Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy in Patients with Multinodular Goiters: A Meta-Analysis of Randomized Controlled Trials.

A potential reduction of goiter volume (GV) of recombinant human thyrotropin (rhTSH) on multinodular goiters (MNG) was previously reported but controversial. Hence we conducted a meta-analysis to estimate the effect of rhTSH-stimulated radioiodine therapy in patients with MNG. PubMed, Cochrane, CNKI, VIP, and Wanfang databases were searched. Mean difference (MD) and odds ratios with 95% confidence intervals (95% CI) were derived by using an inverse variance random-effects model and fixed-effects model, respectively. Six studies (n=237) were involved in the analysis. For 12 months follow up, high dose (>0.1 mg) of rhTSH significantly reduced GV (MD=17.61; 95% CI=12.17 to 23.04; p<0.00001) compared with placebo. No effective pooled results of low dose of rhTSH (<0.1 mg) were applicable for only one study included. For 6 months follow up, the source of heterogeneity was determined by subgroup and sensitivity analysis. High dose group showed vast improvement in GV reduction (MD=16.62; 95% CI=1.34 to 31.90; p=0.03). The reduction of low dose group compared with placebo was inferior to high dose group. No available data were obtained to assess the influence of rhTSH after 36 months follow up for the only included study. Hypothyroidism incidence was higher for rhTSH group. No publication bias was seen. High dose of rhTSH treatment-stimulated radioactive 131I therapy after 6 months and 12 months follow up had a better effect in reducing GV, but with higher incidence of hypothyroidism. Owing to the limited methodological quality, more clinical researches are warranted in the future.

Recombinant human thyrotropin stimulated 131I treatment for multinodular goiter.

The aim of the study was to investigate the effects of rhTSH stimulation before 131I treatment in patients with MNG. METHODS: Sources included the Cochrane Library, MEDLINE, EMBASE, and SCOPUS database (all until January 2016). Randomized controlled trials (RCTs) that assessed the efficacy of rhTSH-stimulated 131I treatment compared to placebo or 131I treatment alone were collected. Two authors performed the data extraction independently. RESULTS: Six RCTs involving 294 patients with MNG were included in this review. Altogether 168 patients were randomized to rhTSH-stimulated 131I therapy, and 126 to either placebo and 131I or 131I alone. rhTSH-stimulated 131I vs placebo and 131I or 131I alone for MNG showed no statistically significant difference in quality of life and all-cause mortality. rhTSH- (at a dose of 0.03 mg and above) stimulated 131I treatment for MNG showed significant benefits in thyroid volume reduction. 131I treatment with rhTSH stimulation at high doses (0.03 mg, 0.1 mg, 0.3 mg and 0.45 mg) for MNG caused significantly higher adverse effects and hypothyroidism. CONCLUSIONS: The overall results indicated that using rhTSH at high doses of 0.03-0.45 mg before 131I therapy resulted in a greater TVR than 131I therapy alone for patients with non-toxic MNG. However, an increased incidence of adverse effects and hypothyroidism was observed in patients receiving high-dose of rhTSH pretreatment than in patients who received low-dose rhTSH pretreatment. Therefore, a dose of 0.03 mg rhTSH pretreatment before 131I therapy may be more potent than 131I alone in treating patients with non-toxic MNG who either had a contraindication for or declined surgery.

[Lazer-inducted interstitial thermotherapy in the treatment of solid nodulus of thyroid].

The results of treatment 272 patients with a nodular colloid goiter with the use of lazerinducted termotherapy (LITT) are analysed. I is established that in the developed modes of LITT application does not cause destructive changes in paranodular tissue and disorders of thyroid gland hormonal function. Duration of reverse development and substituting of nodular for a connecting tissue is determined by echogene and volume. With it increase the intensity of nodulus substituting for a connecting tissue goes down, extended the terms of nodulus regress. The indication to the repeated application of termotherapy is remaining tissue in the projections of nodulus scope from 42% and more an initial volume through 6 ms treatment. Absolute indications to repeated LITT is a presence of thyroid epithelium in remaining tissue of nodulus.

Modified-release recombinant human TSH (MRrhTSH) augments the effect of (131)I therapy in benign multinodular goiter: results from a multicenter international, randomized, placebo-controlled study.

