Short-term overt hypothyroidism induces sympathovagal imbalance in thyroidectomized differentiated thyroid carcinoma patients.

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.

Autonomic nervous system function in chronic exogenous subclinical thyrotoxicosis and the effect of restoring euthyroidism.

CONTEXT: Knowledge on the relationship between the autonomic nervous system and subclinical hyperthyroidism is mainly based upon cross-sectional studies in heterogeneous patient populations, and the effect of restoration to euthyroidism in subclinical hyperthyroidism has not been studied. OBJECTIVE: We investigated the long-term effects of exogenous subclinical hyperthyroidism on the autonomic nervous system and the potential effects of restoration of euthyroidism. DESIGN: This was a prospective single-blinded, placebo-controlled, randomized trial. SETTING: The study was performed at a university hospital. PATIENTS: A total of 25 patients who were on more than 10-yr TSH suppressive therapy after thyroidectomy was examined. INTERVENTION: Patients were studied at baseline and subsequently randomized to a 6-month thyroid hormone substitution regimen to obtain either euthyroidism or maintenance of the subclinical hyperthyroid state. MAIN OUTCOME MEASURES: Urinary excretion of catecholamines and heart rate variability were measured. Baseline data of the subclinical hyperthyroidism patients were compared with data obtained in patients with hyperthyroidism and controls. RESULTS: Urinary excretion of norepinephrine and vanillylmandelic acid was higher in the subclinical hyperthyroidism patients compared with controls and lower compared with patients with overt hyperthyroidism. Heart rate variability was lower in patients with hyperthyroidism, intermediate in subclinical hyperthyroidism patients, and highest in the healthy controls. No differences were observed after restoration of euthyroidism. CONCLUSIONS: Long-term exogenous subclinical hyperthyroidism has effects on the autonomic nervous system measured by heart rate variability and urinary catecholamine excretion. No differences were observed after restoration to euthyroidism. This may indicate the occurrence of irreversible changes or adaptation during long-term exposure to excess thyroid hormone that is not remedied by 6-month euthyroidism.

Quality of life in cured patients with differentiated thyroid carcinoma.

OBJECTIVE: This study was performed to evaluate the impact of cured differentiated thyroid carcinoma (DTC) on quality of life. Previous studies on quality of life in patients with DTC were hampered by small patient numbers or limited quality-of-life parameters or were uncontrolled. DESIGN: This was a cross-sectional case-control study. METHOD: We assessed quality of life in 153 cured DTC patients with a median duration of cure of 6.34 yr (range 0.3-41.8) and studied the contribution of disease-specific, biochemical, and social variables, focusing on the degree of TSH suppression. Four validated health-related questionnaires were used (Short Form-36, Multidimensional Fatigue Index-20, Hospital Anxiety and Depression Scale, and Somatoform Disorder Questionnaire), including multiple aspects of physical, psychological, and social functioning. Patients were compared with 113 controls selected by patients themselves (control group I) and 336 pooled age- and gender-matched controls from other Leiden quality-of-life studies (control group II). RESULTS: Patients had significantly decreased quality of life in 11 of 16 subscales when compared with control group I. In comparison with control group II, decreased scores in 13 of 16 items were observed. An important independent predictor for quality of life was duration of cure. Quality-of-life parameters were not influenced by serum TSH levels both measured at the time of quality-of-life assessment and measured over time since initial therapy. CONCLUSIONS: Patients cured for DTC have impaired quality of life, independently of TSH level. Quality-of-life parameters were inversely affected by duration of cure and consequently may be restored after prolonged follow-up.

Induction of stimulating thyrotropin receptor antibodies after radioiodine therapy for toxic multinodular goitre and Graves' disease measured with a novel bioassay.

BACKGROUND: Radioactive iodine therapy (RaI) in toxic multinodular goitre (TMNG) has been associated with the occurrence of Graves'-like hyperthyroidism. It has been postulated that pre-existing autoimmunity may contribute to this phenomenon. OBJECTIVE: To study whether RaI induces thyrotropin receptor stimulating antibodies (TSAbs) in the short term in TMNG and whether pre-existing autoimmunity is relevant. PATIENTS: Thirty-one patients with relapsing Graves' disease and 17 patients with TMNG, all eligible for RaI. METHODS: Before and 6 weeks after RaI, sera were collected and analysed for the presence of thyroglobulin (Tg), thyroid peroxidase antibodies (TPO-Abs) and thyrotropin receptor binding antibodies (TBIIs). TSAbs were analysed with a novel high-sensitive luciferase-based bioassay based on the JP-26-26 cell line, which constitutively expresses the TSH receptor. RESULTS: In Graves' disease, RaI did not induce or increase the levels and proportion of patients with measurable levels of any of the antibodies measured, despite a significant increase in Tg. In contrast, in TMNG, RaI induced TBIIs in three TMNG patients, which was accompanied by measurable TSAbs on one occasion. CONCLUSIONS: We conclude from the present study that induction of TBIIs and TSAbs may occur shortly after RaI in TMNG and that pre-existing autoimmunity may not be a requirement for the induction of TBIIs, as evidenced by the lack of effect of RaI on TBIIs in Graves' disease.

