical evaluation of a TIOD family is reported. The propositus is an Italian girl with congenital hypothyroidism and positive perchlorate discharge test. Two TPO frameshift mutations were documented: a C deletion at 477 in exon 5, and a GGCC duplication at 1277 in exon 8. Unaffected family members, heterozygous for one of the two TPO mutations, were also studied in order to evaluate in vivo the functional activity of a single TPO allele. They have been found to have normal thyroid morphology and function with normal perchlorate test. In conclusion, the present study reports the clinical and molecular investigations in an Italian TIOD family. The results show that the TIOD phenotype in the propositus is associated to a compound heterozygous pattern, while a single TPO mutation does not significantly affect in vivo the efficiency of iodide organification. Therefore, extensive analyses of TPO gene and 2p25 locus are needed in the frequent TIOD cases in whom conventional investigations disclosed only one mutant allele.

Radioiodine treatment of non-toxic multinodular goitre: effects of combination with lithium.

PURPOSE: This study aimed to evaluate the effects of radioiodine ((131)I), alone or in combination with lithium, on thyroid volume and the prevention of radioiodine-induced thyrotoxicosis. This is the first clinical trial including only patients with multinodular goitre, normal TSH values and negative anti-thyroid auto-antibodies at baseline. METHODS: Eighty consecutive patients were randomised to receive (131)I plus lithium (group I+L) or (131)I alone (group I). Thyroid ultrasonography and biochemical analyses were performed at baseline and at 1, 3, 6, 12 and 24 months after treatment. RESULTS: At 1-4 weeks after treatment, (131)I-induced hyperthyroidism was observed in 58.8% of patients and was prevented by lithium administration. A low incidence of hypothyroidism (19%) was recorded at 24 months, whereas up to 44% of patients developed anti-thyroid antibodies. A significant reduction in thyroid volume was observed after (131)I, with a mean decrease of 47.2% (median 48.2%) at 24 months, without differences between the groups. Moreover, it was shown that the decrease in thyroid volume after (131)I was also due to the significant shrinkage of thyroid nodules. CONCLUSION: This demonstrates that adjunctive lithium is able to reduce radioiodine-induced hyperthyroidism. Therefore, such treatment appears to be safe in older patients and those with underlying cardiovascular disease. In the present large series, (131)I therapy was demonstrated to be highly effective in reducing thyroid and nodular volume even in patients treated with low (131)I doses (2.5 MBq/ml of thyroid tissue), further supporting the view that radioiodine therapy represents a real alternative to surgery.

Different responses to chronic somatostatin analogues in patients with central hyperthyroidism.

OBJECTIVE: Central hyperthyroidism is mainly due to two different causes, TSH-secreting pituitary adenoma (TSH-oma) and resistance to thyroid hormone in its pituitary variant, i.e. patients presenting with signs and symptoms of hyperthyroidism (PRTH). Because therapeutic approach and the clinical follow-up are extremely different in these two disorders, a correct differential diagnosis is mandatory. Unfortunately, no definite pathognomonic tool is presently available and an extensive biochemical and instrumental workup is frequently needed in order to reach the correct diagnosis. Aim of the present study was to investigate the use of somatostatin analogues in the differential diagnosis between TSH-omas and PRTH, as well as the possible treatment of PRTH with these analogues. DESIGN AND PATIENTS: Eight patients with TSH-oma and four with PRTH underwent the acute test with somatostatin analogue Octreotide (0.1 mg subcutaneously), as well as long-acting Octreotide-LAR (30 mg intramuscularly every 28 days) for two months. MEASUREMENTS: Serum TSH, FT3 and FT4 were evaluated in basal condition, at time 0 and every hour for 6 h during acute test, and every 15 days for 2 months during chronic treatment. RESULTS: During acute test, in both patients with PRTH and TSH-oma, a similar reduction in immunoreactive TSH and FT3 levels was observed, while no variations were found in FT4 concentrations. In contrast, during the administration of Octreotide-LAR, no significant variations of all tested parameters were observed in PRTH group, whereas FT3 and FT4 concentrations normalized or presented a significant reduction (> 30% of pretreatment values) in seven of eight patients with TSH-oma, despite minor variation of immunoreactive TSH levels. CONCLUSIONS: Chronic administration of long-acting somatostatin analogues in patients with central hyperthyroidism caused a marked decrease of FT3 and FT4 levels in all patients but one with TSH-oma, while patients with PRTH did not respond at all. Thus, administration of long acting somatostatin analogues for at least 2 months can be useful in the differential diagnosis in problematic cases of central hyperthyroidism. Furthermore, the present findings exclude the possibility of a beneficial effect of chronic administration of somatostatin analogues in controlling thyrotoxic symptoms in PRTH patients.

BRAF mutations in an Italian cohort of thyroid cancers.