BACKGROUND: Recombinant human TSH (rhTSH) can be used to enhance (131)I therapy for shrinkage of multinodular goiter (MG). OBJECTIVE, DESIGN, AND SETTING: The objective of the study was to compare the efficacy and safety of 0.01 and 0.03 mg modified-release (MR) rhTSH as an adjuvant to (131)I therapy, vs. (131)I alone, in a randomized, placebo-controlled, international, multicenter study. PATIENTS AND INTERVENTION: Ninety-five patients (57.2 ± 9.6 yr old, 85% females, 83% Caucasians) with MG (median size 96.0, range 31.9-242.2 ml) were randomized to receive placebo (group A, n = 32), MRrhTSH 0.01 mg (group B, n = 30), or MRrhTSH 0.03 mg (group C, n = 33) 24 h before a calculated activity of (131)I. MAIN OUTCOME MEASURES: The primary end point was a change in thyroid volume (by computerized tomography scan, at 6 months). Secondary end points were the smallest cross-sectional area of the trachea; thyroid function tests; Thyroid Quality of Life Questionnaire; electrocardiogram; and hyperthyroid symptom scale. RESULTS: Thyroid volume decreased significantly in all groups. The reduction was comparable in groups A and B (23.1 ± 8.8 and 23.3 ± 16.5%, respectively; P = 0.95). In group C, the reduction (32.9 ± 20.7%) was more pronounced than in groups A (P = 0.03) and B. The smallest cross-sectional area of the trachea increased in all groups: 3.8 ± 2.9% in A, 4.8 ± 3.3% in B, and 10.2 ± 33.2% in C, with no significant difference among the groups. Goiter-related symptoms were effectively reduced and there were no major safety concerns. CONCLUSION: In this dose-selection study, 0.03 mg MRrhTSH was the most efficacious dose as an adjuvant to (131)I therapy of MG. It was well tolerated and significantly augmented the effect of (131)I therapy in the short term. Larger studies with long-term follow-up are warranted.

Time to reconsider nonsurgical therapy of benign non-toxic multinodular goitre: focus on recombinant human TSH augmented radioiodine therapy.

The treatment of benign multinodular goitre (MNG) is controversial, but surgery is recommended in large compressive goitres. While some patients decline surgery others may have contraindications due to comorbidity, since MNG is prevalent in the elderly. Therefore, non-surgical treatment alternatives are needed. Until recently, levothyroxine therapy was the preferred non-surgical alternative, but due to low efficacy and potential side-effects, it is not recommended for routine use in recent international guidelines. Conventional radioiodine ((131)I) therapy has been used for two decades as an effective and safe alternative to surgery in the treatment of symptomatic non-toxic MNG. Since much higher activities of (131)I are employed when treating non-toxic rather than toxic MNG, there has been reluctance in many countries to use this treatment modality. Frequently, the (131)I -uptake in a non-toxic MNG is low, which makes (131)I therapy less feasible. Another challenge is the negative correlation between the initial goitre size and goitre volume reduction (GVR). With its ability to more than double the thyroid (131)I-uptake, recombinant human TSH (rhTSH) increases the absorbed radiation dose and thus enhances the GVR by 35-56% at the expense of up to fivefold higher rate of permanent hypothyroidism. An alternative strategy is to reduce the administered (131)I-activity with a factor corresponding to the rhTSH induced increase in (131)I-uptake. Hereby, the extrathyroidal irradiation can be reduced without compromising efficacy. Thus, although in its infancy, and still experimental, rhTSH-augmented (131)I therapy may profoundly alter the non-surgical treatment of benign non-toxic MNG.

Recombinant human TSH increases the efficacy of a fixed activity of radioiodine for treatment of multinodular goitre.

CONTEXT: High doses of (131)I are usually needed in the treatment of multinodular goitre (MNG) for effective thyroid volume (TV) reduction. Recombinant human thyroid-stimulating hormone (rhTSH) is an adjuvant to enhance (131)I uptake, allowing a decrease in radiation activity and enhancing (131)I efficacy. OBJECTIVE: To evaluate whether rhTSH increases the efficacy of a fixed activity of (131)I for the treatment of MNG. DESIGN: Two-year, observational, placebo-controlled study. SETTING: Patients received 0.1 mg rhTSH (A), 0.005 mg rhTSH (B) or placebo (C). A fixed activity of 1.11 GBq of (131)I was administered 24 h after rhTSH or placebo. PATIENTS: A total of 28 outpatients (26 females and two males) with MNG. MEASUREMENTS: TSH, free T4, T3, thyroglobulin (Tg) and TV. RESULTS: Basal radioactive iodine uptake and TV values were comparable among all groups. After rhTSH or placebo, peak levels of TSH, free T4, T3 and Tg were higher in A than in B or in C (p < 0.05). Hyperthyroidism was observed in A (n = 2), B (n = 6) and C (n = 4). Thyroid enlargement was reported in A (n = 3) and B (n = 6). After 24 months, 10 patients developed hypothyroidism (four in A, three in B and three in C). TV reduction was similar between A and B (37.2 +/- 25.5% vs. 39.3 +/- 27.9%, p = 0.88), but different from the non-significant reduction in C (15.3 +/- 28.3%, p = 0.08). CONCLUSIONS: Followed by 1.11 GBq, a very low dose of 0.005 mg rhTSH was equally safe and effective as 0.1 mg rhTSH. Both doses increased the efficacy of radioiodine. Adverse events were mild, transient and readily treatable.

