Search

Objective: Head and neck paragangliomas (HNPGL) are associated with mutations in genes encoding subunits of succinate dehydrogenase (SDH). The aim of this study was to evaluate SDH mutations, family history and phenotypes of patients with HNPGL in the Netherlands., Design: We evaluated the clinical data and the mutation status of 236 patients referred between 1950 and 2009 to Leiden University Medical Center., Results: The large majority of the patients carried mutations in SDHD (83%), and the p.Asp92Tyr Dutch founder mutation in SDHD alone accounted for 72% of all patients with HNPGL. A mutation in SDHAF2 was found in 4%, mutations in SDHB in 3% and a mutation in SDHC was identified in a single patient (0·4%). Over 80% of patients presented with positive family history, of whom 99·5% carried a mutation in an SDH gene. SDH mutations were also found in 56% of isolated patients, chiefly in SDHD (46%), but also in SDHB (8%) and SDHC (2%). The clinical parameters of these different subgroups are discussed: including the age at diagnosis, associated pheochromocytomas, tumour multifocality and malignancy rate., Conclusion: The majority of Dutch patients with HNPGL present with a positive family history, in contrast to other European countries. The clinical characteristics of patients with HNPGL are chiefly determined by founder mutations in SDHD, the major causative gene in both familial and isolated patients with HNPGL. The high frequency of founder mutations in SDHD suggests a higher absolute prevalence of paraganglioma syndrome in the Netherlands., (© 2011 Blackwell Publishing Ltd.)

Context: The majority of patients with head and neck paragangliomas (HNPGL) have biochemically silent tumours. Chromogranin A (CgA) is a tumour marker for neuroendocrine tumours., Objective: To assess the role of CgA as a tumour marker in patients with hereditary HNPGL., Patients and Methods: We included 95 consecutive patients with hereditary HNPGL for screening of plasma CgA levels and catecholamine excess by measurement of 24-h urinary excretion of (nor)metanephrine, (nor)adrenaline, VMA, dopamine and 3-methoxytyramine. In all patients with catecholamine excess, abdominal/intrathoracic paragangliomas were excluded by (123) I-MIBG scintigraphy, MRI and/or CT., Results: Plasma CgA levels were increased in only 15 of 95 patients (16%). Thirty-three of the 95 patients (35%) had increased urinary excretion rates of catecholamines. Six of these 33 patients (18%) had increased plasma CgA levels. Nine of the 62 patients (15%) with a biochemically silent tumour, i.e. no increased urinary excretion of catecholamines or their metabolites, had increased CgA levels. Increased plasma CgA levels were positively correlated with urinary excretion rates of noradrenaline (r = 0·68, P = 0·005) and normetanephrine (r = 0·68, P = 0·005). There was a positive correlation between maximal HNPGL diameter and plasma CgA levels in the 57 patients with a single HNPGL (r = 0·57, P = 0·001)., Conclusions: Plasma CgA levels are increased in only a small portion of patients with hereditary HNPGL and have limited additional value to the combination of radiological and routine biochemical assessment of patients with HNPGL. Increased plasma CgA levels are associated with increased noradrenergic activity and tumour size in patients with a single HNPGL., (© 2011 Blackwell Publishing Ltd.)

Context: In the management of patients with medullary thyroid carcinoma (MTC), calcitonin doubling time (dt) has gained interest as an independent predictor of recurrence and survival., Objective: To perform a structured meta-analysis of the diagnostic value of calcitonin dt, carcinoembryonic antigen (CEA) dt and the combination and to define dt strata with the highest predictive power. Design The study was a meta-analysis using individual data., Methods: Ten studies containing data on the post-operative kinetics of tumour marker(s) and (recurrence free) survival were included., Results: Calcitonin- and CEA-dt are significant indicators for survival (hazard ratios (HR) 21.52 respectively infinite for dt 0-1 year compared to dt >1 year) and recurrence (HR 5.33 respectively 6.80 for dt 0-1 year compared to dt >1 year). The highest predictive power was found for the dt classification 0-1 year vs. >1 year. CEA dt has a higher predictive value than calcitonin dt in the subgroup of patients for which both parameters were available., Conclusion: The dts of both calcitonin and CEA are strong prognostic indicators for MTC recurrence and death. CEA dt has a higher predictive value than calcitonin dt and therefore measuring both tumour markers is essential for proper risk stratification.