OBJECTIVE: Recently, a somatic point mutation of the BRAF gene (V599E) has been identified as the most common genetic event in papillary thyroid carcinoma (PTC) with a variable frequency (about 25-70%) in different series from USA, Japan, Portugal and Ukraine. DESIGN: In the present study, the genetic analysis of BRAF in an Italian cohort of 65 thyroid tumours with corresponding normal tissues and 21 thyroid benign disorders is reported. METHODS: For BRAF analysis, the somatic DNA was PCR amplified by means of specific intronic primers and PCR products were directly sequenced. Statistical analyses were obtained by means of Fisher's exact test. RESULTS: All mutations detected involved a T > A transversion at 1796 (V599E) and were heterozygous. Overall, BRAF(V599E) mutation was found in 18/56 (32.1%) PTCs. According to the histological type of the tumour, the mutation was present in 38.3% of cases of conventional PTC (18/47), in 0/6 follicular variant of PTC, in 0/3 oncocytic variant of PTC. No BRAF mutations were detected either in five follicular carcinomas, or in four poorly differentiated or undifferentiated cancers or in benign thyroid disorders. No statistically significant correlation of BRAF mutation with patient age and gender, with multicentricity of the tumour, with the lymphocytic infiltration of the tissue, with the stage and with the recurrence rate, was found. BRAF(V599E) tended to be associated, although not significantly, with a greater volume and extension of the tumour and with lymph-nodal metastases at surgery. CONCLUSIONS: In conclusion, the present study on the first Italian series of thyroid cancers shows a frequency of 38.3% of BRAF(V599E) in the classical variant of PTC, confirming the key role of this mutation in promoting tumourigenesis.

Recombinant human TSH testing is a valuable tool for differential diagnosis of congenital hypothyroidism during L-thyroxine replacement.

OBJECTIVE: The differential diagnosis of congenital hypothyroidism (CH) is aimed to distinguish transitory from permanent forms, to optimize L-thyroxine (L-T4) therapy to replacement or TSH-suppressive regimens, and to reach accurate definition of the clinical and biochemical phenotype for subsequent genetic investigations and counselling. Therefore, L-T4 therapy is presently withdrawn in most instances and investigations are performed in a disturbing hypothyroid state. DESIGN: The availability of recombinant human TSH (rhTSH) prompted us to assess its efficacy in the differential diagnosis of CH during L-T4 therapy. PATIENTS AND MEASUREMENTS: Eight adult patients with permanent CH remained on L-thyroxine and underwent a new protocol for rhTSH (Thyrogen) testing with injections [4 g/kg/day intramuscularly (i.m.)] at days 1, 2 and 3. At day 3, 123I was administered and uptake obtained after 2 and 24 h. Serum TSH and thyroglobulin (Tg) levels were measured at days 1-4. Neck ultrasound was carried out in all cases. RESULTS: Serum TSH reached levels > 20 mU/l at day 2 and remained above 30 mU/l on days 3 and 4. Stimulation of Tg levels was seen in five patients with peak at day 4. Lingual thyroid was documented at scintigraphy (TS) in three Tg-responsive patients who were previously diagnosed as having thyroid agenesia. In one patient with dyshormonogenesis and high Tg, TS confirmed the presence of goitre with positive perchlorate test. TS was negative in the remaining four cases. All tests indicated complete agenesia in one, whereas a minimal Tg response was marker of nearly complete agenesia in another. The last two TS-negative patients had hypoplastic glands at ultrasound, and refractoriness to TSH stimulation was confirmed by absent Tg response. CONCLUSIONS: We report the first application of rhTSH for differential diagnosis of patients with permanent CH, avoiding the undesirable transient hypothyroidism consequent to L-T4 withdrawal. The data obtained led to the change of the diagnosis at presentation in 4/8 patients and to a more accurate description of the clinical picture in all patients. The proposed protocol has been proved to cause Tg increases even in the presence of small amounts of responsive thyroid cells. The rhTSH testing led to the desired disease characterization, thus allowing specific management and targeted genetic analyses.

Highly sensitive serum thyroglobulin and circulating thyroglobulin mRNA evaluations in the management of patients with differentiated thyroid cancer in apparent remission.

