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Objective: Treatment options in Graves' disease (GD) are limited and do not target the underlying autoimmunity, and relapse rates following a course of antithyroid drug (ATD) reach 50%. Previous research has shown promising results for a role of vitamin D in GD. We aimed to investigate whether vitamin D reduces failure to enter and sustain remission in patients with GD treated with ATD. Design: A multicenter, double-blinded, randomized placebo-controlled trial comparing vitamin D 70 mcg once daily (2800 IU) or placebo. The intervention was given first as add-on to ATD treatment, maximally 24 months, and then for 12 months after ATD cessation. Inclusion period was from 2015 to 2017 and study completion by December 2020. Patients included were adults with a first-time diagnosis of GD treated with ATD. Exclusion criteria included pregnancy and glucocorticoid treatment. The primary endpoint was failure to enter and sustain remission defined as relapse of hyperthyroidism within 12 months after ATD cessation, inability to stop ATD within 24 months, or radioiodine treatment or thyroidectomy. Two hundred seventy-eight patients were included in the study, and 4 patients withdrew consent. No adverse effects were found. Results: Participants were aged 44 ± 14 years at enrollment and 79% were female. The risk of failure to enter and sustain remission was 42% [95% confidence interval (CI) 33-50%] in the vitamin D group and 32% [CI 24-40%] in the placebo group corresponding to a relative risk of 1.30 [CI 0.95-1.78]. Conclusions: Vitamin D supplementation did not improve the treatment of GD in patients with normal or insufficient vitamin D status. Thus, supplementation with high-dose vitamin D cannot be recommended for GD. Study registration: ClinicalTrials.gov NCT02384668.

PURPOSE: Risk of cardiovascular disease (CVD) is increased in Graves' disease (GD). CVD is predicted by increased pulse wave velocity (PWV) and blood pressure (BP). GD and these risk factors are all associated with lower levels of vitamin D. We aimed to assess the effect of supplemental vitamin D on PWV and BP in GD.METHODS: In a double-blinded trial, newly diagnosed GD patients were randomized to vitamin D3 70 µg/day (n = 44) or placebo (n = 42) as add-on to anti-thyroid medication. At baseline, 3 and 9 months PWV, BP and wave analysis were performed in office and 24 h setting. Between-group differences in change at 9 months were analyzed using linear mixed modelling. In subanalysis, effect of intervention in regard to baseline vitamin D insufficiency (25(OH)D RESULTS: PWV was unaffected by intervention in main analysis. However in the subanalysis, comparing the response to intervention in the vitamin D insufficient (n = 28) and the vitamin D replete patients, supplemental vitamin D induced a significant decrease in office PWV of 1.2 (95% CI: -2.3; -0.1) m/s compared to placebo. Of notice, baseline PWV was non-significantly higher among the vitamin D insufficient as compared to the replete participants. In response to vitamin D, office central systolic BP (-3.9 (95% CI: -7.5; -0.3) and brachial mean BP (-3.3 (95% CI: -6.5; -0.3) declined whereas 24 h measurements were unaffected.CONCLUSIONS: High-dose vitamin D supplementation did not affect PWV. We observed significant reduction in office but not 24 h BP. Subanalysis showed a clinically relevant PWV reduction among vitamin D insufficient participants, although regression towards the mean might contribute to findings. Further studies on supplemental vitamin D in GD should focus on patients with vitamin D insufficiency.

Background: Reduced muscle strength is an acknowledged symptom of Graves' disease, but the knowledge on severity is sparse. This study aimed to investigate muscle strength, balance, and muscle function in patients with Graves' disease compared to age-and sex-matched healthy controls. Methods: Using a cross-sectional design, 55 patients newly diagnosed with Graves' disease were compared to 55 euthyroid controls, matched on sex, age, and menopausal status. Isometric muscle strength (N) and maximum force production (N/s) were measured across different muscles groups using a dynamometer chair and postural stability (balance) in different positions using a stadiometer. Muscle function was assessed using the Timed-Up-and-Go test and the Repeated Chair Stand test. Results: Patients and controls were well matched. Handgrip maximum muscle strength as well as strength at elbow and knee flexion and extension were significantly impaired in patients compared to controls. Maximum force production was only significantly reduced at elbow flexion. Patients performed the Timed-Up-and-Go and the Repeated Chair Stand test significantly slower than controls, and postural stability was significantly reduced in patients compared to controls in all positions. Free triiodothyronine correlated with reduced muscle strength and postural stability. Conclusions: At the time of diagnosis, Graves' disease is associated with impaired maximum muscle strength, performance, and balance, whereas maximum force production is overall comparable to euthyroid controls.