Context: Thyroid hormone impacts on the cardiovascular system. (Subclinical) hyperthyroidism results in sympathovagal imbalance due to decreased vagal tone. However, conflicting data have been reported on the effects of hypothyroidism on the activity of the autonomic nervous system (ANS). In hypothyroidism, both increased and decreased sympathetic activity and increased vagal tone have been found., Objective: To study the effects of acute short-term overt hypothyroidism and thyroxine replacement therapy on the ANS by measuring urinary excretion of catecholamines and heart rate variability (HRV)., Design: Prospective study., Setting: University hospital., Patients: We studied 11 patients, previously treated with thyroidectomy for differentiated thyroid carcinoma, during hypothyroidism caused by cessation of thyroxine substitution for 4 weeks and during thyroxine replacement therapy, and 21 matched healthy controls., Main Outcome Measures: The activity of the ANS was assessed by measuring urinary excretion of catecholamines and HRV at rest and during a challenge of the ANS by a mental stress test., Results: Urinary dopamine excretion was significantly lower during hypothyroidism. Although in the patients total variability was unchanged, HRV analysis showed a significantly lower low frequency/high frequency ratio, indicating sympathovagal imbalance with sympathetic withdrawal. The mental stress test in the patients resulted in a significant increase in heart rate to the extent of 16-18%. This response was not different between the hypothyroid state and during thyroxine replacement therapy suggesting that cardiovascular reflexes in these patients remain intact., Conclusion: Acute short-term overt hypothyroidism results in sympathovagal imbalance with sympathetic withdrawal, with preservation of the cardiovascular reflexes to (mental) stress.

Formerly used concepts for phaeochromocytomas and paragangliomas have been challenged by recent discoveries that at least 24% of tumours are familial and thereby often multiple in various locations throughout the body. Furthermore, tumours are often malignant and perhaps more aggressive if associated with SDHB gene mutations. Some paragangliomas are clinically silent and may present only with dopamine hypersecretion. In the current era where CT and MRI are more commonly used, tumours are more often found as incidentalomas and MRI may be less specific for phaeochromocytoma and paraganglioma than previously thought. Because of unique tumour characteristics (e.g. the presence of cell membrane and intracellular vesicular norepinephrine transporters) these tumours were 'born' to be imaged by means of specific functional imaging approaches. Moreover, additional recent discoveries related to apoptosis, hypoxia, acidosis, anaerobic glycolysis and angiogenesis, often disturbed in tumour cells, open new options and challenges to specifically image phaeochromocytomas and paragangliomas and possibly link those results to their pathophysiology, genotypic alterations and metastatic potential. Functional imaging, especially represented by positron emission tomography (PET), offers an excellent approach by which tumour-specific processes can be detected, evaluated and seen in the context of tumour-specific behaviour and its genetic signature. In this review, we address the recent developments in new functional imaging modalities for phaeochromocytoma and paraganglioma and provide the reader with suggested imaging approaches in various phaeochromocytomas and paragangliomas of sympathetic origin. Current imaging algorithms of head and neck parasympathetic paragangliomas are not discussed. Finally, this review outlines some future perspectives of functional imaging of these tumours.

Objective: Adults patients previously treated for craniopharyngioma have increased general and physical fatigue compared to healthy controls. This could be related to disturbed sleep patterns. The aim of this study was to compare sleepiness and sleep patterns in those patients to healthy controls and to patients treated for nonfunctioning macroadenomas (NFMA) of the pituitary., Design: Case-control study., Patients and Methods: Sleepiness and sleep patterns were assessed in 27 adult patients [14 men, 8 patients diagnosed at childhood age, mean age of 53 years (range 27-80 year)] after long-term follow-up and compared to 50 healthy controls and 38 age-, gender- and BMI-matched patients with NFMA. We used two validated questionnaires for sleep parameters (Epworth sleepiness score and Münchener Chronotype Questionnaire)., Results: Sleep patterns (onset, sleep timing, duration and rise time) were not statistically different between the three groups. However, daytime sleepiness scores were increased in patients treated for craniopharyngioma compared to healthy controls, but not different from patients with NFMA. Thirty-three percent of patients with craniopharyngiomas had ESS scores above 10 compared to 8% of healthy controls (P = 0.005), indicating severe daytime hypersomnolence. Neither type of surgery, previous radiotherapy, or age at diagnosis influenced the sleepiness scores in patients with craniopharyngioma., Conclusion: Patients treated for craniopharyngioma or NFMA have increased daytime somnolence despite normal sleep patterns, compared to healthy subjects. The results indicate that increased daytime somnolence is a general consequence of large tumours, and/or their treatment, in the hypothalamic/pituitary region, rather than a specific feature of craniopharyngiomas per se.