We studied the potential role of innovative diagnostic tools for the management of patients with differentiated thyroid cancer (DTC). Several methods for the detection of the tumor marker thyroglobulin (Tg) have been employed in 36 patients in apparent remission at the moment of the study. All patients had negative anti-Tg antibodies and were evaluated during L-T(4) suppressive therapy before and after stimulation with recombinant human TSH (rhTSH). Serum Tg was measured by means of conventional [nonhighly sensitive (nhs)] or highly sensitive (hs) immunoassays with positive cut-off values set at 1.0 and 0.18 microg/liter, respectively. The RT-PCR conditions for the qualitative determination of Tg mRNA from peripheral blood were optimized to prevent interference by illegitimate transcription. The patients have been classified on the basis of a hs-basal Tg testing by taking into account the results of their baseline samples in hs immunoassay and RT-PCR method; hs-basal Tg testing was considered positive when the marker was detectable in at least one of the two tests. The predictive value of hs-basal Tg testing was estimated on the basis of a global clinical evaluation, including serum Tg response after rhTSH stimulation and reports of contemporary (131)I scan and neck ultrasound. The clinical evaluation was considered positive when at least one of these criteria yielded positive results. Although nhs-Tg measurement was poorly predictive of the clinical status, basal hs-Tg evaluation was found to be concordant with the clinical evaluation in 71% of cases. Results of basal Tg mRNA detection did not vary after rhTSH stimulation and were concordant with the clinical evaluation in 66% of cases. Tg mRNA evaluation alone showed 10 apparently false-positive results, and serum basal hs-Tg was falsely negative in 11 additional cases, suggesting that a suitable predictability could be obtained by the association of these 2 parameters. Indeed, the combination of hs-Tg assay and mRNA detection in the hs-basal Tg testing allowed the identification of 22 patients with a positive persistent/recurrent disease or normal thyroid residue, as well as identification of all 6 patients with a negative clinical evaluation. In conclusion, the combined evaluation of circulating Tg mRNA and serum Tg by means of hs noncompetitive immunoassay (hs-basal Tg testing) can give useful information on the clinical status of patients with DTC who are apparently disease-free, even on L-T(4) TSH-suppressive therapy. Therefore, these combined evaluations retain a potential role in the clinical monitoring of DTC patients. In particular, a negative hs-basal Tg testing would indicate disease remission and the opportunity to lengthen the intervals between rhTSH stimulations and/or to shift patients to a less profound TSH suppression with L-T(4).

Differential diagnosis between Pendred and pseudo-Pendred syndromes: clinical, radiologic, and molecular studies.

The disease gene for Pendred syndrome has been recently characterized and named PDS. It codes for a transmembrane protein called pendrin, which is highly expressed at the apical surface of the thyroid cell and functions as a transporter of chloride and iodide. Pendrin is also expressed at the inner ear level, where it appears to be involved in the maintenance of the endolymph homeostasis in the membranous labyrinth, and in the kidney, where it mediates chloride-formate exchange and bicarbonate secretion. Mutations in the PDS gene and the consequent impaired function of pendrin leads to the classic phenotype of Pendred syndrome, i.e. dyshormonogenic goiter and congenital sensorineural hearing loss. In the present study, we performed a detailed clinical, radiologic, and molecular analysis of six families presenting with clinical diagnosis of Pendred syndrome. In two families a homozygous pattern for PDS mutations was found, whereas the affected members of the other four families were compound heterozygotes. One family did not harbor PDS mutations. Among the four novel mutations described, one is a transversion in exon 2 (84C>A), leading to the substitution S28R. Two other novel mutations lie in exon 4 (398T>A) and in exon 16 (1790T>C), leading to the substitutions S133T and L597S, respectively. The fourth novel mutation (1614+1G>A) is located in the first base pair of intron 14, probably affecting the splicing of the PDS gene. Clinically, all patients had goiter with positive perchlorate test, hypothyroidism, and severe or profound sensorineural hearing loss. In all the individuals harboring PDS mutations, but not in the family without PDS mutations, inner ear malformations, such as enlargement of the vestibular aqueduct and of the endolymphatic duct and sac, were documented. The pseudo-Pendred phenotype exhibited by the family without PDS mutations is likely caused by an autoimmune thyroid disease associated with a sensorineural hearing loss of different origin.

Serum activin A levels in different thyroid disorders.

Activin A belongs to the transforming growth factor-beta superfamily that exerts a wide range of biologic activities on cellular proliferation and differentiation. Although it was suggested that gonadal tissue is the primary site of activin production, several extragonadal sources have subsequently been identified, including human thyrocytes. The goal of the present study was to evaluate serum activin A levels in a series of patients with different thyroid disorders during the active state of the diseases and after recovery. Serum activin A levels were evaluated in 60 healthy subjects (controls), 8 with multinodular nontoxic goiter (MNG), 30 hyperthyroid (15 with Graves' disease (GD), 12 with autonomous hyperfunctioning adenoma (ATA), and 3 with thyrotropin (TSH)-secreting pituitary adenoma, 16 hypothyroid (11 with Hashimoto's thyroiditis and 5 after total thyroidectomy), and 9 patients with resistance to thyroid hormone (RTH) by commercial enzyme-linked immunosorbent assay (ELISA) kit. Patients with GD and ATA showed activin A levels higher than those found in controls and similar to those observed in MNG (GD, 0.74 +/- 0.3 ng/mL; ATA, 0.86 +/- 0.4; and MNG; 1.0 +/- 0.2 vs. controls: 0.39 +/- 0.5, p < 0.001), while in patients with Hashimoto's thyroiditis, total thyroidectomy or RTH activin A levels were similar to those of controls. In conclusion, this study demonstrates that thyroid hyperplasia and hyperfunction result in increased levels of activin A, although the normal levels observed in thyroidectomized patients clearly demonstrate that the thyroid gland is not the predominant source of activin A in normal conditions. Because activin A may exert negative action on thyrocyte proliferation, it is conceivable that activin A hypersecretion in thyroid disorders might represent a counteracting mechanism.