Introduction and Objective: The excess cardiovascular morbidity and mortality in hyperthyroidism and Graves’ disease (GD) is inadequately understood. We aimed to elucidate whether well-established cardiovascular risk factors such as arterial stiffness in terms of pulse wave velocity (PWV) and blood pressure differ in GD and controls. Methods: This was a cross-sectional study comparing 55 hyperthyroid patients with newly diagnosed GD and 55 euthyroid, population-based controls matched for age, sex and menopausal status. PWV and blood pressure were measured in office (SphygmoCor Xcel) and 24-h ambulatory settings (Arteriograph). Differences between groups were assessed using adjusted linear regression analysis. Results: Compared to controls, GD patients showed higher PWV in the 24-h but not in the office setting with an adjusted 24-h PWV difference of 1.0 (95% CI: 0.6–1.5) m/s. PWV was higher in GD at both day and night, and nightly PWV dipping was lower (–5.5, 95% CI: –10.4 to –0.6%). Furthermore, central and brachial pulse pressure was significantly higher in both the office and 24-h setting, whereas nightly central pulse pressure dipping was significantly lower in GD (–5.4, 95% CI: –10.5 to –0.2%). Mean arterial pressure did not differ between the groups. Conclusions: Despite comparable blood pressure, GD is associated with a higher 24-h PWV that was not detected in the office setting. Pulse pressure was higher in GD, whereas mean arterial pressure did not differ between the groups. Longitudinal studies should pursue whether higher PWV might be a piece to the puzzle of understanding the increased risk of cardiovascular disease in hyperthyroidism and GD.

Context: An interaction between ghrelin, which is implicated in the regulation of short- and long-term energy balance, and thyroid function has been reported in hyperthyroidism in which ghrelin levels are reversibly suppressed. We measured serum ghrelin levels and metabolic indices in hypothyroid patients before and after l-thyroxine replacement. Patients and Methods: Eleven patients were examined twice: 1) in the hypothyroid state and 2) after at least 2 months of euthyroidism. Ten healthy subjects served as a control group. Ghrelin was measured in conjunction with indirect calorimetry and a hyperinsulinemic euglycemic clamp. Results: Serum ghrelin levels were increased by 32% under basal conditions in the hypothyroid state (PRE) as compared with posttreatment (POST) (picograms per milliliter): 976.4 ± 80.8 vs. 736.8 ± 67.1 (P < 0.001). This difference prevailed during the clamp, but a decline was observed in both states: 641.4 ± 82.2 vs. 444.3 ± 66.8 μg/ml (P = 0.005). The hypothyroid state was associated with decreased resting energy expenditure, increased respiratory quotient, and insulin resistance. Serum ghrelin levels as well as the metabolic aberrations became normalized after l-thyroxine replacement as compared with the control subjects. Conclusion: Serum ghrelin levels are reversibly increased in hypothyroid patients. It remains to be investigated whether this represents a direct effect of iodothyronines on ghrelin secretion or clearance or a compensatory response to the abnormal energy metabolism in hypothyroid patients.

Summary Background Studies have documented an altered body composition in Turner syndrome (TS). Body fat is increased and muscle mass is decreased. Ovarian failure necessitates substitution with female hormone replacement therapy (HRT), and HRT induces favourable changes in body composition. It is unknown how HRT affects protein metabolism. Aim To test whether alterations in body composition before and after HRT in TS are a result of altered protein metabolism. Design We performed a randomized crossover study with active treatment (HRT in TS and oral contraceptives in controls) or no treatment. Materials and methods We studied eight women (age 29·7 ± 5·6 (mean ± SD) years) with TS, verified by karyotype, and eight age-matched controls (age 27·3 ± 4·9 years). All subjects underwent a 3-h study in the postabsorptive state. Protein dynamics of the whole body and of the forearm muscles were measured by an amino acid tracer dilution technique using [15N]phenylalanine and [2H4]tyrosine. Substrate metabolism was examined by indirect calorimetry. Results Energy expenditure was comparable among TS and controls, and did not change during active treatment. Whole-body phenylalanine and tyrosine fluxes were similar in the untreated situations, and did not change during active treatment. Amino acid degradation and protein synthesis were similar in all situations. Muscle protein breakdown was similar among groups, and was not affected by treatment. Muscle protein synthesis rate and forearm blood flow did not differ among groups or due to treatment. Conclusion Protein metabolism in TS is comparable to controls, and is not affected by HRT.