Objective: Quality of life (QoL) is impaired in patients treated for pituitary adenomas. However, differences in age and gender distributions hamper a proper comparison of QoL. Therefore, we compared age- and gender-specific standard deviations (SD) scores (Z-scores) of QoL parameters in patients treated for pituitary adenomas., Patients and Methods: We determined Z-scores for health-related questionnaires [the Hospital Anxiety and Depression Scale (HADS), Multidimensional Fatigue Inventory (MFI)-20, Nottingham Health Profile (NHP), and Short Form Health Survey (SF-36)] in patients during long-term follow-up (13 +/- 8 years) after treatment for pituitary adenomas. Z-scores were calculated by comparing the data for 403 patients with acromegaly (n = 118), Cushing's disease (CD; n = 58), prolactinoma (n = 128), and nonfunctioning macroadenoma (n = 99) with a control population (n = 440) for each subscale of the questionnaires and for total QoL score., Results: All subscales of the questionnaires and the total QoL score were negatively affected in patients compared to controls. Comparing the Z-scores, patients treated for acromegaly reported more impairment in physical ability and functioning and more bodily pain compared to patients treated for nonfunctioning macroadenoma and those treated for prolactinoma. Patients with CD reported impairment in physical functioning compared to patients treated for nonfunctioning macroadenoma. Linear regression analysis, with correction for age and gender, confirmed these findings. Additionally, CD was associated with increased anxiety. Hypopituitarism negatively influenced multiple aspects of QoL., Conclusion: QoL is impaired in patients during long-term follow-up after treatment of pituitary adenomas. Patients with pituitary adenomas should be informed of these persistent adverse effects of their disease on QoL to prevent inappropriate expectations with respect to the long-term results of treatment.

Objective: Cross-sectional studies have shown impaired quality of life (QoL) in patients in biochemical control of acromegaly. The aim of this study was to assess longitudinal changes in QoL in a homogenous cohort of patients with sustained biochemical control of acromegaly., Design: Prospective follow-up study., Patients and Methods: QoL was assessed using four health-related QoL questionnaires (HADS, Hospital Anxiety and Depression Scale; MFI-20, Multidimensional Fatigue Index; NHP, Nottingham Health Profile; and SF-36, Short Form-36) and one disease-specific acromegaly quality of life (ACRO-QOL) questionnaire in 82 patients (43 men) with strict biochemical control of acromegaly, aged 56 years (range 29-84 years) at baseline and after 4 years of follow-up. The mean duration of controlled disease was 12 years (range 1-26 years)., Results: During follow-up, scores in 5 of 26 QoL subscales significantly worsened: physical and social functioning (SF-36), physical fatigue (MFI-20), and psychological well-being and personal relations (ACRO-QOL). Using linear regression analysis, baseline item scores predicted the follow-up scores, indicating individual stability over time. Previous radiotherapy (n = 27, 33%) negatively influenced several QoL subscales at follow-up: energy, pain and social isolation (NHP), physical fatigue and reduction in activity and motivation (MFI-20), depression and total anxiety and depression scores (HADS) and physical performance (ACRO-QOL)., Conclusion: During 4 years of follow-up in patients with long-term biochemical control of ACRO-QOL is subtly, but progressively impaired. Radiotherapy was the predominant indicator of progressive impairment in QoL.

Objective: To evaluate the effects of pretreatment with the retinoid X receptor (RXR) agonist bexarotene on the efficacy of radioiodine therapy for metastases of differentiated thyroid carcinoma (DTC) with limited uptake of radioiodine (I-131)., Design: An open prospective intervention study., Methods: Eight patients with metastases of DTC, with insufficient uptake of I-131 who showed increased uptake of radioiodine after previous treatment with bexarotene were treated with radioiodine (7400 MBq), preceded by 6 weeks of treatment with bexarotene 300 mg/day. Outcome parameters were serum thyroglobulin (Tg) levels and dimensions of metastases at computed tomography (CT), measured before and 6 months after therapy. Tissues of primary tumours were stained with antibodies against retinoic acid receptor (RAR) and RXR subtypes., Results: Bexarotene pretreatment induced radioiodine uptake in metastases in all eight patients, although uptake was only discernable at single photon emission computed tomography (SPECT) and had incomplete matching with the metastases visualized by CT scanning. Six months after radioiodine therapy, six patients had progressive disease (defined as a > 10% increase in serum Tg and/or a > 25% increase in tumour dimensions), whereas two patients had stable disease. No relationship was observed between retinoid receptor staining pattern at immunohistochemistry and the outcome of therapy., Conclusions: Bexarotene therapy did not result in restoration of susceptibility to radioiodine therapy.

