The association of insulin resistance with subclinical thyrotoxicosis.

BACKGROUND: Although overt thyrotoxicosis is associated with reduced insulin sensitivity (IS), the effects of subclinical thyrotoxicosis (SCTox) (i.e., suppressed serum thyroid-stimulating hormone with free thyroxine and tri-iodothyronine within the reference range) on glucose metabolism are not clear. SCTox may be of endogenous origin or due to ingestion of supraphysiological amounts of thyroid hormone. Our hypotheses were that reduced IS is present in SCTox and that the degree of reduction differs between SCTox of endogenous and exogenous origin. METHODS: The study population consisted of 125 premenopausal, normal-weight women, divided into four groups: exogenous SCTox due to L-T4 treatment for benign goiter or hypothyroidism (SCTox-ExogG) (n = 53), endogenous SCTox (SCTox-Endog) (n = 12), exogenous SCTox due to L-T4 treatment for differentiated thyroid cancer (SCTox-ExogDTC) (n = 20), and finally euthyroid women (C) (n = 40) as a control group. After a mixed meal challenge, glucose and insulin were determined at baseline and 120 minutes later. IS was assessed by homeostasis model assessment of insulin resistance (HOMA-IR) index, quantitative IS check index (QUICKI), and 2 hours IS Avignon's index amended by Aloulou for mixed food. Secretion by pancreatic B-cells was calculated by HOMA-B index. Comparison among groups was done by analysis of variance followed by Tukey test. Linear regression analysis of T3 versus HOMA-IR was calculated. RESULTS: IS was reduced in all types of SCTox when compared with C. All SCTox groups had significantly higher levels of insulin (baseline and postmeal) and HOMA-IR and lower values of QUICKI and Aloulou when compared with controls. SCTox-Endog, however, had higher baseline insulin levels and HOMA-IR and a lower QUICKI index than the rest of the SCTox groups. Although within the normal range, total T4, free T4, and T3 levels were also significantly higher in the SCTox groups than in euthyroids. In SCTox-Endog, T3/T4 ratio was increased above the rest of SCTox groups. A moderate linear relationship between T3 and HOMA-IR was found in the whole population. CONCLUSIONS: IR is associated with SCTox of either endogenous or exogenous origin. However, based on our findings of lower IS compared with the rest of the SCTox groups, the endogenous subclinical form might have an even larger metabolic impact.

Metformin treatment for small benign thyroid nodules in patients with insulin resistance.

OBJECTIVE: It has been shown that patients with insulin resistance (IR) have a higher prevalence of thyroid nodules and bigger thyroid glands. We evaluated the ability of metformin (M) alone or combined with levothyroxine (L-T4) to reduce the nodular size in benign thyroid hyperplastic nodules (<2 cm in diameter). METHODS: A total of 66 women with IR and nodular hyperplasia, diagnosed by fine needle aspiration biopsy (FNAB), who completed this prospective 6-month duration protocol, were assigned to one of four groups: Group I (GI) (n = 14), patients treated with M; GII (n = 18), patients treated with M plus L-T4; GIII (n = 19), patients treated with L-T4; and GIV (n = 15), patients without any treatment. RESULTS: All groups of included patients had no statistically significant different mean baseline characteristics. Patients from GII and GIII showed drops in thyroid-stimulating hormone (TSH) levels and GI and GII normalized the homeostasis model assessment (HOMA) index after treatment, as expected. The median baseline size of all included nodules was 298 mm³ ≈0.84 cm in diameter (range, 32-3,616 mm³). After treatment, patients of Group I and II showed significant reductions in their nodule size [median reduction, 108.50 mm³ (30%) and 184.5 mm³ (55%), P < 0.008 and P < 0.0001, respectively]. Patients in GIII and GIV did not have a significant reduction of their nodules [P = not significant (N.S.)]. CONCLUSIONS: We conclude that M produced a significant decrease in the nodular size in patients with IR and small thyroid nodules, whereas the combination of M with L-T4 was the best treatment in these women.

High prevalence of thyroid nodules in patients with achrocordons (skin tags). Possible role of insulin-resistance.