The abundance and size-distribution of the sea anemone Metridium senile was investigated at 6 stations in an area of Limfjorden, Denmark in May and September 2001. Two stations were located at a mussel fishing ground and four stations in an nearby area that have been closed for mussel dredging since 1988. In the closed area two stations were placed in a sheltered habitat (low flow velocity) and two stations in an exposed habitat (moderate flow velocity). A significantly reduced amount of shell debris was observed in the fished area compared to the closed area. Furthermore, M. senile had a lower density in the fished area than in the closed area. In the closed area, the moderate flow stations accommodated significantly higher densities of M. senile than the low flow stations. The mean size (pedal disc diameter) of the sea anemones was smaller in the closed area than in the fished area. It is hypothesised that the quantity and quality of the substratum determines the density and size of M. senile. ...

Udgivelsesdato: 2010-Apr-28 Context: Thyroid disease is associated with major metabolic changes, comprising changes in lipid metabolism. Thyroid hormones have previously been shown to increase UCP2 mRNA expression in fat biopsies from hyperthyroid patients, but data from hypothyroid patients have so far not been reported. Patients and Methods: Eleven hypothyroid patients were studied before and after L-T4 replacement, and 10 healthy controls matched for sex, age, and body mass index were studied once. Subcutaneous fat biopsies were performed, and UCP2 mRNA expression was measured in these biopsies. Patients also underwent indirect calorimetry and blood sampling. Results: Patients were profoundly hypothyroid at study entry with significantly increased TSH levels (149.9 +/- 60.4 mU/liter). UCP2 mRNA expression was reduced in the hypothyroid state as compared with the euthyroid state (0.0081 +/- 0.0028 vs. 0.0420 +/- 0.0076, P < 0.01). Using pooled data from hypothyroid patients and control subjects, we found positive correlations between lipid oxidation rates and adipose tissue UCP2 expression (r = 0.63; P < 0.004), basal free fatty acid levels and UCP2 expression (r = 0.51; P < 0.03), and T3 levels and UCP2 (r = 0.69; P < 0.001). Conclusion: Our study demonstrates that hypothyroidism is associated with a profound decrease in UCP2 mRNA expression. It supports the notion that UCP2 is a determinant of fat oxidation pathways and may be involved in the changes seen in the metabolic pathways in thyroid disease.

Udgivelsesdato: 2010-Jul-8 Background: Hypothyroidism decreases energy expenditure and combustion of fuels, but the reported effects on lipid metabolism and insulin sensitivity are divergent and there is a lack of studies assessing rates of lipolysis and lipid oxidation. The present study was conducted to test the hypotheses that hypothyroidism decreases lipolysis, blood concentrations of free fatty acid, lipid oxidation, and insulin sensitivity. Methods: We studied 11 hypothyroid patients (thyroid-stimulating hormone: 150 mU/L) with autoimmune thyroiditis (i) before and (ii) after 2 months of triiodothyronine-euthyroidism upon levothyroxine treatment and (iii) compared the patients to 10 healthy volunteers. Subjects underwent a 3-hour study in the basal state followed by a 3-hour euglycemic clamp study, and we used a combination of lipid blood concentrations, palmitate tracer dilution, and indirect calorimetry to assess lipid metabolism. Results: Compared to euthyroid control subjects and/or euthyroid posttreatment values hypothyroid patients were characterized by (i) 40%-50% decreased concentrations of plasma free fatty acids, palmitate, and 3-OH-butyrate (p < 0.05); (ii)>50% decreased lipid oxidation by indirect calorimetry (p < 0.001); (iii) unchanged whole-body lipolysis by palmitate dilution (all p's > 0.45); (iv) 50% increased triglyceride levels (p < 0.05); and (v) approximately 30% decreased insulin sensitivity judged by glucose infusion rate values (p = 0.05). Conclusions: Our data show that hypothyroidism leads to decreased concentrations and oxidation rates of lipid intermediates and increased triglyceride concentrations in the presence of unaltered rates of lipolysis. The combination of normal lipolysis, low lipid oxidation rates, and high triglyceride concentrations is compatible with increased triglyceride synthesis.

