Thyroxine Withdrawal Research Articles

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

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. 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. 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. 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.

Sequential Follow-up of Serum Thyroglobulin and Whole Body Scan in Thyroid Cancer Patients without Initial Metastasis

To investigate the usefulness of whole body scan (WBS) and serum thyroglobulin (Tg) measurement after thyroxine withdrawal during sequential follow-ups in patients with differentiated thyroid cancer (DTC). Two hundred and sixty-five consecutive DTC patients were enrolled. They were previously treated with near-total thyroidectomy and I-131 remnant ablation, without initial metastases or Tg antibodies. All had the first follow-up WBS and serum Tg measurement 6-12 months after initial treatment, and 165 patients received the second follow-up without further therapy. Positive/negative predictive values (PPV/NPV) were calculated by the outcome of patients being followed up for more than 8 years (mean+/-SD: 133+/-26 months). Serum Tg levels while the patients were off thyroxine therapy decreased spontaneously in 39.3% of the cases without further therapy. The NPV of the first follow-up serum Tg level was excellent: <2 microg/L and <0.5 microg/L were 95.1% and 98.2%, respectively. However, the PPV of the first follow-up serum Tg level was low: >10 microg/L and 2-10 microg/L were 40% and 9.6%, respectively. The trend of Tg levels was more informative; the PPV was 62.5% in cases with an increase of serum Tg of >10 microg/L and 16.6% with an increase of <5 microg/L. However, decreasing Tg levels may associate with rapid deterioration of disease, in which cases decrease of Tg indicated dedifferentiation of the tumor. The diagnostic WBS showed the same picture in 91.5% of the patients. Only one patient (0.6%) turned from negative study to positive during the follow-up. In the meanwhile his serum Tg levels increased from 0.56 to 13.6 microg/L. It is most informative when both the trend and the levels of Tg during sequential follow-up are considered. The diagnostic WBS may be performed for selected patients with indication based on Tg levels to localize the disease.

Recombinant Human Thyrotropin-Assisted Radioiodine Therapy for Patients with Metastatic Thyroid Cancer Who Could Not Elevate Endogenous Thyrotropin or Be Withdrawn from Thyroxine

The value of recombinant human thyrotropin (rhTSH) as preparation for radioiodine therapy was assessed in 115 patients with metastatic thyroid cancer. Patients who were either unable to elevate endogenous TSH during thyroxine withdrawal, or in whom thyroxine withdrawal was contraindicated for medical reasons were eligible. Their physicians requested rhTSH as part of the Thyrogen Compassionate Use Program. This is a retrospective summary of the nonrandomized uncontrolled experience. We assessed the ability of rhTSH to elevate the serum TSH; to avoid the complications of hypothyroidism; to stimulate radioiodine uptake; and to stimulate the serum thyroglobulin. Disease response and adverse events were also assessed. After rhTSH, the serum TSH levels rose to >or=25mU/L in every patient in whom levels were measured (n = 112). Hypothyroid complications were avoided in 22 of 25 patients who had experienced them in the past, and in 47 of 51 patients who were at high risk for hypothyroid complications. Radioiodine uptake was present on whole-body scans (WBS) in 105 of the 115 patients. Serum thyroglobulin levels were lower than baseline in 73% of patients assessed at 12 months. Cancer-related symptoms were improved in approximately 25%. Two patients had serious adverse events that were thought to be related to rhTSH. rhTSH elevates serum TSH and facilitates radioiodine uptake in patients who cannot produce endogenous TSH or who cannot tolerate hypothyroidism.

Health‐Related Quality‐of‐Life Study in Patients With Carcinoma of the Thyroid After Thyroxine Withdrawal for Whole Body Scanning