Due to the observation of a great number of patients having achrocordons, when they underwent fine needle biopsies for thyroid nodules, we decided to perform a prospective study to investigate the relationship between this finding and the presence of insulin resistance (IR), since achrocordons are commonly seen in hyperinsulinemic subjects. A total of 120 consecutive women, aged 18-35 yrs were studied. All subjects were also evaluated by thyroid ultrasound (US) for measuring thyroid volume and the presence of non-palpable nodules. Basal and post-prandial serum insulin was measured in all of them, as well as the Homeostasis Model Assessment (HOMA). Subjects were divided in two groups: Group A, with achrocordons (n = 44) and Group B, without achrocordons (n = 76). Group A showed 24 patients (54.5%) with thyroid nodules, whereas Group B only 13 subjects (17.1%); p = 0.0087. When we considered, as having high normal thyroid volume, the glands weighting more than 16 grams by US, without nodules, it was found that 8/44 cases from Group A (18.6%) and 3/76 from Group B (3.9%) fitted in such category, p = 0.0076. In patients with nodules and/or bigger thyroids, IR was observed in 36/44 (81.8%) of Group A and 14/76 (18.4%) of Group B, p = 0.0069, while the overall prevalence of IR was 0.47 in Group A and 0.05 in Group B, p = 0.00094. It is concluded that patients with achrocordons have a higher prevalence of US-detected thyroid nodules and larger thyroid glands. Then, it may be beneficial to search for thyroid abnormalities in those subjects with skin tags.

High prevalence of thyroid nodules in patients with achrocordons (skin tags): Possible role of insulin-resistance / Alta prevalencia de nódulos tiroideos en pacientes con acrocordones (fibromas blandos): Posible papel de la insulino-resistencia

Due to the observation of a great number of patients having achrocordons, when they underwent fine needle biopsies for thyroid nodules, we decided to perform a prospective study to investigate the relationship between this finding and the presence of insulin resistance (IR), since achrocordons are commonly seen in hyperinsulinemic subjects. A total of 120 consecutive women, aged 18-35 yrs were studied. All subjects were also evaluated by thyroid ultrasound (US) for measuring thyroid volume and the presence of nonpalpable nodules. Basal and post-prandial serum insulin was measured in all of them, as well as the Homeostasis Model Assessment (HOMA). Subjects were divided in two groups: Group A, with achrocordons (n = 44) and Group B, without achrocordons (n = 76). Group A showed 24 patients (54.5%) with thyroid nodules, whereas Group B only 13 subjects (17.1%); p = 0.0087. When we considered, as having high normal thyroid volume, the glands weighting more than 16 grams by US, without nodules, it was found that 8/44 cases from Group A (18.6%) and 3/76 from Group B (3.9%) fitted in such category, p = 0.0076. In patients with nodules and/or bigger thyroids, IR was observed in 36/44 (81.8%) of Group A and 14/76 (18.4%) of Group B, p = 0.0069, while the overall prevalence of IR was 0.47 in Group A and 0.05 in Group B, p = 0.00094. It is concluded that patients with achrocordons have a higher prevalence of US-detected thyroid nodules and larger thyroid glands. Then, it may be beneficial to search for thyroid abnormalities in those subjects with skin tags.

Debido a la alta frecuencia de acrocordones en pacientes que concurrían a nuestro servicio para realizar punciones aspirativas de nódulos tiroideos, realizamos un estudio prospectivo para investigar la relación entre este hallazgo y la presencia de insulino resistencia (IR), dado que los acrocordones son frecuentemente observados en pacientes hiperinsulinémicos. Se incluyeron 120 pacientes consecutivas, con edades entre 18 y 35 años. Todas fueron evaluadas con una ecografía tiroidea para determinar su volumen y la presencia de nódulos no palpables. Se midió insulinemia basal y post prandial, así como el índice Homeostasis Model Assessment (HOMA). Las pacientes se dividieron en 2 grupos: Grupo A, con acrocordones (n = 44) y Grupo B, sin acrocordones (n = 76). En el Grupo A se encontraron 24 (54.5%) con nódulos tiroideos, mientras que el Grupo B, sólo 13 (17.1%); p = 0.0087. Cuando consideramos la presencia de una glándula tiroides de tamaño elevado pero dentro de los límites normales, medida por ecografía (peso mayor a 16 gramos sin nódulos), encontramos que 8/44 casos del Grupo A (18.6%) y 3/76 del Grupo B (3.9%) entraron en esta categoría, p = 0.0076. En aquellas pacientes con nódulos tiroideos o glándula tiroides de mayor tamaño, observamos IR en 36/44 (81.8%) del Grupo A y en 14/76 (18.4%) del Grupo B, p = 0.0069, mientras que la prevalencia total de IR fue del 0.47 en el Grupo A y del 0.05 en el Grupo B, p = 0.00094. En conclusión, las pacientes con acrocordones tuvieron mayor prevalencia de nódulos tiroideos detectados por ecografía, glándula tiroides de mayor tamaño y mayor proporción de insulino resistencia.