Udgivelsesdato: 2008-Oct CONTEXT: Hyperthyroidism increases energy expenditure, glucose turnover, lipolysis, and protein breakdown. OBJECTIVE: Our objective was to test whether increased protein breakdown occurs independently of other catabolic effects in mild experimental hyperthyroidism. DESIGN: We conducted a single-blind, randomized, placebo-controlled, crossover study. Protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique ([(15)N]phenylalanine and [(2)H(4)]tyrosine). All subjects underwent a 3-h study in the basal state followed by a 3-h euglycemic clamp study. SETTING: The study took place at a university clinical research unit. PARTICIPANTS: Eight healthy women (24-46 yr old) participated. INTERVENTION: Intervention included 6 d thyroid hormone (T(4) 50 microg and T(3) 0.67 microg/kg.d) or placebo administration. RESULTS: Thyroid hormone administration led to mild T(3) hyperthyroidism with more than a doubling of T(3) levels and suppression of TSH. Energy expenditure and body composition was unchanged. Glucose infusion rates, forearm glucose uptake, and levels of lipid intermediates were also alike. Basal whole-body phenylalanine flux and tyrosine flux (reflecting whole-body protein breakdown) were increased (P < 0.05) as were whole-body protein synthesis rate (P = 0.05). Basal forearm rate of appearance and disappearance for phenylalanine (reflecting muscle protein breakdown and synthesis) were similar. CONCLUSIONS: Mild short-term experimental hyperthyroidism increases whole-body protein turnover and breakdown before any measurable changes in energy expenditure or glucose and fat metabolism, suggesting that amino acid and protein metabolism is an early and primary target for thyroid hormone action in humans.

Background: Recent studies have indicated the existence of causal links between the endocrine and immune systems and cardiovascular disease. Mannan-binding lectin (MBL), a protein of the innate immune system, may constitute a connection between these fields. Methods: To test whether thyroid hormone regulates MBL levels, we studied eight patients with Graves’ hyperthyroidism before and after methimazole therapy, eight healthy subjects before and after short-term experimental hyperthyroidism, and eight hypothyroid patients with chronic auto-immune thyroiditis before and after L-thyroxine substitution. Results: In all hyperthyroid patients, MBL levels were increased – median (range), 1886 ng/ml (1478–7344) – before treatment and decreased to 954 ng/ml (312–3222) after treatment (P = 0.01, paired comparison: Wilcoxon’s signed ranks test). The healthy subjects had MBL levels of 1081 ng/ml (312–1578). Administration of thyroid hormones to these persons induced mild hyperthyroidism and increased MBL levels significantly to 1714 ng/ml (356–2488) (P = 0.01). Two of the eight hypothyroid patients had undetectably low levels of MBL both before and after L-thyroxine substitution. The other six hypothyroid patients had decreased levels of MBL of 145 ng/ml (20–457) compared with 979 ng/ml (214–1533) after L-thyroxine substitution (P = 0.03, paired comparison: Wilcoxon’s signed ranks test). Conclusion: Our data show that thyroid hormone increases levels of MBL. MBL is part of the inflammatory complement system, and this modulation of complement activation may play a role in the pathogenesis of a number of key components of thyroid diseases.

Thyroid hormones have significant metabolic effects, and muscle wasting and weakness are prominent clinical features of chronic hyperthyroidism. To assess the underlying mechanisms, we examined seven hyperthyroid women with Graves' disease before (Ht) and after (Eut) medical treatment and seven control subjects (Ctr). All subjects underwent a 3-h study in the postabsorptive state. After regional catheterization, protein dynamics of the whole body and of the forearm muscles were measured by amino acid tracer dilution technique using [15N]phenylalanine and [2H4]tyrosine. Before treatment, triiodothyronine was elevated (6.6 nmol/l) and whole body protein breakdown was icreased 40%. The net forearm release of phenylalanine was increased in hyperthyroidism (μg·100 ml−1·min−1): −7.0 ± 1.2 Ht vs. −3.8 ± 0.8 Eut ( P = 0.04), −4.2 ± 0.3 Ctr ( P = 0.048). Muscle protein breakdown, assessed by phenylalanine rate of appearance, was increased (μg·100 ml−1·min−1): 15.5 ± 2.0 Ht vs. 9.6 ± 1.4 Eut ( P = 0.03), 9.9 ± 0.6 Ctr ( P = 0.02). Muscle protein synthesis rate did not differ significantly. Muscle mass and muscle function were decreased 10–20% before treatment. All abnormalities were normalized after therapy. In conclusion, our results show that hyperthyroidism is associated with increased muscle amino acid release resulting from increased muscle protein breakdown. These abnormalities can explain the clinical manifestations of sarcopenia and myopathy.