The authors studied the change of health-related quality of life (HR-QOL) in patients with differentiated thyroid carcinoma (DTC) with thyroxine (T4) withdrawal in preparation for whole body radioactive iodine scanning. Seventy-eight patients with DTC and history of radioactive iodine (RAI) ablation were prospectively recruited. They completed the Functional Assessment of Cancer Treatment-General (FACT-G) questionnaire on weeks 0, 2, and 4 after T4 withdrawal with corresponding checking of serum thyroid-stimulating hormone (TSH). Overall, 74.5% (58 of 78) of patients completed all FACT-G. Comparing FACT-G scores at weeks 0 and 4, "physical" (P < .001), "social" (P = .04), and "emotional" (P = .047) aspects were lowered as well as "total" HR-QOL (P = .001). However, the "functional" domain of HR-QOL was not affected (P = .14). Comparing FACT-G scores at week 0 and 2, we found that "physical" (P = .049) and "total" (P = .05) HR-QOL were affected early (in the first 2 weeks) in T4 withdrawal. Comparison of week 2 and 4 showed that in the later half of the withdrawal period, "physical" (P = .001), "emotional" (P = .02), and "total" FACT-G scores (P = .002) were affected. Mean TSH level (in mIU/L) increased gradually: 2.8 (week 0), 42.8 (week 2), 97 (week 3), and 153 (week 4). The percentage of patients attaining TSH level of >30 mIU/L were 55% (week 2), 96.2% (week 3), and 100% (week 4). HR-QOL declines with time of T4 withdrawal. The impact is more severe in the later period of T4 withdrawal. In 3 weeks, 96.2% of our patients attained TSH level of 30 mIU/L. To minimize the impact on HR-QOL, duration of T4 withdrawal can be decreased to 3 weeks.

Effects of Thyroid Hormones on Serum Levels of Adipokines as Studied in Patients with Differentiated Thyroid Carcinoma During Thyroxine Withdrawal

Previous studies addressing the influence of thyroid hormones on serum levels of adipokines yielded conflicting results. We aimed to study the impact of short-term overt hypothyroidism on serum leptin, resistin, and adiponectin levels in an in vivo human model. Twenty-two women with differentiated thyroid carcinoma were studied the last day of their thyroxine-suppressive treatment, 4-7 days after withdrawal, and the day before whole-body scanning. Evaluations included serum thyroid hormone, leptin, resistin, and adiponectin concentrations, fasting glucose and insulin, lipid profiles, body temperature, body mass index, and total body fat mass. Thyroid function changed from subclinical or mild hyperthyroidism to normal free thyroxine and triiodothyronine levels, ending in overt hypothyroidism. Thyroxine withdrawal resulted in an increase in serum resistin (p = 0.007) and leptin (p = 0.006) concentrations, whereas adiponectin levels remain unchanged. A significant decrease in body temperature during thyroxine withdrawal was paralleled by a decrease in fasting glucose (p = 0.006) and insulin resistance (p = 0.033), which occurred despite an increase in estimated total body fat mass. Thyroid hormones are important regulators of energy balance and intermediate metabolism, influencing the serum concentrations of leptin and resistin.

Managing thyroid cancer without thyroxine withdrawal

Thyroxine (T4) withdrawal or recombinant TSH is used for the stimulation of thyroglobulin (Tg), whole-body scanning (WBS) and iodine-131 treatment in patients with thyroid carcinoma. This study evaluated the T4 dose reduction protocol as an alternative for patients' preparation. Fifty-one patients were submitted to total T4 withdrawal for WBS and Tg measurement. T4 treatment was then resumed and maintained until TSH reached levels < 0.3 mIU/l. The T4 dose was then decreased to 0.8 microg/kg/day and TSH was measured weekly. Tg was assayed when TSH was > 30 mIU/l. Patients diagnosed with the disease upon initial evaluation were treated. We also evaluated the clinical and laboratory changes observed for both preparations. Using the reduced dose protocol, TSH levels > 30 mIU/l were reached within 6 and 8 weeks in 84.6 and 100% of the patients, respectively. T4 withdrawal was associated with more common symptoms of hypothyroidism and elevation of creatine kinase (CK) and LDL cholesterol. The T4 dose reduction protocol proved to be useful for Tg stimulation and ablative therapy, without the complication of severe hypothyroidism or the cost of recombinant TSH.

Three‐Week Thyroxine Withdrawal: A Thyroid‐Specific Quality of Life Study

The purpose of this study is to determine the impact of a 3-week T4 withdrawal test on the quality of life (QOL) of patients undergoing investigation for residual/recurrent well-differentiated thyroid cancer. Prospective survey study. 181 patients with well-differentiated thyroid cancer were surveyed using a thyroid-specific QOL-thyroid survey at three times throughout the study: prior to T4 withdrawal, after the 3-week withdrawal period, and 4 weeks after resuming T3/T4 combination therapy. A very small, though statistically significant, reduction was observed in the four domains of QOL defined by the QOL-thyroid survey from baseline values to 3 weeks after T4 withdrawal. The maximal difference was 2.04 (fatigue), out of a possible 10 point score, in the physical well-being category. The thyroid-specific QOL questionnaire demonstrates a statistically significant though very small and probably not clinically significant reduction in the QOL of thyroid cancer patients undergoing an induced 3-week hypothyroid state. Three-week T4 withdrawal is a simple, cost-effective, and readily available test.