Background: Radiation induces time-dependent loss of anterior pituitary function, attributed to damage of the pituitary gland and hypothalamic centres. The development of growth hormone deficiency (GHD) in irradiated acromegaly patients is not well defined., Objective: Detailed analysis of spontaneous 24-h GH and prolactin (PRL) secretion in relation to other pituitary functions and serum IGF-I concentrations in an attempt to find criteria for GHD in acromegalic patients with a GH response < 3 microg/l during the insulin tolerance test (ITT)., Design: Plasma hormone profiles obtained by 10 min sampling for 24 h in postoperatively irradiated acromegalic patients, compared with patients cured by surgery only and matched healthy controls., Setting/participants: University setting. Fifteen subjects in each group., Outcome Measures: GH and PRL secretory parameters quantified by deconvolution, cluster, cosinor and approximate entropy (ApEn) analyses, IGF-I concentrations., Results: Irradiation attenuated pulsatile secretion of GH and PRL, but total PRL secretion was unchanged. GH and PRL secretory regularity were diminished. Circadian timing remained intact. Pulsatile GH secretion and IGF-I were correlated (R = 0.30, P = 0.04). Criteria of pulsatile GH secretion = 12 microg/l/24 h and ApEn = 0.800 separated 12 of 15 irradiated patients from all others., Conclusion: Irradiated acromegaly patients with a subnormal GH response to ITT have very limited spontaneous GH secretion, with specific attenuation of the size of GH bursts and a highly irregular pattern, but with retained diurnal properties. These patients are thus likely GH-deficient and might benefit from GH replacement.

Objective: Most studies on the diagnostic value of serum thyroglobulin (Tg) concentrations in differentiated thyroid carcinoma (DTC) use fixed cut-off levels in heterogeneous groups of patients with respect to initial therapy and do not provide prognostic data. The objective was to investigate the prognostic values of serum Tg for disease-free remission and death, measured at fixed time-points after initial therapy using receiver operator characteristic (ROC) curve analyses., Design: Single-centre observational study with 366 consecutive patients with DTC, who had all been treated according to the same protocol for initial therapy and follow-up., Methods: Tg concentrations were measured at five fixed time-points after initial surgery. Tg cut-off values with the highest accuracy were calculated with ROC analyses., Results: During the 8.3 +/- 4.6 years of follow-up, 84% of the patients were cured. Pre-ablative Tg levels were an independent prognostic indicator for disease-free remission (Tg cut-off value 27.5 microg/l, positive predictive value 98%). The highest diagnostic accuracies of serum Tg for tumour presence were found during TSH-stimulated Tg measurements, 6 months after initial therapy (Tg cut-off value 10 microg/l; sensitivity 100%, specificity 93%). DTC-related mortality was 14%. TSH-stimulated Tg levels before ablation and 6 months after initial therapy were independent prognostic indicators for death., Conclusion: Optimal institutional Tg cut-off levels for diagnosis and prognosis should be defined using ROC analyses for each condition and time-point. Tg measurements 6 months after initial therapy during TSH stimulation had an excellent diagnostic value. Tg levels are independent prognostic indicators for disease-free remission and death. Using this strategy, high-risk patient groups can be selected based on Tg levels, in addition to conventionally used prognostic indicators.

Objective: The impact of prolonged subclinical hyperthyroidism on glucose and lipid metabolism is unclear. Therefore, we evaluated glucose and lipid metabolism in patients with differentiated thyroid carcinoma (DTC) on TSH suppressive thyroxine therapy as a model for subclinical hyperthyroidism and investigated whether restoration to euthyroidism affects metabolism., Design: We performed a prospective, single-blinded, placebo-controlled, randomised trial of 6 months duration with 2 parallel groups., Patients: Twenty-five subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with l-thyroxine completed the study. l-thyroxine dose was replaced by study medication containing l-thyroxine or l-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group, 13 patients) and euthyroidism (euthyroidism group, 12 patients)., Measurements: We evaluated glucose metabolism by glucose tolerance test and HOMA (IR) and lipid metabolism by lipid profile. In addition, we measured plasma concentrations of glucoregulatory hormones., Results: At baseline, glucose tolerance, HOMA (IR), lipid profile and plasma concentrations of glucoregulatory hormones were within the normal range. No significant differences between the low TSH and euthyroidism group were observed. After 6 months, neither glucose nor lipid metabolism in the low TSH group were different from baseline values., Conclusion: In summary, glucose and lipid metabolism in patients with DTC and long-term subclinical hyperthyroidism in general are not affected. Restoration of euthyroidism in general does not affect glucose and lipid metabolism.