Human metapneumovirus in adults.

Human metapneumovirus (HMPV) is a relative newly described virus. It was first isolated in 2001 and currently appears to be one of the most significant and common human viral infections. Retrospective serologic studies demonstrated the presence of HMPV antibodies in humans more than 50 years earlier. Although the virus was primarily known as causative agent of respiratory tract infections in children, HMPV is an important cause of respiratory infections in adults as well. Almost all children are infected by HMPV below the age of five; the repeated infections throughout life indicate transient immunity. HMPV infections usually are mild and self-limiting, but in the frail elderly and the immunocompromised patients, the clinical course can be complicated. Since culturing the virus is relatively difficult, diagnosis is mostly based on a nucleic acid amplification test, such as reverse transcriptase polymerase chain reaction. To date, no vaccine is available and treatment is supportive. However, ongoing research shows encouraging results. The aim of this paper is to review the current literature concerning HMPV infections in adults, and discuss recent development in treatment and vaccination.

Added value of use of a purified protein derivative-based enzyme-linked immunosorbent spot assay for patients with Mycobacterium bovis BCG infection after intravesical BCG instillations.

In this case series, we describe four cases in which the use of gamma interferon release assays with purified protein derivative (PPD) as a stimulating antigen was able to demonstrate PPD-specific immune activation. This may help to improve the adequate diagnosis of (systemic) Mycobacterium bovis BCG infections after intravesical BCG instillations for bladder carcinoma.

The type 2 deiodinase Thr92Ala polymorphism is associated with increased bone turnover and decreased femoral neck bone mineral density.

The role of type 2 deiodinase (D2) in the human skeleton remains unclear. The D2 polymorphism Thr92Ala has been associated with lower enzymatic activity, which could result in lower local triiodothyronine (T(3)) availability in bone. We therefore hypothesized that the D2 Thr92Ala polymorphism may influence bone mineral density (BMD) and bone turnover. We studied 154 patients (29 men, 125 women: 79 estrogen-replete, 46 estrogen-deficient) with cured differentiated thyroid carcinoma. BMD and bone turnover markers [bone-specific alkaline phosphatase (BAP), cross-linking terminal C-telopeptide of type I collagen (CTX), procollagen type 1 amino-terminal propeptide (P1NP), and cross-linked N-telopeptide of type I collagen (NTX)] were measured. Effects of the D2 Thr92Ala polymorphism on BMD and bone turnover markers were assessed by a linear regression model, with age, gender, estrogen state, body mass index (BMI), serum calcium, 25-hydroxyvitamin D, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), and free triiodothyroxine (T(4)) as covariables. Sixty patients were wild type (Thr/Thr), 66 were heterozygous (Thr/Ala), and 28 were homozygous (Ala/Ala) for the D2 polymorphism. There were no significant differences in any covariables between the three genotypes. Subjects carrying the D2 Thr92Ala polymorphism had consistently lower femoral neck and total hip densities than wild-type subjects (p = .028), and this was accompanied by significantly higher serum P1NP and CTX and urinary NTX/creatinine levels. We conclude that in patients with cured differentiated thyroid carcinoma, the D2 Thr92Ala polymorphism is associated with a decreased femoral neck BMD and higher bone turnover independent of serum thyroid hormone levels, which points to a potential functional role for D2 in bone.

Type 2 iodothyronine deiodinase in skeletal muscle: effects of hypothyroidism and fasting.

CONTEXT: The iodothyronine deiodinases D1, D2, and D3 enable tissue-specific adaptation of thyroid hormone levels in response to various conditions, such as hypothyroidism or fasting. The possible expression of D2 mRNA in skeletal muscle is intriguing because this enzyme could play a role in systemic as well as local T3 production. OBJECTIVE: We determined D2 activity and D2 mRNA expression in human skeletal muscle biopsies under control conditions and during hypothyroidism, fasting, and hyperinsulinemia. DESIGN: This was a prospective study. SETTING: The study was conducted at a university hospital. PATIENTS: We studied 11 thyroidectomized patients with differentiated thyroid carcinoma (DTC) on and after 4 wk off T4( replacement and six healthy lean subjects in the fasting state and during hyperinsulinemia after both 14 and 62 h of fasting. MEAN OUTCOME MEASURES: D2 activity and D2 mRNA levels were measured in skeletal muscle samples. RESULTS: No differences were observed in muscle D2 mRNA levels in DTC patients on and off T4 replacement therapy. In healthy subjects, muscle D2 mRNA levels were lower after 62 h compared to 14 h of fasting. Insulin increased mRNA expression after 62 h, but not after 14 h of fasting. Skeletal muscle D2 activities were very low and not influenced by hypothyroidism and fasting. CONCLUSION: Human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism. The lack of a clear effect of D2 mRNA modulation on the observed low D2 activities questions the physiological relevance of D2 activity in human skeletal muscle.

Physiological thyroid hormone levels regulate numerous skeletal muscle transcripts.