Assessing Hypothyroidism in the Preparation of Patients With Thyroid Cancer

This study evaluated the effects of iatrogenic hypothyroidism in patients with thyroid carcinoma on cardiovascular risk, renal function, drug metabolism, persistence of elevated thyroid-stimulating hormone (TSH), and absence from work. Serum levels of C-reactive protein, low-density lipoprotein cholesterol, lipoprotein a, apolipoprotein B, and malonyl dialdehyde, as well as microalbuminuria and creatinine clearance, were determined in 31 patients during levothyroxine treatment (TSH ranging from 0.05 to 0.5 mIU/mL) and 5 weeks after thyroxine withdrawal with triiodothyronine given during the first 2 weeks. TSH values >65 mIU/mL were observed in all patients. Two months after reintroduction of levothyroxine, 26% of the patients still showed TSH levels >5 mIU/mL. The mean number of missed days of work resulting from hypothyroidism was 8.7 days. Except for creatinine clearance, which was significantly reduced, all other parameters studied increased during hypothyroidism. We also present 2 cases of marked elevation of serum digoxin and phenobarbital levels during acute hypothyroidism. This study demonstrates that hypothyroidism induced to prepare patients with thyroid carcinoma for therapy is persistent and associated with a significant increase in risk factors for atherosclerosis, decrease in renal function, changes in drug metabolism, and important absence from work. We suggest that recombinant TSH should be the preparation of choice, thus freeing the patients from these and other undesired effects.

The occurrence of permanent thyroid failure in patients with subclinical postpartum thyroiditis

The long-term effect of the subclinical form of postpartum thyroid dysfunction (PPTD) has not been well established. This study was conducted to evaluate the outcome of permanent hypothyroidism in a large cohort of women with PPTD. Of 213 women with PPTD, 172 (81%) returned for follow-up. There were 27 (16%) with subclinical (group 1) and 145 (84%) with overt hypothyroidism (group 2). They were all treated with levothyroxine for 23 +/- 16 months and followed-up for thyroid function after thyroxine (T(4)) withdrawal. In group 1, the time of occurrence of PPTD was longer, serum T(4) was higher and TSH was lower than in group 2. After T(4) withdrawal, 59 and 64% of patients became hypothyroid in groups 1 and 2 respectively; however, serum TSH was increased in group 2 as compared with group 1 (29.7 +/- 8.4 vs 16.4 +/- 15.4 mU/l, P < 0.002). The duration of euthyroidism, serum free T(4) and triiodothyronine indices and thyroperoxidase antibodies were not significantly different between the two groups. It was concluded that a high percentage of patients with the subclinical form of PPTD proceed to permanent thyroid failure. The timely recognition of mild to severe cases of PPTD is important for the improvement of life for mothers and infants.

The effects of thyroid hormones on circulating markers of cell-mediated immune response, as studied in patients with differentiated thyroid carcinoma before and during thyroxine withdrawal

To address the influence of thyroid hormones on circulating markers of cell-mediated immune response in an in vivo human model. Twenty-two patients with stage I differentiated thyroid carcinoma were studied on the last day of thyroxine suppressive treatment, 4-7 days after withdrawal, and the day before whole body scanning. Three patients were excluded because of residual disease. Twenty euthyroid individuals served as controls. Serum thyrotrophin and thyroid hormones were measured by an immunometric assay, circulating cytokines by enzyme-linked immuno-sorbent assay and lymphoid populations by flow cytometry. Thyroid function in patients changed from subclinical or mild hyperthyroidism at the first visit, to a situation of normal circulating levels of free thyroxine and triiodothyronine at the second, ending in a state of overt hypothyroidism. Thyroxine suppressive treatment in patients increased serum interleukin-18 concentrations (IL-18, mean+/-s.d., 280+/-122 vs 183+/-106 pg/ml, F = 3.192, P = 0.029), soluble interleukin-2 receptor levels (sIL-2R, 4368+/-1480 vs 2564+/-846 pg/ml, F = 21.324, P < 0.001), and the percentage of natural killer (NK) cells in peripheral blood (15.9+/-8.6 vs 10.5+/-3.6%, F = 4.977, P = 0.004) compared with controls. After thyroxine withdrawal, serum levels of IL-18, sIL-2R and the percentage of NK cells decreased progressively. Our present results suggest that thyroid hormones modulate the cell-mediated immune response in humans.