Objective: Lithium has been reported to increase radioactive iodine (RaI) doses in benign thyroid disease and in differentiated thyroid carcinoma (DTC). It is not known whether lithium influences the outcome of RaI therapy in DTC. We therefore studied the clinical effects of RaI without and with lithium carbonate in patients with proven metastatic DTC. Controversy also exists on the mechanism by which lithium increases RaI dose in DTC. We performed an in vitro study specifically aimed at examining the effects of lithium on the sodium iodide symporter (NIS)., Design: In a clinical study, 12 patients were selected with metastases of DTC who had received previous RaI therapy without lithium (control) that had not influenced tumour progression, despite RaI accumulation in metastases. The patients received 1200 mg lithium carbonate/day followed by 6000 MBq RaI. Outcome parameters were RaI uptake, serum thyroglobulin (Tg) levels and radiological dimensions of metastases compared between RaI with lithium and control. In an in vitro study, iodide uptake was studied in the benign rat thyroid cell line FRTL-5, in the polarized non-thyroid MDCK cell line, stably transfected with human sodium iodide symporter (hNIS) to study the effects of lithium on NIS in a non-thyroid background, and the human follicular thyroid carcinoma cell line FTC133-hNIS to study lithium effects in a background of DTC. Lithium chloride (LiCl) was added in concentrations up to 2 mM for 0-48 h. Both steady-state iodide uptake (30 min) and initial rate (2 min) were studied using a specific activity of 100 mCi/mmol I, the latter experiment to determine lithium effects on substrate dependency. Iodide efflux studies were performed as well., Results: Despite an increased uptake of RaI in seven patients, no beneficial effect of RaI with lithium was observed on the clinical course as assessed by serum Tg measurements and radiographically. In the in vitro studies, no effects of LiCl on iodide uptake or efflux were observed., Conclusions: The addition of lithium to RaI did not have any beneficial effects on the clinical course in 12 patients with metastatic DTC. No beneficial effects of lithium on iodide uptake were observed in vitro. Therefore, the clinical value of lithium in DTC remains subject to debate.

Background: TSH receptor antibodies (TBII) in Graves' disease (GD) may be TSH receptor stimulating (TSAb) and blocking (TBAb) antibodies. In commercially available assays however, only total TBII titres can be measured, without discriminating between TSAb and TBAb., Objective: To design a TBII bioassay to detect of TSAb and to correlate TSAb activity with severity of hyperthyroidism in de novo GD patients., Patients: Thirty-five patients with de novo GD and 27 controls., Methods: The JP-26-26 cell line, which constitutively expresses the TSH receptor (TSHR), was stably transfected with a cyclic adenosine monophosphate responsive element--luciferase construct. The clone B1 exhibited a near linear increase in luminescence from 0.2 mU/l to 50 mU/l bovine TSH and was used as a TBII bioassay. TBII, free T4 and TSH were measured in the sera of all patients and controls., Results: In the sera of 35 GD patients, TBII titres did not correlate with serum free T4 concentrations. In contrast, a strong and highly significant correlation was found between TSHR stimulating activity (luminescence) as measured with the TBII bioassay and serum free T4 levels (R = 0.80, P < 0.001). Interestingly, the luminescence/TBII ratio had a wide range at low TBII titres, whereas high TBII titres were associated with a low degree of TSHR activation. The TBII bioassay also detected TBAb in GD patients who spontaneously developed hypothyroidism., Conclusions: The B1-TBII-bioassay as developed in our laboratory has a high sensitivity for the detection of TSAb in GD and predicts the severity of hyperthyroidism in untreated GD patients. In addition, we found that high TBII titres are associated with weak TSHR activation.

Objective: The impact of prolonged subclinical hyperthyroidism on quality of life is unclear. Therefore, we evaluated quality of life in patients with differentiated thyroid carcinoma (DTC) on TSH-suppressive thyroxine therapy as a model for subclinical hyperthyroidism and we investigated whether restoration to euthyroidism affects quality of life., Design: We performed a prospective, single-blinded, placebo-controlled, randomized trial of 6 months' duration with two parallel groups., Patients and Methods: Twenty-four subjects with a history of differentiated thyroid carcinoma with > 10 years TSH-suppressive therapy with L-thyroxine completed the study. L-thyroxine dose was replaced by study medication containing L-thyroxine or L-thyroxine plus placebo. Medication was titrated to establish continuation of TSH suppression (low-TSH group) and euthyroidism (euthyroid group). Both groups consisted of 12 patients. We evaluated quality of life using five validated questionnaires., Results: At baseline, the somatic disorder questionnaire (SDQ) indicated more somatic dysfunction in patients as compared with reference values, whereas the depression score (HADS) revealed a better score than the reference group. All other quality of life parameters were normal. At baseline, no significant differences between the low-TSH and the euthyroidism groups were observed. After 6 months, none of the quality of life parameters in the low-TSH group was different from baseline values. In the euthyroid group, motivation was significantly improved (Multidimensional Fatigue Index-20, P = 0.003), although this parameter did not differ from the reference group at baseline. A probable worsening in role limitations as a result of physical problems (Short Form-36; P = 0.050) was observed. No improvement in the SDQ score was observed., Conclusion: In summary, quality of life in patients with DTC and long-term subclinical hyperthyroidism in general is preserved. Restoration of euthyroidism in general does not affect quality of life.