CONTEXT: Skeletal muscle is an important target tissue for thyroid hormone (TH). It is currently unknown which genes are regulated by physiological TH levels. OBJECTIVE: We examined the effects of l-thyroxine on human skeletal muscle transcriptome. DESIGN: Microarray analysis of transcript levels was performed using skeletal muscle biopsies from patients under euthyroid and hypothyroid conditions. SETTING: The study was conducted in a university hospital laboratory. PATIENTS: We studied skeletal muscle obtained from 10 thyroidectomized patients with differentiated thyroid carcinoma on and after 4 wk off L-thyroxine replacement. MEAN OUTCOME MEASURES: Gene expression changes were measured using microarrays. Results were analyzed using dedicated statistical methods. RESULTS: We detected 607 differentially expressed genes on L-thyroxine treatment, of which approximately 60% were positively and approximately 40% were negatively regulated. Representative genes were validated by quantitative PCR. Genes involved in energy and fuel metabolism were overrepresented among the up-regulated genes, of which a large number were newly associated with thyroid state. L-thyroxine therapy induced a large down-regulation of the primary transcripts of the noncoding microRNA pair miR-206/miR-133b. CONCLUSION: We demonstrated that physiological levels of TH regulate a myriad of genes in human skeletal muscle. The identification of novel putatively TH-responsive genes may provide the molecular basis of clinical effects in subjects with different TH status. The observation that TH regulates microRNAs reveals a new layer of complexity by which TH influences cellular processes.

Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma.

OBJECTIVE: Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. DESIGN: Open, single center, single arm 26-week prospective phase II study with open-ended extension. METHODS: We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. RESULTS: At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47-68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. CONCLUSIONS: Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake.

Thyroid hormone independent associations between serum TSH levels and indicators of bone turnover in cured patients with differentiated thyroid carcinoma.

OBJECTIVE: It has been proposed that TSH has thyroid hormone-independent effects on bone mineral density (BMD) and bone metabolism. This concept is still controversial and has not been studied in human subjects in detail. We addressed this question by studying relationships between serum TSH concentration and indicators of bone turnover, after controlling for triiodothyronine (T(3)), free thyroxine (FT(4)), and non-thyroid factors relevant to BMD and bone metabolism. We also studied the contribution of the TSH receptor (TSHR)-Asp727Glu polymorphism to these relationships. DESIGN: We performed a cross-sectional study with 148 patients, who had been thyroidectomized for differentiated thyroid carcinoma. METHODS: We measured BMD of the femoral neck and lumbar spine. FT(4), T(3), TSH, bone-specific alkaline phosphatase, procollagen type 1 aminoterminal propeptide levels, C-cross-linking terminal telopeptide of type I collagen, and urinary N-telopeptide of collagen cross-links were measured. Genotypes of the TSHR-Asp727Glu polymorphism were determined by Taqman assay. RESULTS: We found a significant, inverse correlation between serum TSH levels and indicators of bone turnover, which was independent of serum FT(4) and T(3) levels as well as other parameters influencing bone metabolism. We found that carriers of the TSHR-Asp727Glu polymorphism had an 8.1% higher femoral neck BMD, which was, however, no longer significant after adjusting for body mass index. CONCLUSION: We conclude that in this group of patients, serum TSH was related to indicators of bone remodeling independently of thyroid hormone levels. This may point to a functional role of the TSHR in bone in humans. Further research into this mechanism needs to be performed.

Rituximab in relapsing Graves' disease, a phase II study.

OBJECTIVE: Conventional therapies for Graves' disease, consisting of medical therapy or radioiodine are unsatisfactory, because of limited efficacy and adverse events. Interventions aimed at the underlying autoimmune pathogenesis of Graves' disease may be worthwhile to explore. We therefore performed a prospective, 26-week phase II study with open-ended observational extension to assess the efficacy of rituximab in patients with recurrent Graves' disease. DESIGN: We performed a prospective, 26-week phase II study with open-ended observations. METHODS: Thirteen patients with relapsing Graves' disease (9 females and 4 males, age 39.5+/-9.5 years) received 2 dosages of rituximab 1000 mg i.v. with a 2-week interval. Before administration and on several periods after the administration of TSH, free thyroxine (FT(4)), thyrotropin binding inhibitory immunoglobulins (TBII) and the proportion of CD19 and MS4A1 positive peripheral blood mononuclear cells were measured. RESULTS: The proportion of MS4A1 positive lymphocytes decreased in all patients from 5.8% at baseline to 1.4% at 26 weeks (P=0.007). Four patients with high initial FT(4) levels did not respond to treatment. All remaining patients had a decrease in FT(4) levels at 26 weeks (P=0.001) and an increase in TSH levels (P=0.011). TBII decreased in all remaining patients (P=0.003). At a follow-up time of 14-27 months, nine of these patients were still euthyroid with normal FT(4) (P<0.001) and TSH levels (P=0.008). CONCLUSIONS: The present study results suggest a beneficial role of rituximab in mild relapsing Graves' disease. A subsequent randomized controlled trial with rituximab is recommended.

Serum thyroglobulin concentrations predict disease-free remission and death in differentiated thyroid carcinoma.

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.