Role of 131I in the treatment of well differentiated thyroid cancer

(131)I is an integral component in postsurgical management of well-differentiated thyroid cancer (WDTC), which includes papillary and follicular types. (131)I is used postsurgically to either destroy remaining thyroid tissue (thyroid ablation) or to treat recurrence and metastases (radioiodine therapy). (131)I is no longer a routine diagnostic modality, but it is widely used for remnant ablation after thyroidectomy for WDTC > 1 cm, under conditions of thyroxine withdrawal. It is generally-though not unanimously-accepted that postsurgical radioiodine is the most powerful method by which to lengthen disease-free survival. (131)I cannot be used if the residual thyroid remnant is large; many surgeons therefore perform near-total or total thyroidectomy for all WDTC > 1 cm. Since 1997, radioiodine treatment has been performed in outpatient settings, where side effects are common, but mild and transient. Secondary screening is by physical exam, thyroglobulin measurements, and (131)I diagnostic whole-body scans. This is performed under conditions of thyrotropin stimulation, which is accomplished either by thyroxine withdrawal or administration of recombinant human thyrotropin. While most cancers are well treated with radioiodine, some advanced cancers may no longer take up radioiodine, rendering them resistant to treatment. For these cancers, redifferentiation therapy and molecular target-specific medicines hold future promise for improved treatment.

Manifestações clínicas e diagnóstico de metástases distantes de carcinoma diferenciado de tireóide após a terapia inicial

We studied 58 patients with distant metastases of differentiated thyroid carcinoma diagnosed after initial therapy. Lymph node metastases were observed in 65% of the patients on initial presentation. All lymph node metastases, ninety percent of the lung metastases and only 25% of the bone metastases were asymptomatic. Radiography revealed lytic metastases in cases of bone involvement, was normal in 39.6% of the patients, and showed micrometastases in 34.5% and macrometastases in 25.8% of the patients with lung disease. Thyroglobulin (Tg) under thyroxine use was detectable in all patients without antibodies at a cut-off > 1 ng/ml, in 90% at > 5 ng/ml and in 80% at > 10 ng/ml, and after thyroxine withdrawal in 100% at a cut-off > 5 ng/ml and in 94% at > 10 ng/ml. In the case of patients with antibodies (13.8%), Tg was undetectable in half of them. Diagnostic scanning was positive in 83 and 77.6% of the patients with bone and lung metastases, respectively. After ablative therapy, the sensitivity was 100 and 93%, respectively. Eighty-five percent of patients with a negative diagnostic scan had lung metastases visible on radiographs. The determination of serum Tg is the best method in the follow-up of patients with differentiated thyroid cancer. Elevated Tg levels suggest the presence of metastases, indicating the need for ablative therapy with posttreatment scanning, which might reveal non-apparent metastases.

Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis.

To investigate to what extent thyroid remnant ablation and withdrawal from thyroxine are required to achieve sufficient accuracy of serum thyroglobulin (Tg) measurements as an indicator of tumour recurrence in the follow-up of patients with differentiated thyroid carcinoma. We conducted a meta-analysis of the literature from 1975 to 2003 on serum Tg measurements in the follow-up of differentiated thyroid carcinoma. In a computer-based search, we initially found 915 articles that were finally narrowed down to 120. These 120 papers were subjected to strict in/and exclusion criteria, leaving 46 articles (totalling 9094 patients). Data from these articles were extracted in a structured fashion and were grouped according to initial therapy, TSH status, Tg assay method and definition of a 'gold standard'. Original 2 x 2 tables were pooled by summary receiver operating characteristic curve analysis (sROCa), best estimates of sensitivity and specificity being obtained by the combination of sROCa and Mantel-Haenszel odds ratios. Despite considerable differences between series in laboratory and clinical methodology, we consistently found higher specificity for Tg measurements after thyroid remnant ablation than after surgery alone. Highest pooled sensitivity 0.961 +/- 0.013 (SE) was found for immunometric assay (IMA) after thyroid remnant ablation and thyroid hormone withdrawal, at a specificity of 0.947 +/- 0.007. Pooled sensitivity decreased significantly if ablated patients were tested while on thyroid hormone (0.778 +/- 0.023, at a specificity of 0.977 +/- 0.005). Significantly decreased pooled specificity was found in patients who did not undergo remnant ablation (sensitivity 0.972 +/- 0.023, at a specificity of 0.759 +/- 0.028). If recombinant human TSH (rhTSH) stimulation was used as a substitute for thyroxine withdrawal, sensitivity remained high (0.925 +/- 0.018) while specificity decreased to 0.880 +/- 0.013. In all analyses, specificity of Tg would decrease when unspecified activity in the thyroid region at scintigraphy was considered benign, whereas sensitivity decreased when such activity was considered malignant. This study confirms that the best accuracy of Tg-guided follow-up in patients treated for differentiated thyroid carcinoma is obtained if treatment includes remnant ablation, and Tg testing is performed while off thyroxine.