Introduction: The treatment of craniopharyngiomas is associated with long-term morbidity., Aim of the Study: To assess the long-term functional outcome and mortality rates after treatment for craniopharyngiomas, we audited our data with special focus on cardiovascular, neurological and psychosocial morbidity., Patients and Methods: Between 1965 and 2002, 54 consecutive patients underwent surgery for craniopharyngiomas at the Leiden University Medical Centre (LUMC). Fifteen patients (25%) received additional postoperative radiation therapy. The median follow-up period was 10 years (range 1-37 years)., Results: Long-term cure rate was 82% and long-term recurrence rate 18%. Visual fields/visual acuity stabilized or improved in 74% of cases. The long-term prevalence rate of hypopituitarism was 89%. In addition, long-term cardiovascular, neurological and psychosocial morbidity rates were high: 22% (risk factors 57%), 49% and 47%, respectively. Female sex was an independent predictor of increased cardiovascular, neurological and psychosocial morbidity (odds ratio 3.78, P = 0.031). Ten patients (18%) died during an 828 person-year follow-up. The actuarial patient survival rates 5, 10 and 20 years after the initial operation were 95, 85 and 85%, respectively. The standardized mortality ratio (SMR) was 2.88 [95% confidence interval (CI) 1.35-4.99]., Conclusion: Craniopharyngioma is associated with excessive long-term multisystem morbidity and mortality, especially in female patients, despite a high cure rate. These observations indicate that dedicated long-term follow-up of these patients is required. The purpose of the follow-up should be: first, to look for recurrences and to ensure appropriate endocrine replacement, especially oestrogen replacement in premenopausal females; and second, to achieve intensive control of glucose, lipids, blood pressure and weight, as in any other patient with increased risk for cardiovascular disease.

Objective: 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., Design and Methods: 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., Results: 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., Conclusion: 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.

Objective: As described originally, Nelson's syndrome is characterized by grossly elevated ACTH concentrations, a sellar mass and skin hyperpigmentation emerging in the course of Cushing's disease after bilateral adrenalectomy. No detailed studies have defined whether the mechanisms directing ACTH secretion differ in Nelson's syndrome and untreated Cushing's disease., Patients and Methods: To address this pathophysiological issue, we studied nine patients fulfilling the criteria of Nelson's syndrome receiving glucocorticoid and mineralocorticoid replacement; nine patients with untreated pituitary-dependent Cushing's disease and nine gender- and age-matched controls. ACTH release was appraised by monitoring plasma ACTH concentrations in blood samples collected every 10 min for 24 h. ACTH secretion rates and endogenous decay were quantified by multiparameter deconvolution analysis. The orderliness of the ACTH release process was delineated by the approximate entropy (ApEn) statistic. Diurnal variation in ACTH secretion was appraised by cosinor analysis., Results: Basal ACTH secretion was increased sixfold and pulsatile secretion ninefold in patients with Nelson's syndrome compared with Cushing's disease (P

Background: GH-deficient patients respond to recombinant human GH (rhGH) replacement therapy by increasing bone mineral density (BMD) at a rate of about 1% a year for at least 4 years. Predictive factors for a beneficial effect on bone are a low bone mass at baseline and gender. Whether the beneficial skeletal effects of GH are sustained in the long term remains to be established. It is also not known whether osteoporotic GH-deficient patients may require additional antiresorptive drugs and whether this treatment would be effective concomitantly with GH replacement., Design: We performed a long-term, controlled study in 30 GH-deficient adults: 15 with osteoporosis and 15 control subjects with low bone mass. All patients were treated with rhGH for at least 4 years; thereafter, 3 years of additional alendronate treatment was given to patients with osteoporosis, while controls continued on GH therapy alone. The GH dose was individualized to maintain an IGF-I within the normal reference range for the duration of the study, and was equal between genders., Results: At the end of 4 years of rhGH replacement therapy, a significant increase in mean lumbar spine BMD was observed in both the osteoporosis group (3.6%) and the control group (7.0%), with no significant difference between groups. Males had a larger increase in BMD than females (P = 0.032). After 4 or 5 years of GH treatment patients with persisting osteoporosis received additional alendronate (10 mg/day) for 3 years. Lumbar spine BMD increased by 8.7% after 3 years (P = 0.001) vs 1.5% (P = NS) in the control group continuing on rhGH replacement alone. The alendronate effect was gender independent (P = 0.59). Mean bone area of the lumbar spine did not change in both groups for the duration of the study. Femoral neck BMD increased significantly in the osteoporosis group (3.5%) and was unchanged in the control group. Five osteoporotic GH-deficient patients had a total of 12 vertebral fractures before start of alendronate. Only one of these patients developed two new vertebral fractures within the first year of treatment with alendronate., Conclusion: We observed a significant increase in lumbar spine BMD in the first 4 years of rhGH replacement. The effect of GH on bone was gender dependent, but not BMD dependent. After more than 4 years of GH replacement, BMD seemed to reach a plateau, at least as measured in the 3-4 years thereafter, as no significant increase was present in patients treated with GH alone. By contrast, alendronate rapidly augmented BMD and this effect was maintained for at least 3 years. These increases in BMD were associated with a low incidence of (vertebral) fractures. The long-term use of GH does not preclude a beneficial effect of an additional antiresorptive agent in GH-deficient patients with osteoporosis.