Increased prevalence of insulin resistance in patients with differentiated thyroid carcinoma.

BACKGROUND: Patients with insulin resistance (IR) have a higher prevalence of thyroid nodules. In the present study, we present original data showing that patients with differentiated thyroid carcinoma (DTC) also have a higher frequency of IR. METHODS: Twenty women with DTC (group 1, G1) and 20 euthyroid individuals (control group, CG) were investigated for IR. G1 and CG subjects were matched in pairs by age, gender, and body mass index (BMI). The diagnosis of IR was made when the homeostasis model assesment of insulin resistance (HOMA-IR) index was higher than 2.5. According to the BMI, 20 women (10 with DTC and 10 of the CG) had a BMI < 25, whereas the other 20 had higher BMI values (overweight and obese patients). RESULTS: IR was present in the 50% of G1, but only in the 10% of the CG (P < 0.001). In the groups with lower BMI (<25), we found IR in 30% of G1 and no cases in the CG, whereas in those with BMI > 25 the IR was present in 70% of G1 and 20% of CG. There were no differences between the two subgroups regarding the time in which the IR tests were performed. IR was present in 56.3% of patient with papillary anol 25% of follicular thyroid carcinomas, respectively. CONCLUSIONS: We conclude that such a high prevalence of IR would be an important risk factor for developing DTC, as it is well known with some other nonthyroid carcinomas.

Age-related neoplastic risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germ line RET Cys634Trp (TGC>TGG) mutation.

RET testing in multiple endocrine neoplasia type 2 for molecular diagnosis is the paradigm for the practice of clinical cancer genetics. However, precise data for distinct mutation-based risk profiles are not available. Here, we survey the clinical profile for one specific genotype as a model, TGC to TGG in codon 634 (C634W). By international efforts, we ascertained all available carriers of the RET C634W mutation. Age at diagnosis, penetrance, and clinical complications were analyzed for medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism (HPT), as well as overall survival. Our series comprises 92 carriers from 20 unrelated families worldwide. Sixty-eight subjects had MTC diagnosed at age 3-72 years (mean 29). Lymph node metastases were observed in 16 subjects aged 20-72 and distant metastases in 4 subjects aged 28-69. Forty-one subjects had pheochromocytoma detected at age 18-67 (mean 36). Amongst the 28 subjects with MTC and pheochromocytoma, six developed pheochromocytoma before MTC. Six subjects had HPT diagnosed at age 26-52 (mean 39). Eighteen subjects died; of the 16 with known causes of death, 8 died of pheochromocytoma and 4 of MTC. Penetrance for MTC is 52% by age 30 and 83% by age 50, for pheochromocytoma penetrance is 20% by age 30 and 67% by age 50, and for HPT penetrance is 3% by age 30 and 21% by age 50. These data provide, for the first time, RET C634W-specific neoplastic risk and age-related penetrance profiles. The data may facilitate risk assessment and genetic counseling.

Introducing the thyroid gland as another victim of the insulin resistance syndrome.

BACKGROUND: Insulin is a thyroid growth factor that stimulates proliferation of thyroid cells in culture. In order to evaluate the effects of insulin resistance (IR) on the thyroid gland, we developed a prospective study in euthyroid women. METHODS: One hundred eleven women (mean age 32.2 +/- 7 years) were evaluated by a thyroid ultrasound (US) and basal and postprandial serum insulin. Subjects were divided into four groups as follows: G1 (n = 42), subjects with IR and obesity; G2 (n = 21), subjects with obesity without IR; G3 (n = 17), subjects with IR and normal weight; and G4 (n = 31) control group (without IR and obesity). RESULTS: The thyroid volume (TV), measured by US, showed the following values: G1, 17 +/- 3 mL; G2, 13.8 +/- 2.8 mL; G3, 16.2 +/- 2.1 mL; and G4,12.1 +/- 2.4 mL. There was no significant difference in TV between G1 and G3, but differences between G1 and G2, and between G3 and G4 were significant at p < 0.05. The percentage of nodular thyroid glands observed by US in each group was as follows: G1, 50%; G2, 23.8%; G3, 61%; G4, 16.1%. Again, the differences between G1 and G2 and between G3 and G4 were statistically significant (p < 0.005 and p < 0.001, respectively, for each comparison). CONCLUSIONS: It is concluded that the higher circulating levels of insulin cause increased thyroid proliferation. The clinical manifestations are the larger thyroid volume and the formation of nodules. Thus, the thyroid gland appears to be another victim of the insulin resistance syndrome.