Chronic thyrotropin-suppressive therapy with levothyroxine and short-term overt hypothyroidism after thyroxine withdrawal are associated with undesirable cardiovascular effects in patients with differentiated thyroid carcinoma.

To evaluate cardiovascular functionality in patients with thyroid cancer, we have performed echocardiography and ambulatory blood pressure monitoring in 19 women with differentiated thyroid carcinoma during thyroxine withdrawal, at three time points: the last day on TSH-suppressive thyroxine doses (subclinical or mild hyperthyroidism), 4-7 days after withdrawal (normal free thyroxine (FT4) and free triiodothyronine (FT3) levels), and before 131I whole body scanning (overt hypothyroidism). Twenty-one healthy euthyroid women served as controls. When compared with the values at visit 2, when patients had normal serum FT4 and FT3 levels, night-time systolic and mean blood pressure were increased when the patients were mildly hyperthyroid, and night-time systolic, diastolic and mean blood pressure were increased during overt hypothyroidism. The proportion of nondippers (absence of nocturnal decline in blood pressure) was markedly increased compared with healthy controls (7%), when patients were hyper- or hypothyroid (58% and 50% respectively), but not when patients had normal FT4 and FT3 levels (12%). No changes were observed in office blood pressure or in daytime ambulatory blood pressure readings. Diastolic function worsened during thyroxine withdrawal (E and A waves (early and late mitral flow) decreased, and the E/A ratio and the isovolumic relaxation time increased), and cardiac output decreased in parallel with the decrease in heart rate and systolic blood flow. In conclusion, the chronic administration of TSH-suppressive doses of thyroxine and the withdrawal of thyroxine frequently used for the management of differentiated thyroid carcinoma, are associated with undesirable cardiovascular effects.

Repercussões da persistência de grandes remanescentes tireoideanos após tireoidectomia bilateral para carcinoma diferenciado de tireóide

Twenty-three patients submitted to thyroidectomy and before ablative therapy and with cervical uptake >10% were compared to 48 patients with uptake <2%. All but 3 patients with large remnants reached TSH levels >30 mIU/l after thyroxin withdrawal. Cervical pain requiring anti-inflammatory treatment after radioiodine was more frequent in patients with larger remnants (34.7% vs. 10.4%). Remnant ablation was successful in 56% of the individuals with uptake >10% and in 93.3% of those with uptake <2%. The sensitivity of diagnostic scanning for pulmonary metastases was similar (71.4% vs. 77.7%). The specificity of stimulated thyroglobulin at a cut-off of 5 ng/ml was 100% for patients with discrete remnants but only 37.5% for the others. We conclude that significant thyroid remnants (cervical uptake >10%) result in a lower efficacy of ablation, cause more local symptoms after radioiodine, and compromise the specificity of thyroglobulin measurements.

Gastric emptying function changes in patients with thyroid cancer after withdrawal of thyroid hormone therapy.