Administration of a single dose of recombinant human thyrotrophin enhances the efficacy of radioiodine treatment of large compressive multinodular goitres.

OBJECTIVE: Patients with very large multinodular goitres, frequently found among elderly people, often suffering from cardiovascular or other disabling disorders, may be considered as unsuitable for surgery. We have evaluated the feasibility of relatively high-dose 131I therapy in such patients. As subclinical or clinical hyperthyroidism is commonly found in these patients, associated with a low radioiodine (RAI) uptake at 24 h, we pretreated a group of patients with a single intramuscular injection of recombinant human TSH (rhTSH 0.45 mg) in order to increase the uptake of the therapeutic dose of RAI. DESIGN AND PATIENTS: Forty-one patients with large, long-standing multinodular goitres, were recruited for this study. After a careful and detailed clinical and laboratory evaluation, 34 patients (28 women, six men) were included and randomly assigned to group 1 (control, n = 17, 15 women, two men, age 63.1 +/- 11.2 years) receiving only RAI. Patients in group 2 (n = 17, 13 women, four men, age 63.6 +/- 12.3 years) received the therapeutic dose of RAI, having been pretreated (24 h) with 0.45 mg of rhTSH. Both groups of patients were submitted to a low iodine diet, 4-6 months before RAI treatment, while seven thyrotoxic patients also received methimazole (40 mg/day) until they reached euthyroidism. Ultrasonographic studies were performed for all patients and fine-needle aspiration biopsy (FNAB) were performed on one or two nodules before RAI treatment. RAI was given as a single oral dose to the hospitalized isolated patients. Blood samples for thyroid function tests and serum thyroglobulin (Tg) were collected daily during the first week following RAI treatment, and at 1, 3, 6, 9 and 12 months thereafter. MEASUREMENTS: Goitre volume was estimated by computed tomography scan. Thyroid function tests (total T3, free T4, TSH and serum Tg) were assayed with commercial kits. Urinary excretion of iodine was assayed by the Sandell-Kolthoff method. RESULTS: After the RAI therapeutic dose, serum thyroid function tests were carried out daily for the first week and then on a monthly basis (1, 3, 6, 9 and 12 months). Serum TSH levels rose to a peak level of 45.9 +/- 19.1 mU/l (24 h) in group 2 returning to normal at 72 h. Free T4 serum concentrations rose significantly to 59.35 +/- 21.61 pmol/l at 48 h (in group 2) returning to normal at 7 days. Similarly, serum TT3 also peaked above normal levels only in group 2 (6.12 +/- 1.89 nmol/l) at 24 h. Serum Tg increased in both groups (significantly higher in group 2) and remained elevated during the following 12 months. Both groups had a significant reduction in goitre volume at 12 months (group 2: 57.8%vs. group 1: 39.7%, P < 0.05). Hypothyroidism was detected after RAI treatment, respectively, in 21.4% (group 1) and 64.7% (group 2), of the patients at 12 months. CONCLUSIONS: Our results indicate that the use of hTSH increased the efficacy of the RAI therapeutic dose. This was basically due to an increased uptake of the radionuclide (as a consequence of the higher serum TSH levels) and a more extensive distribution of 131I within the nodules of the multinodular goitre. A more intense radiation effect was reflected in there being a higher output of serum Tg and thyroid hormones (group 2). As a consequence this group had a significantly higher reduction of the goitre volume. Also incidence of hypothyroidism post-RAI was significantly higher in group 2. We concluded that pretreatment with rhTSH in elderly patients with large multinodular goitres increases the uptake of the RAI therapeutic dose, thereby significantly reducing the multinodular goitre volume and relieving the compressive symptoms with relatively few side-effects.

Management of the nontoxic multinodular goitre: a European questionnaire study.