[Detection of a non-standard mutation in the ret protoncogene by site directed mutagenesis]. / Detección de una mutación no estándar en el proto-oncogen ret por mutagénesis dirigida.

MEN2A is an autosomic dominant disease, characterized by medullary thyroid cancer, pheochromocytoma and parathyroid hyperplasia. Mutations in the ret proto-oncogene are associated with this disease, with almost 100% of penetrance. The gene, situated on chromosome 10q11.2, codes for a transmembrane protein with a tyrosinkinase-like receptor function. Mutations that affect its extracellular domain, stimulate spontaneous homodimerization and elevate the basal tyrosinkinase activity. The codon 634 of the gene is considered a hot-spot site, since it is mutated in 85% of the MEN2A families. Our group developed in 2002 an indirect and costless strategy to detect alterations in this site. We present a family suspected of having MEN2A. We applied our PCR based indirect strategy on the DNA of the index patient and found that there was no mutation in that site. Posterior sequencing of exon 10 and 11 confirmed that the mutation affecting this family was in codon 611. Thus, we developed a new costless family-specific strategy based on mutagenic PCR and enzymatic cuts to diagnose all the family members. A seven-year old boy with this mutation was preventively thyroidectomized. In this way, combining the indirect methodology for codon 634 previously developed by our group, and a posterior family-specific mutation detection strategy, we were able to diagnose and intervene presymptomatically the family members, avoiding sending all the samples to foreign centers.

A PCR-mutagenesis strategy for rapid detection of mutations in codon 634 of the ret proto-oncogene related to MEN 2A.

BACKGROUND: Multiple endocrine neoplasias type 2A (MEN 2A) is a dominantly inherited cancer syndrome. Missence mutations in the codon encoding cysteine 634 of the ret proto-oncogene have been found in 85% of the MEN 2A families. The main tumour type always present in MEN 2A is medullar thyroid carcinoma (MTC). Only 25% of all MTC are hereditary, and generally they are identified by a careful family history. However, some familial MTCs are not easily detected by this means and underdiagnosis of MEN 2A is suspected. METHODS: DNA samples from MEN 2A patients were amplified by PCR. The products were incubated with the restriction enzyme Bst ApI or Bgl I. The samples were loaded in non-denaturing 10% Polyacrilamyde Gel and run at 120 volts for 40 min. The gels were stained with 10 microg/ml ethidium bromide, and the bands were visualized under a UV lamp. RESULTS: We developed a PCR-mutagenic method to check the integrity of the three bases of the cysteine 634 codon. CONCLUSION: The method can be used to detect inherited mutations in MTC patients without a clear family history. The method is relatively simple to use as a routine test in these patients to decrease the underdiagnosis of MEN 2A. In addition, the assay can be used to screen affected families with any mutation in cysteine 634.

Very early detection of RET proto-oncogene mutation is crucial for preventive thyroidectomy in multiple endocrine neoplasia type 2 children: presence of C-cell malignant disease in asymptomatic carriers.

BACKGROUND: Multiple endocrine neoplasia type 2 (MEN 2) is an inherited disease caused by germline mutations in the RET proto-oncogene, and is responsible for the development of endocrine neoplasia. Its prognosis is dependent on the appearance and spread of medullary thyroid carcinoma (MTC). Relatives at risk can be identified before clinical or biochemical signs of the disease become evident. METHODS: Twenty-one families with MEN 2 (16 families with MEN 2A and 5 families with MEN 2B) were studied. Peripheral blood DNA was amplified by polymerase chain reaction. DNA sequence or restriction enzyme analysis was performed to detect mutations of RET proto-oncogene exons 10, 11, and 16. Molecular analysis was carried out in all index patients as well as in 98 relatives of MEN 2A patients (60 juveniles, ages 6 months to 21 years, and 38 adults, ages 22 to 81 years) and in 13 relatives (6 juveniles ages 10 to 21 years, and 7 adults ages 41 to 66 years) from MEN 2B families. RESULTS: Molecular studies showed a mutation at codon 634, exon 11 in all MEN 2A patients. All MEN 2B patients showed an ATG to ACG (Met918Thr) mutation. In MEN 2A families, 42 out of 98 relatives were affected. Total thyroidectomy was performed in 18 juvenile carriers ages 17 months to 21 years. Histopathologic studies of the glands revealed parafollicular cell (C-cell) hyperplasia in all of these carriers, medullary thyroid carcinoma in 15 carriers, and only one carrier with lymph node metastases. CONCLUSIONS: The consistent finding of C-cell disease in all the juvenile carriers who underwent preventive thyroidectomy emphasizes the relevance of early screening in children at risk of developing MTC. The presence of MTC in the specimen of prophylactic thyroidectomy from a 17 month old girl highlights the importance of thyroidectomy as soon as the molecular diagnosis is confirmed.