Hypothyroidism is commonly thought to cause decreased gastric emptying but is mostly associated with autoimmune disease. In the present study the gastric emptying function of thyroid cancer patients with severe hypothyroidism of short duration was evaluated with a radionuclide solid meal gastric emptying study. Twenty-two patients who had undergone surgical operation and (131)I ablation for thyroid cancer participated in solid meal gastric emptying studies before the withdrawal of thyroxine and then again 4 weeks after the withdrawal of thyroxine. Eleven patients had an additional gastric emptying study at 6 weeks after withdrawal of thyroxine. Gastric emptying curves and emptying parameters were calculated. Student's paired t-test was used for statistical analysis of data for all cases between the baseline and at 4 weeks after withdrawal. An additional repeated measure anova with multiple comparisons was performed on data between baseline, 4 weeks and 6 weeks after withdrawal for the other 11 patients. All P values presented are two-tailed and the significance level is 0.05. Hypothyroidism status was confirmed by the marked change of the serum thyroxine and thyroid-stimulating hormone 4 weeks and 6 weeks after withdrawal of the thyroxine replacement (P < 0.001). The gastric half-emptying time and emptying rate changed significantly after short-term severe thyroid hormone deficiency (P < 0.005). However, the length of the lag phase did not have a statistically significant change at 4 weeks or 6 weeks after withdrawal of the thyroxin replacement (P = 0.219 and 0.142). Hypothyroidism following the withdrawal of the thyroxine replacement in thyroid cancer patients preparing for (131)I cancer work-up can significantly prolong gastric half-emptying time and emptying rate.

Three-week thyroxine withdrawal thyroglobulin stimulation screening test to detect low-risk residual/recurrent well-differentiated thyroid carcinoma.

Measurement of serum TSH-stimulated thyroglobulin (Tg) is recognized as a sensitive method for detecting residual/recurrent well-differentiated thyroid carcinoma (WDTC) in patients previously treated by surgery and radioactive iodine (RAI) ablation therapy. WDTC patients who have an undetectable serum Tg on thyroid hormone therapy (THT) in the absence of Tg-antibody interference are considered to be at low risk for residual/recurrent disease. Traditional management has been to withdraw T4 for 4-6 weeks or T3 for 2 weeks to stimulate endogenous TSH. However, this prolonged THT withdrawal induces hypothyroidism and its concomitant morbidity. In the present study, we assess the efficacy of shortening the time of T4 withdrawal to only 3 weeks for detecting residual/recurrent WDTC as a sufficient serum TSH stimulus for obtaining a positive serum Tg result without a routine diagnostic whole body scan (WBS). Additionally, we have evaluated the impact of such a T4 withdrawal interval on quality of life and loss of employment time. A total of 181 patients with WDTC selected for study had previously been treated with a bilateral surgical thyroidectomy followed by RAI ablation therapy (average post-surgery to follow-up interval of 10.8 yr). All of the cohort had an undetectable (< 1 microg/l) serum Tg on THT without Tg-antibody interference. Serum TSH and Tg were measured before and after cessation of T4 therapy for 3 weeks. A serum Tg > or = 2 microg/l was considered positive for residual/recurrent disease. A quality of life questionnaire [Short-Form 36 (SF-36)] was administered before withdrawal, at peak TSH and after resumption of therapy. From the completed SF-36 questionnaires, the overall degree of functional impairment was not severe and did not result in loss of employment time. Moreover, this protocol identified three possible responses to the 3-week T4 withdrawal interval as follows: a) serum Tg undetectable with TSH > or = 25 mIU/l (approximately 75% of total cohort); b) serum Tg > or = 2 microg/l (approximately 10% of total cohort) which will require further investigation and treatment for residual/recurrent disease; c) undetectable serum Tg with inadequate TSH rise (approximately 15% of total cohort), which will require TSH stimulation by either longer T4 withdrawal or recombinant human TSH to exclude residual disease. We conclude that a stimulated serum Tg test performed 3 weeks after T4 withdrawal is a simple and cost-effective first-line screening test with minimal morbidity which is sufficient to evaluate low-risk WDTC patients for recurrent/residual carcinoma.

Recombinant human thyrotropin (rhTSH) in the follow-up and treatment of patients with thyroid cancer.