BACKGROUND AND OBJECTIVE: The optimum management strategy for the patient with a multinodular nontoxic goitre is still a matter of debate. Our aim was to assess the attitudes towards management of such patients throughout Europe by means of a questionnaire. DESIGN: The questionnaire was circulated to all clinician members of the European Thyroid Association (ETA). A case report was followed by diagnostic investigations and choice of therapy in the index case (a 42-year-old woman with an irregular nontender bilaterally enlarged thyroid of 50-80 g and no clinical suspicion of malignancy). Eleven variations of the basic case report were proposed in order to evaluate the impact on management of each alteration. SUBJECTS AND METHODS: One hundred and sixty-seven members replied to the letter, and 120 individuals from 22 countries completed the questionnaire (corresponding to approximately two-thirds of the clinical members of the ETA). RESULTS: Based on the index case, serum TSH was the routine choice of 100%, and serum free T4/T4-index was included by 74%. Serum TPO autoantibodies, Tg autoantibodies and calcitonin were measured by 65%, 49% and 32%, respectively. The median number of blood tests used was four (range 1-11). Considerable intercountry variations were seen in the preferred imaging methods. Ninety-one percent of the clinicians would use at least one imaging modality. Ultrasound (US) was used by 84%, thyroid scintigraphy by 76%, and both methods by 69%. US had first priority (53% vs. 19% for scintigraphy). If scintigraphy was performed, fine-needle aspiration cytology was routinely used by 17% (inhomogeneous uptake) and 95% (dominant 'cold' area), and 63% used US-guidance. L-T4 treatment was supported by 52% of the clinicians, iodine supplementation by 4%, radioiodine by 6% and surgery by 10%. In the case of a suppressed serum TSH, radioiodine treatment was preferred by 44%, while surgery was the favoured recommendation in four clinical variations with a large goitre or suspicion of malignancy. Marked differences between the countries were suggested by L-T4 therapy being the dominant treatment in Italy, France and Germany in contrast to the prevailing use of radioiodine in Denmark and a wait and see policy in the UK. CONCLUSIONS: Fundamental differences between European countries exist as regards diagnosis and treatment of the multinodular nontoxic goitre suggesting difficulties in reaching a consensus.

[Postoperative organotherapy for multinodular goiter]. / La opoterapia post chirurgica nei pazienti operati per struma multinodulare.

Post-operative therapy with L-Tiroxine can have a suppressive or substitutional aim. After a total thyroidectomy the patients need a substitutional therapy, while after subtotal thyroidectomy the aim of the therapy is to suppress the TSH secretion. In the second case we want either to avoid the recurrence, either to give the hormones that residual gland cannot produce. The drug of choice is L-Tiroxine for both suppressive o substitutional therapy: There is a difference in dosage, that must be greater in first case. While there are some doubts in the literature on the success of the suppressive therapy, we believe that there is enough evidence of his utility.

[Organotherapy treatment in the course of normofunctional goiter. Long-term results in 104 patients]. / Trattamento opoterapico nell'evoluzione del gozzo normofunzionante. Risultati a distanza di tempo in 104 pazienti.

Results of therapy with thyroid hormones (LT4 and/or LT3) were evaluated in 104 patients (95 females and 9 males) with simple diffuse or nodular goiter. The mean interval of observation was 7.2 years. The reported results were analysed in relation to patient's age at the onset of the pathology, time elapsed since its appearance, place of origin and sex of the patient, results of laboratory studies, and clinical signs.

The autonomously functioning thyroid nodule: Goetsch's disease.

The AFTN was established as a clinical entity by the 1918 report of Goetsch, correlating cellular mitochondrial content with nodular function, and showing the inverse correlation between AFTN function and extranodular tissue function. Degeneration, common in AFTNs, can preclude development of hyperthyroidism, eliminate hyperthyroidism, or even induce transient spontaneously resolving hyperthyroidism. AFTNs are nearly always benign. Most reports of malignant AFTNs are inadequately documented. Whether AFTNs are toxic can be determined by clinical evaluation, with laboratory confirmation using principally serum T3 assays and TRH testing. Whether warm nodules are AFTNs may be determined by suppression imaging. Nontoxic AFTNs are usually observed. For older patients with borderline high serum T3 levels, blunted responses to TRH, or subnormal responses on supersensitive TSH assays, prophylactic therapy may be prudent. Toxic AFTNs may be treated surgically (patients younger than 40) or with radioactive iodine (older patients). High dose radioactive iodine therapy is preferred because it more consistently ablates AFTN function.

Diagnosis and management of large toxic multinodular goiters.

Toxic multinodular goiters, estimated weight 100 g or more, occurred in 35 patients between 1961 and 1984. All but two were older than 50; 32 were females. Twenty had goiters of 100-130 g; four of 140-200 g; and 11 were massive. Radioiodine uptakes were 30% or less for 22. Seven of 17 with both T4 and T3 data had T4 toxicosis. Thirty-two patients received radioiodine therapy, delivering 200 microCi per gram when possible. Doses were 25-30 mCi for 17 patients; 50-100 mCi for 12 patients, and 150-200 mCi for three patients. Hyperthyroidism was eliminated with one dose in 25 patients (78%); five patients required two doses. Twenty-two patients were euthyroid after radioiodine; 25 of 28 had persistent goiters. Two patients were treated successfully surgically. One refused surgery and radioiodine, and has been maintained on antithyroid drugs for 10 yr. Two patients died within a few months of an unsuccessful initial dose of radioiodine. Large dose radioiodine therapy is simple, safe, and effective for most patients with large toxic multinodular goiters.