Diagnostico por mutagenesis dirigida de una mutacion en el gen hMSH2 vinculada a cancer colorrectal hereditario no poliposo / Diagnosis of hereditary nonpolyposis colorectal cancer by directed mutagenesis in a mutation at the hMSH2 gene

El cáncer colorrectal hereditario no poliposo (HNPCC) es la forma más común de cáncer de colon hereditario, y una de las afecciones autosómicas dominantes más frecuentes. Clínicamente se caracteriza por su temprana apacición (< 50 años), la localización proximal de los tumores colónicos y un alto riesgo de desarrollar tumores colorrectales primarios múltiples y extracolónicos. La enfermedad es causada por diferentes mutaciones en alguno de los por lo menos cuatro genes reparadores de discordancias del AND (genes MMR: hMSH2, hHLH1, hPMS1 y hPMS2. Se calcula que afecta a 1:200 1:2000 personas de la población occidental. La identificación de estos genes responsables de HNPCC ha permitido la búsqueda de mutaciones germinales en individuos afectados. En una familia mendocina con cáncer de colon hereditario se realizó la búsqueda del gen afectado a través de un centro holandés de diagnóstico de HNPCC donde detectaron una mutación en el exón 13 del gen hMSH2. La mutación introduce un codón de finalización temprano lo que provoca la expresión de una proteína truncada. Esta mutación en particular no estaba registrada en la base de datos de mutaciones relacionadas con HNPCC. Luego de la detección en el paciente índice, desarrollamos en nuestro laboratorio un procedimiento rápido y eficiente para detectar mutaciones en el resto de los familiares. La metodología consistió en la amplificación del exón 13 del gen hMSH2 mediante un cebador para el extremo 5' que linda con el sitio de la mutación puntual e introduce parte de la secuencia de corte para la enzima Haelll que es completada sólo en el alelo sano. Este análisis genético nos permitió hasta la fecha diagnosticar 17 individuos de los cuales 9 resultaron afectados y están entrando en un programa de seguimiento clínico y consultoría genética.

Management of overt and subclinical hypothyroidism: factors influencing L-thyroxine dosage

With the aim of establishing optimal dosage schedules, 171 women with either orvet (OH, n=80) or subclinical (SCH, n=91) hypothyroidism were assessed before and 6 months after starting L-thyroxine (LT4) replacement therapy. Each group was further classified into four subgroups according to post-therapy serum TSH level, as follows; A) complete suppression; B) partial suppression; C) normal range and D) above normal range (insufficient response). In all subgroups, LT4 doses were higher for OH than for SCH, whether expressed as total daily dose (mug) or as a function of either actual or ideal body weight (mug/kg BW). In OH, LT4 dose was higher for subgroups A or B as compared with either C or D. In SCH, subgroup A received a larger dose than the other subgroups. Post-treatment serum thyroxine levels showed the same pattern for both OH and SCH. Mean LT4 dose was similar in patients with high and normal antithyroid antibodies and in patients with goiter and in those without it. In goitrous patients thyroid volume decreased in subgroup B, particularly in those patients that had elevated antithyroid antibodies, but not in subgroup C. In OH patients a significant negative correlation was found between daily LT4 dose per Kg actual BW and actual BW, especially in subgroup C for patients with a body mass index > 27 kg/cm2 (r = -0.90, p<0.001). In subgroup C of the SCH group, a negative correlation between LT4 dose and age was noticed. Both in OH and in SCH, LT4 dose per kg actual BW required to obtain a serum TSH within the normal range was lower in women with a body mass index (BM) > 27 kg/m2 than in those with a BMI = 27 kg/m2. LT4 doses for subgroup C did not differ from those needed in hypothyroid patients with previous Graves' disease, in either OH or SCH patients.