Objective: Most patients with differentiated thyroid carcinoma (DTC) undergo total thyroidectomy followed by routine radioiodide thyroid remnant ablation. Most centres that routinely perform radioiodide ablation prescribe a low-iodide diet (LID) to increase the radioiodide accumulation in thyroid remnants. The efficacy of an LID on thyroid remnant ablation, however, has never been demonstrated convincingly., Design and Methods: In a retrospective study, we studied two groups of DTC patients without distant metastases, who had received either a standard diet or an LID during ablation (LID group, n = 59, and control group, n = 61). Both groups were compared for radioiodide uptake in thyroid remnants during ablation and efficacy parameters of remnant ablation, 6 months after ablation. A subgroup without extrathyroidal tumour growth was analysed separately (stages T1-3, N0)., Results: In the total group, the LID during ablation decreased the 24-h urinary iodide excretion to 26.6 micro g compared with 158.8 micro g in controls whereas radioiodide uptake in thyroid remnants was increased by 65% (P < 0.001). Six months after ablation, patients were investigated after thyroid hormone withdrawal. In the total group, no significant effects of the LID during ablation were observed on thyroglobulin (Tg) or the percentage of patients with persistent neck activity after 185 MBq 131I. However, in the LID group, 65% of patients without Tg antibodies had undergone successful ablation (defined by absent neck activity and Tg < 2 micro g/l) compared with 48% in the control group (P < 0.001). In the subgroup (T1-3, N0), 8% of the patients who had undergone the LID had Tg >/= 2 micro g/l vs. 32% in the control group (P = 0.012), whereas successful ablation was achieved in 71% of patients without Tg antibodies in the LID vs. 45% in the control group (P < 0.001)., Conclusion: We conclude from this study that a low-iodide diet during thyroid remnant ablation improves the efficacy of this treatment.

Introduction: Depot preparations of long-acting somatostatin analogues are being used increasingly in the treatment of GH hypersecretion in patients with acromegaly, either as primary treatment or as secondary treatment following incomplete surgery. In 60% of these patients, Sandostatin long-acting release (LAR), the depot preparation of octreotide, achieves effective suppression of serum GH (< 5 mU/l) and IGF-I levels. The advice is to administer Sandostatin LAR at 4-week intervals. After injection, serum octreotide shows an initial peak and thereafter maximal values between 14 and 42 days. There have been suggestions that the dose interval of this preparation could be increased, resulting in reduced costs, although this concept has not been confirmed by studies., Aim of the Study: We performed a prospective, cohort study in patients with active acromegaly but with normal serum GH and IGF-I levels during Sandostatin LAR treatment to assess whether the dose interval could be safely increased from 4 to 6 weeks, without significant effect on serum GH concentrations or other biochemical and clinical markers of GH hypersecretion., Patients and Methods: Fourteen patients (seven males) with GH concentrations below 5 mU/l during Sandostatin LAR treatment entered an 8-week withdrawal study following an injection. Subsequently, during an interval study patients received injections at 6-week intervals (t = 0, 8, 14, 20, 26, 32, 38 and 44 weeks). Study parameters (fasting GH, average GH of eight plasma samples, IGF-I, and octreotide concentrations, symptoms score and quality-of-life score) were assessed 2, 4, 6 and 8 weeks following the first injection (withdrawal) and at 26 and 44 weeks (interval study) before the next injection., Results: During the withdrawal study, mean serum GH concentration increased significantly from 1.68 +/- 0.3 at 4 weeks to 2.57 +/- 0.5 mU/l at 6 weeks (P = 0.04, 4 vs. 6 weeks) and to 2.89 +/- 0.4 mU/l at 8 weeks (P < 0.001, 4 vs. 8 weeks). Mean serum GH concentration was below 5 mU/l in all patients at all time points, except for one patient at 8 weeks, and IGF-I levels remained normal in all patients. During withdrawal up to 8 weeks there was no significant change in serum IGF-I concentration, symptoms score or quality-of-life score. Mean serum octreotide decreased significantly from 1610 +/- 355 ng/l at 2 weeks to 1045 +/- 272 ng/l at 6 weeks (P = 0.002, 2 and 4 vs. 6 weeks) and to 559 +/- 147 ng/l at 8 weeks. In the interval study, one patient had mean serum GH above 5 mU/l associated with an increase in symptoms at 26 weeks and she was withdrawn from the study. The remaining 13 patients completed the 6-weekly injection study protocol and in the long term no significant changes in mean serum GH concentration, IGF-I concentration or symptom scores were observed (6 vs. 26 and 44 weeks). All patients had a mean serum GH concentration < 5 mU/l and serum IGF-I remained normal in 11 out of 14 patients at 26 weeks and nine out of 13 patients at 44 weeks. Moreover, the mean octreotide concentrations measured 6 weeks after a Sandostatin LAR injection did not decrease in the long term., Conclusion: On the basis of serum GH concentrations, most patients with serum GH levels < 5 mU/l during Sandostatin LAR treatment using a 4-weekly schedule can be effectively treated with 6-weekly injections. However, during long-term treatment with 6-weekly injections, discordant IGF-I and GH results were observed in 30% of the patients and careful clinical monitoring is therefore required.