The follow-up of thyroid cancer is based on the detection of residual and recurrent thyroid carcinoma. This is traditionally done by means of measurements of serum thyroglobulin (Tg) combined with various imaging techniques (131I-whole body scan, ultrasound and other modalities). Tg serum levels and the uptake of 131I on a whole body scan (WBS) depend on TSH stimulation, which in thyroidectomized patients can be obtained either by withdrawal of thyroid hormone treatment (thyroxine) or by administration of exogenous TSH. At present exogenous human TSH is obtained by means of recombinant DNA technology, (recombinant human TSH (rhTSH), Thyrogen). Even if the administration of rhTSH and withdrawal of thyroid hormone are not completely equivalent, the use of rhTSH has already entered the clinical routine (rhTSH Tg test and rhTSH WBS) because with rhTSH the morbidity and discomfort associated with the withdrawal of thyroid hormone can be avoided. At a recent International Consensus Conference on the follow-up of differentiated thyroid carcinoma it was proposed to carry out only Tg measurement after rhTSH stimulation; moreover, it was stated that 131I whole body scan has to be discouraged in patients submitted to radical surgery and radioiodine ablation with no clinical evidence of residual tumor and with undetectable levels of Tg during hormonal suppression of TSH. Similar strategies in this respect tend to eliminate the 131I WBS and propose only the rhTSH Tg test combined with head and neck ultrasound (US). This is still a matter of debate, also because it is not valid for all risk groups and not all patients undergo the same clinical management (radical surgery or not, thyroid ablation with 131I or not). However, the availability of rhTSH will definitely change the management of papillary and follicular thyroid carcinoma, also with regard to iodine treatment. In fact, rhTSH can be used during radioiodine treatment to enhance the 131I uptake by the cancer cells in particular groups of patients. Patients who could benefit from this approach can be divided into three subgroups: 1) patients in whom thyroxine withdrawal may be dangerous because of the effects of long-term TSH stimulation on the tumor mass (brain metastases, vertebral metastases, presence of neurological signs, heart diseases); 2) patients affected by tumors with marked biological aggressiveness and a low iodine uptake (variants of follicular carcinoma, insular carcinoma, tall and columnar cell variants of papillary thyroid carcinoma, Hürthle cell carcinoma); 3) patients with hypothalamic-pituitary alterations. The potential efficiency of rhTSH in radiometabolic treatment is an important issue that has been studied in a limited number of patients, but is worthy of further investigations in large perspective. A recent clinical prospective trial has been proposed by the Thyroid Cancer Study Group of the Istituto Nazionale Tumori and is now ongoing.

Recombinant TSH-Stimulated, Radioguided Differentiated Thyroid Carcinoma Surgery

A novel approach to locating and surgically resecting occult metastatic foci in a 25-year-old female with a history of total thyroidectomy for differentiated thyroid carcinoma was attempted. Two iodine-131 (131I) body scans were performed: one after the patient underwent a 2-3 week thyroxine withdrawal, and another the following week utilizing recombinant TSH-stimulation. Then the patient was treated with 151 mCi of 131I, and 2 weeks later, without further hormonal manipulation, she had radioguided surgery. The two diagnostic 131I body scans were negative, but the post-therapy scan was positive. Two weeks later after pre-operative skin marking, radioguided surgery localized metastatic foci in the central compartment neck just dorsal to the suprasternal notch. No other foci were identified with the probe at surgery. At pathology, 2 of the 12 nodes were positive, as well as a 1 mm metastatic focus in the fat. Provocative imaging protocols, aggressive radioiodine therapy, and the novel use of radioguided surgery to attempt a cure in an 131I image-negative metastatic thyroid carcinoma patient was performed. No other cases using these combined diagnostic and therapeutic efforts have been reported in the literature.

Thyroid Carcinoma

Purpose Reports state that scan results for as many as 25% of patients with differentiated thyroid carcinoma will convert to iodine-131 (I-131) negative over time with positive thyroglobulin levels. Tl-201, positron emission tomography (PET), and sestamibi or tetrofosmin have all helped to identify I-131–negative thyroid carcinomas. The authors have identified a case of reversal of I-131 findings from negative to positive after short-term thyroxine withdrawal combined with treatment with recombinant human thyroid-stimulating hormone (rhTSH). Materials and Methods The authors obtained multiple I-131 whole-body scans with 4-week thyroid hormone withdrawal, post–I-131 therapy scans, nonthyroid withdrawal Tl-201 chloride whole-body tumor images, and finally combined 2.5-week thyroid hormone withdrawal and rhTSH-stimulation I-131 whole-body scans before and after therapy. Results The authors examined one patient during a period of 9 years whose I-131 whole-body scan results were at first positive and then became negative. After a combination of rhTSH stimulation and thyroid hormone withdrawal, the results changed again to I-131 positive. Conclusions This is the first known case in which I-131 findings changed from negative to positive. A combination of rhTSH stimulation and nearly adequate withdrawal may help convert more I-131–negative whole-body scans to positive.