Survivors of pediatric differentiated thyroid carcinoma (DTC) receive thyrotropin-suppressive therapy to minimize disease recurrence. However, knowledge about long-term effects of subclinical ...hyperthyroidism on bone mineral density (BMD) in pediatric DTC survivors is scarce, as is the information regarding long-term consequences of permanent hypoparathyroidism on BMD. We evaluated BMD in pediatric DTC survivors and investigated if BMD was affected by subclinical hyperthyroidism and/or permanent hypoparathyroidism during long-term follow-up.
In this nationwide longitudinal study, we determined BMD in the lumbar spine and femur by dual energy X-ray absorptiometry in 65 pediatric DTC survivors. Measurements were repeated after minimal 5 years of follow-up in 46 pediatric DTC survivors. BMD results were evaluated according to the recommendations of the International Society for Clinical Densitometry (ISCD) and WHO. At both visits, we determined biochemical parameters and markers of bone resorption (C-terminal telopeptide of type I collagen β-CTX) and formation (N-propeptide of type I collagen PINP and osteocalcin).
First and second BMD measurements were done after a median follow-up of 17.0 (interquartile range IQR 8.0-25.0) and 23.5 (IQR 14.0-30.0) years after diagnosis, respectively. Median age at diagnosis was 15 years (IQR 13.0-17.0). Twenty-nine percent of the survivors had subclinical hyperthyroidism. In most survivors, BMD T- and Z-scores were within the reference range during both BMD evaluations. However, after 23.5 years of follow-up, a low BMD was found in 13.0%. In the 13 survivors with permanent hypoparathyroidism, BMD values did not differ after 5 years of follow-up compared with baseline values or in comparison with the 33 survivors without permanent hypoparathyroidism. During follow-up, turnover markers β-CTX and PINP remained stable.
This longitudinal study of pediatric DTC survivors demonstrated normal and stable median lumbar spine and femur BMD values after a median time of 17 and 23.5 years after diagnosis. However, compared with controls, a lower BMD was still found in 13.0% after prolonged follow-up despite intensive follow-up. Based on the studied follow-up period, these data do not provide convincing evidence in support of standard monitoring of bone mass among DTC survivors, but may be restricted to individual cases at low frequency.
This follow-up study was registered in The Netherlands Trial Register under no. NL3280 (www.trialregister.nl/trial/3280).
Whether pediatric patients with differentiated thyroid carcinoma (DTC) are at risk of developing treatment-related adverse effects on cardiac function is unknown. We therefore studied in long-term ...survivors of pediatric DTC the prevalence of cardiac dysfunction and atrial fibrillation in relation to treatment variables, and the association between cardiac dysfunction and plasma biomarkers.
In this nationwide prospective multicenter study, cardiac assessments were performed in 66 adult survivors of pediatric DTC (age at diagnosis ≤18 years and follow-up ≥5 years after diagnosis) treated in the Netherlands between 1970 and 2009. Assessment included echocardiography, plasma biomarkers (N-terminal pro-brain natriuretic peptide, high-sensitive troponin-T, galectin-3), and 24-hour Holter electrocardiography. Echocardiographic measurements were compared with retrospective data of 66 sex- and age-matched unaffected Dutch controls. Diastolic dysfunction was defined as an early diastolic septal and/or lateral tissue velocity (e') less than 2 SD of mean age-adjusted reference data.
The survivors (86.4% women) had at DTC diagnosis a median age of 16 years. Median follow-up was 17 years. Left ventricular ejection fraction <50% was found in one survivor, and median global longitudinal systolic strain was near normal. Diastolic dysfunction was present in 14 asymptomatic survivors (21.2%). Overall, diastolic function of survivors was lower compared with controls (e'mean 14.5 versus 15.8 cm/s, P = 0.006). Older attained age and higher waist circumference were associated with decreased diastolic function, whereas thyrotropin levels and cumulative administered radioiodine dose were not. In survivors, biomarkers were not associated with diastolic dysfunction; atrial fibrillation was not observed.
While systolic function is unaffected, diastolic dysfunction is frequently observed in asymptomatic long-term survivors of pediatric DTC, which may suggest early cardiac aging.
We investigated the effects of selective embolization in patients with symptomatic bone metastases of differentiated thyroid carcinoma. A total of 41 embolizations was performed in 16 patients. We ...studied the follow-up (range, 2 months to 8.6 yr) after the first embolization by evaluation of clinical symptoms and tumor dimensions. Success was defined as an improvement in clinical symptoms without tumor progression. The procedure was successful in 24 of 41 occasions (59%). Twenty-six embolizations were preceded or followed up by additional therapies, consisting of surgery (laminectomy), external irradiation, or radioiodine. Subgroup analysis revealed that these additional therapies did not influence the success rate; however, a potential effect on success duration may be present: for embolizations without additional radioiodine or external irradiation therapy, the median success duration was 6.5 months; for embolizations combined with additional radioiodine or external irradiation, this was 15 months (P = 0.0146). The ultimate outcome of the patients was unfavorable: nine patients died and five patients have progressive disease. We concluded that selective embolization of bone metastases may be considered a palliative therapy that may induce rapid, but transient, relief of symptoms. Combination with radioiodine or external irradiation may prolong the duration of success.
