Hugo Niepomniszcze

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.

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.

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.

Peroxidase Deficiency in Familial Goiter with Iodide Organification Defect

Abstract: A 16-year-old girl with euthyroidism and normal hearing had had a goiter since the age of six. Her 21-year-old sister also had goiter with identical clinical findings, suggesting a geneti...

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 Avignons 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.

Familial goitre with partial iodine organification defect, lack of thyroglobulin, and high levels of thyroid peroxidase.

From a sibship of three sisters having congenital goitre and normal hearing, two had impairment of organification of iodide. S1 (4 years old) had goitre since birth, euthyroidism, and a negative perchlorate test. S2 (15 years old) and S3 (13 years old) were hypothyroid, and had radioiodide discharge after potassium perchlorate administration of 19.8% and 26.1%, respectively. Thyroid tissue was obtained at thyroidectomy. Peroxidase activity, in the thyroidal subcellular particles, was found to be qualitatively normal, but quantitatively increased. In the triiodide assay, the activity was: S1 6912 u, S2 2590 u, and S3 3844 u (normal values 900‐1700 u). In the tyrosine‐iodinase assay, the activities, expressed as nmoles of iodide incorporation per gram of tissue, were S1 1046, S2 471, and S3 547 (normal values 220‐410). The activity of the thyroidal NADPH‐cytochrome c reductase, an enzyme possible involved in hydrogen peroxide generation, was: S1 0.084, S2 0.047, and S3 0.055 (normal values 0.018 μEq/min/mg). No thyroglobulin was detected by analytical ultracentrifugation, polyacrylamide gel electrophoresis, or double immunodiffusion in agar of the supernatant fractions. In patient S3, whose gland was labelled in vivo with 125I, 60% of the total radioactivity of the gland (pooled nodular and paranodular specimens) was in a particulate iodoprotein that was solubilized by trypsin, deoxycholate or digitonin. In the soluble fraction there were two iodoproteins: iodoalbumin, and a second iodoprotein similar to the solubilized particulate iodoprotein.

Optimum Recombinant Human Thyrotropin Dose in Patients with Differentiated Thyroid Carcinoma and End-Stage Renal Disease

OBJECTIVE To evaluate serum thyrotropin (TSH) concentrations after conventional (0.9 mg) or half-dose (0.45 mg) administration of recombinant human TSH (rhTSH) injections intramuscularly in patients with end-stage renal disease and differentiated thyroid cancer. METHODS In this case series, we administered 2 doses of 0.9-mg rhTSH or 2 doses of 0.45-mg rhTSH to 3 patients with renal failure and differentiated thyroid cancer who were receiving hemodialysis. Basal serum TSH concentrations were assessed while the patients were taking thyroid hormone therapy. Serum TSH was measured on days 2, 3, 5, 8, 10, 14, and 17 of the study. Thyroglobulin and thyroglobulin antibodies were also measured on days 5 and 7. Patients were asked to report any adverse effects. RESULTS Patient 1, who received 2 injections of 0.9-mg rhTSH administered on days 1 and 3, had persistently elevated serum TSH levels for approximately 11 days. Peak serum TSH measured on day 5 was 644 mIU/L. Self-limited diarrhea was the only reported adverse effect. Patients 2 and 3 received 0.45 mg of rhTSH on 2 consecutive days (days 1 and 2), and both exhibited persistently elevated serum TSH levels for 12 days. The peak serum TSH values on day 3 were 402 mIU/L in Patient 2 and 386 mIU/L in Patient 3. No adverse events were observed in these 2 patients. Patient 2 received thyrotropin alfa for injection to confirm disease status. Patient 3 also received a radioiodine dose because of presumed persistent disease. CONCLUSION High serum TSH levels achieved after conventional and half-dose administration of rhTSH suggest that a dose adjustment might be considered in patients with end-stage renal disease.

Radioiodine Thyroid Remnant Ablation after Recombinant Human Thyrotropin or Thyroid Hormone Withdrawal in Patients with High-Risk Differentiated Thyroid Cancer

To supplement limited relevant literature, we retrospectively compared ablation and disease outcomes in high-risk differentiated thyroid carcinoma (DTC) patients undergoing radioiodine thyroid remnant ablation aided by recombinant human thyrotropin (rhTSH) versus thyroid hormone withdrawal/withholding (THW). Our cohort was 45 consecutive antithyroglobulin antibody- (TgAb-) negative, T3-T4/N0-N1-Nx/M0 adults ablated with high activities at three referral centers. Ablation success comprised negative (<1 μg/L) stimulated serum thyroglobulin (Tg) and TgAb, with absent or <0.1% scintigraphic thyroid bed uptake. “No evidence of disease” (NED) comprised negative unstimulated/stimulated Tg and no suspicious neck ultrasonography or pathological imaging or biopsy. “Persistent disease” was failure to achieve NED, “recurrence,” loss of NED status. rhTSH patients (n = 18) were oftener ≥45 years old and higher stage (P = 0.01), but otherwise not different than THW patients (n = 27) at baseline. rhTSH patients were significantly oftener successfully ablated compared to THW patients (83% versus 67%, P < 0.02). After respective 3.3 yr and 4.5 yr mean follow-ups (P = 0.02), NED was achieved oftener (72% versus 59%) and persistent disease was less frequent in rhTSH patients (22% versus 33%) (both comparisons P = 0.03). rhTSH stimulation is associated with at least as good outcomes as is THW in ablation of high-risk DTC patients.

Recombinant Human TSH: The Argentinean Experience

With great interest we read the editorial ‘‘Expanding Indications of Recombinant Human TSH (rhTSH) in Thyroid Cancer’’ (1), which considered the extensive worldwide clinical experience with rhTSH. It is a very interesting review; however, we would like to clarify several points regarding the use of rhTSH in Argentina. Thyrogen has been used in Argentina for 7 years, and we have published and presented investigations regarding our experience with rhTSH for remnant ablation and treatment of metastatic disease (2–6). We agree with Dr. Rui Maciel, who believes that there is no enough evidence yet to choose the correct radioiodine dose for ablation after rhTSH. However, the worldwide experience has shown that radioiodine doses higher than 50 mCi 131-I are possibly enough for ablation as shown by the European and American coauthors in the mentioned review (1). We would also like to clarify that it is not correct to affirm that rhTSH is routinely used only for ablation in high-risk patients in Argentina, as addressed by Dr. Medeiros-Neto. We have published our experience in 17 patients with lowrisk thyroid cancer retrospectively analyzed (6). In that study, we have shown that rhTSH was a useful method for ablation of normal thyroid remnants in that population. In addition, a new prospective investigation will be published soon showing the effectiveness of rhTSH for remnant ablation in 20 lowrisk papillary thyroid cancer patients (7). Besides, in Argentina, Iorcansky et al. were one of the first in the world showing the use of rhTSH in the pediatric and adolescent population (8). We have also had the opportunity to use rhTSH for radioiodine administration in patients with thyroid cancer and end-stage renal disease (5). We have suggested the necessity for the reduction in rhTSH dosage, utilizing 0.45 mg rhTSH per injection for two injections considering that rhTSH is mainly cleared by the kidney and appears not be removed by hemodialysis (9). Regarding reimbursement in Argentina, rhTSH is reimbursed 100% for retired people. There are also a number of health insurance companies that will pay for 40–60% of the rhTSH cost. We hope that this information will clarify important information regarding Thyrogen use in Argentina. References