Background: Although radioiodine therapy in differentiated thyroid carcinoma without radioiodine accumulation has not been considered harmful, increased thyrotrophin levels during thyroxine withdrawal without the benefit of radiotoxicity as well as the selection of de-differentiated cells may have disadvantageous effects on tumour course., Objective: We therefore analysed retrospectively the effects of radioiodine therapy on the course of serum thyroglobulin levels as a tumour marker in patients with progressive residual or metastatic differentiated thyroid carcinoma, with or without radioiodine accumulation on post-therapeutic whole body scintigraphy., Patients and Methods: Patients who had undergone radioiodine therapies with sufficient pre- and post-therapy thyroglobulin measurements to allow for regression analysis and not preceded or followed by other treatment modalities within a 1-year interval were selected. All patients had undergone total thyroidectomy and ablative therapy. Thirty-nine patients and radioiodine therapies were included (10 males, 29 females, mean age 57 years), and divided into a negative- (n = 17) and a positive post-therapeutic whole body scintigraphy group (n = 22). Pre- and post-therapeutic thyroglobulin course were analysed using non-linear regression, comparing the difference in the thyroglobulin growth coefficient b1 post- and pre-therapy (delta b1: b1(post-therapy)-b1(pre-therapy)). In addition, absolute post- and pre-therapeutic thyroglobulin levels, radiological follow-up and clinical outcome were also analysed., Results: The two groups were comparable with respect to age, sex, tumour stage, histology and prior therapies. Differences between post- and pre-therapeutic b1 values differed significantly in the positive post-therapeutic whole body scintigraphy group (delta b1: -0.65 microg/l-1 years-1, P < 0.001) but not in the negative post-therapeutic whole body scintigraphy group (delta b1: -0.14). Absolute serum thyroglobulin levels and radiological follow-up revealed a favourable response of radioiodine therapy in the positive whole body scintigraphy group but not in the negative group. Delta b1 was related significantly with clinical outcome as revealed by receiver operator curves (ROC): all patients with a positive delta b1 (n = 8) had an unfavourable outcome (progression or death), whereas from the 31 patients with negative delta b1, 61% had an unfavourable outcome., Conclusion: We did not find disadvantageous effects of a single radioiodine therapy on serum thyroglobulin increments in patients with negative post-therapeutic whole body scintigraphy. However, as we did not observe a beneficial effect either, we would not advise the continuation of radioiodine therapy in patients with negative post-therapeutic whole-body scintigraphy, unless a positive response is observed in individual cases.

Dietary carbohydrate content is a major factor determining endocrine and metabolic regulation. The aim of this study was to evaluate the relation between thyroid hormone levels and metabolic parameters during eucaloric carbohydrate deprivation. We measured thyroid hormone levels, resting energy expenditure (by indirect calorimetry) and urinary nitrogen excretion in six healthy males after 11 days of three isocaloric diets containing 15% of energy equivalents as protein and 85%, 44% and 2% as carbohydrates. In contrast to the high and intermediate carbohydrate diets, carbohydrate deprivation decreased plasma T3 values (1.78 +/- 0.09 and 1.71 +/- 0.07 vs. 1.33 +/- 0.05 nmol/l, respectively, P < 0.01), whereas reverse T3, T3 uptake and free T4 levels increased simultaneously compared to the other two diets. TSH values were not different among the three diets. Although dietary carbohydrate content did not influence resting energy expenditure, carbohydrate deprivation increased urinary nitrogen excretion (10.91 +/- 0.67 and 12.79 +/- 1.14 vs. 15.89 +/- 1.10 g/24 h, respectively, P = 0.03). Eucaloric carbohydrate deprivation increases protein catabolism despite decreased plasma T3 levels. Because it has previously been shown that starvation decreases plasma T3 levels, resting energy expenditure and nitrogen excretion, these discordant endocrine and metabolic changes following carbohydrate deprivation indicate that the effects of starvation on endocrine and metabolic regulation are not merely the result of carbohydrate deprivation.