Ghrelin stimulates GH secretion as well as appetite and food intake. To explore whether ghrelin is involved in the regulation of appetite and body weight in hyperthyroidism, circulating ghrelin levels were measured in nine hyperthyroid patients before and after medical treatment and compared with those in eight healthy control subjects. All participants were studied in the postabsorptive state and during a 3-h euglycemic hyperinsulinemic clamp. Before treatment the patients had 3- to 5-fold elevations of T(3), and during treatment the patients gained 5 kg of body weight. Ghrelin levels were decreased in hyperthyroidism both in the fasting state (hyperthyroid, 1080 +/- 195 pg/ml; euthyroid, 1480 +/- 215 pg/ml; P = 0.03) and during clamp (hyperthyroid, 833 +/- 150 pg/ml; euthyroid, 1210 +/- 180 pg/m; P = 0.02). After treatment, ghrelin levels did not differ from those in control subjects. In all three study groups the clamp significantly reduced ghrelin levels compared with fasting levels. In conclusion, ghrelin levels are reduced in hyperthyroidism and become normalized by medical antithyroid treatment. Hyperinsulinemia suppresses ghrelin regardless of thyroid status. Ghrelin is not a primary stimulator of appetite and food intake in hyperthyroidism, and the mechanisms underlying the suppressive effect of hyperthyroidism on ghrelin secretion remain unclear.

The metabolic response to dietary restriction involves a series of hormonal and metabolic adaptations leading to protein conservation. An increase in the serum level of growth hormone (GH) during fasting has been well substantiated. GH has potent protein anabolic actions, as evidenced by a significant decrease in lean body mass and muscle mass in chronic GH deficiency, and vice versa in patients with acromegaly. The present review outlines current knowledge about the role of GH in the metabolic response to fasting, with particular reference to the effects on protein metabolism. Physiological bursts of GH secretion seem to be of seminal importance for the regulation of protein conservation during fasting. Apart from the possible direct effects of GH on protein dynamics, a number of additional anabolic agents, such as insulin, insulin-like growth factor-I, and free fatty acids (FFAs), are activated. Taken together the effects of GH on protein metabolism seem to include both stimulation of protein synthesis and inhibition of breakdown, depending on the nature of GH administration, which tissues are being studied, and on the physiological conditions of the subjects.

Skeletal muscle constitutes the major target organ for the thermogenic action of thyroid hormone. We examined the possible relation between energy expenditure (EE), thyroid status, and the contents of Ca2+-ATPase and Na+-K+-ATPasein human skeletal muscle. Eleven hyperthyroid patients with Graves' disease were studied before and after medical treatment with methimazole and compared with eight healthy subjects. Muscle biopsies were taken from the vastus lateralis muscle, and EE was determined by indirect calorimetry. Before treatment, the patients had two- to fivefold elevated total plasma T3 and 41% elevated EE compared with when euthyroidism had been achieved. In hyperthyroidism, the content of Ca2+-ATPase was increased: (mean ± SD) 6,555 ± 604 vs. 5,212 ± 1,580 pmol/g in euthyroidism ( P = 0.04) and 4,523 ± 1,311 pmol/g in healthy controls ( P = 0.0005). The content of Na+-K+-ATPase showed 89% increase in hyperthyroidism: 558 ± 101 vs. 296 ± 34 pmol/g ( P = 0.0001) in euthyroidism and 278 ± 52 pmol/g in healthy controls ( P < 0.0001). In euthyroidism, the contents of both cation pumps did not differ from those of healthy controls. The Ca2+-ATPase content was significantly correlated to plasma T3 and resting EE. This provides the first evidence that, in human skeletal muscle, the capacity for Ca2+ recycling and active Na+-K+ transport are correlated to EE and thyroid status.

Hyperthyroidism is characterized by increased levels of circulating free fatty acids (FFA) and increased lipid oxidation, but it is uncertain which regional fat depots contribute. The present study was designed to define the participation of femoral and abdominal fat stores in the overall stimulation of lipolysis in hyperthyroidism in the basal state and during insulin stimulation. We studied nine women with newly diagnosed hyperthyroidism (HT) and after (euthyroidism, ET) medical treatment with methimazol and compared with eight control subjects (CTR). All subjects were studied in the postabsorptive state and during a 3-h hyperinsulinemic euglycemic clamp with microdialysis catheters sc in the abdominal and femoral adipose tissue. Before treatment, patients had elevated circulating concentrations of triiodthyronine, FFA, and glycerol. Levels of interstitial glycerol (mol/liter) in abdominal adipose tissue [485 24 (HT), 226 20 (ET) (P < 0.001), 265 34 (CTR) (P < 0.001)] and in femoral adipose tissue [468 41(HT), 245 29 (ET) (P < 0.01), 278 31(CTR) (P < 0.005)] were elevated in the basal hyperthyroid state, and these differences prevailed during the glucose clamp [230 23 (HT), 113 13 (ET) (P < 0.01), 132 22(CTR) (P < 0.01) and 303 39 (HT), 122 15 (ET) (P < 0.01), 166 21(CTR) (P < 0.01)]. These results suggest that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis in hyperthyroidism and that both tissues are resistant to the actions of insulin. (J Clin Endocrinol Metab 87: 4747– 4753, 2002)