Hensen EF, van Duinen N, Jansen JC, Corssmit EPM, Tops CMJ, Romijn JA, Vriends AHJT, van der Mey AGL, Cornelisse CJ, Devilee P, Bayley JP. High prevalence of founder mutations of the succinate ...dehydrogenase genes in the Netherlands.
Mutations in four genes encoding subunits or cofactors of succinate dehydrogenase (SDH) cause hereditary paraganglioma and pheochromocytoma syndromes. Mutations in SDHB and SDHD are generally the most common, whereas mutations in SDHC and SDHAF2 are far less frequently observed. A total of 1045 DNA samples from Dutch paraganglioma and pheochromocytoma patients and their relatives were analyzed for mutations of SDHB, SDHC, SDHD or SDHAF2. Mutations in these genes were identified in 690 cases, 239 of which were index cases. The vast majority of mutation carriers had a mutation in SDHD (87.1%). The second most commonly affected gene was SDHAF2 (6.7%). Mutations in SDHB were found in only 5.9% of samples, whereas SDHC mutations were found in 0.3% of samples. Remarkably, 69.1% of all carriers of a mutation in an SDH gene in the Netherlands can be attributed to a single founder mutation in SDHD, c.274G>T and p.Asp92Tyr. Moreover, 88.8% of all SDH mutation carriers carry one of just six Dutch founder mutations in SDHB, SDHD and SDHAF2. The dominance of SDHD mutations is unique to the Netherlands, contrasting with the higher prevalence of SDHB mutations found elsewhere. In addition, we found that most SDH mutation‐related paragangliomas–pheochromocytomas in the Netherlands can be explained by only six founder mutations in SDHAF2, SDHB and SDHD. The findings underline the regional differences in the SDH mutation spectrum, differences that should be taken into account in the development of effective screening protocols. The results show the crucial role that demographic factors play in the frequency of gene mutations.
Introduction: Malignant paragangliomas have been well described in carriers of mutations of the succinate dehydrogenase B (SDHB) gene, but have rarely been associated with mutations in the succinate ...dehydrogenase D (SDHD) gene.
Aim: The aim of the study was to report the different clinical expression patterns of malignant paragangliomas in five patients with SDHD (D92Y) mutations observed in approximately 200 SDHD (D92Y) mutation carriers followed in our institution.
Results: Metastasis and/or local tumor invasion was documented 0 (n = 2), 1, 18, and 30 yr after the initial diagnosis of paraganglioma. Malignancy was proven by paraganglioma bone metastases (n = 2), intrathoracic paraganglioma with lymph node metastases, locally invasive head-and-neck paraganglioma with destruction of the petrosal bone, and locally invasive paraganglioma of the bladder with lymph node metastases. Four of the five patients developed catecholamine excess during follow-up due to intraadrenal paraganglioma (pheochromocytoma) (n = 1), extra adrenal paraganglioma (n = 2), and presumed subclinical disease (n = 1).
Conclusion: SDHD mutations (D92Y) are associated with malignant paragangliomas and catecholamine excess with remarkable interindividual variations despite the same mutation. We estimate that the prevalence of malignancy in carriers of D92Y mutations is at least 2.5%.
Summary
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.
Fasting readily induces hepatic steatosis. Hepatic steatosis is associated with hepatic insulin resistance. The purpose of the present study was to document the effects of 16 h of fasting in ...wild-type mice on insulin sensitivity in liver and skeletal muscle in relation to 1) tissue accumulation of triglycerides (TGs) and 2) changes in mRNA expression of metabolically relevant genes. Sixteen hours of fasting did not show an effect on hepatic insulin sensitivity in terms of glucose production in the presence of increased hepatic TG content. In muscle, however, fasting resulted in increased insulin sensitivity, with increased muscle glucose uptake without changes in muscle TG content. In liver, fasting resulted in increased mRNA expression of genes promoting gluconeogenesis and TG synthesis but in decreased mRNA expression of genes involved in glycogenolysis and fatty acid synthesis. In muscle, increased mRNA expression of genes promoting glucose uptake, as well as lipogenesis and β-oxidation, was found.
In conclusion, 16 h of fasting does not induce hepatic insulin resistance, although it causes liver steatosis, whereas muscle insulin sensitivity increases without changes in muscle TG content. Therefore, fasting induces differential changes in tissue-specific insulin sensitivity, and liver and muscle TG contents are unlikely to be involved in these changes.
Summary
Objective The type 2 deiodinase (D2)‐Thr92Ala polymorphism has been associated with decreased D2 activity in some in vitro experiments but not in others. So far no association between the ...D2‐Thr92Ala polymorphism and serum thyroid hormone levels has been observed in humans, but in a recent study in athyroid patients, it was suggested that patients homozygous for the Ala92 allele needed higher T4 doses to achieve TSH suppression.
We studied the association between the D2‐Thr92Ala polymorphism with thyroid hormone levels and T4 dosage, in patients treated for differentiated thyroid carcinoma (DTC) and in a group of patients treated for Hashimoto thyroiditis.
Design Cross‐sectional study.
Patients We studied 154 patients with DTC treated with TSH suppressive thyroid hormone replacement therapy for longer than 3 years and 141 patients with Hashimoto thyroiditis treated for at least 6 months with T4.
Measurements In all patients, serum levels of TSH, free T4, T3 and reverse T3 were measured and genotypes of the D2‐Thr92Ala polymorphism were determined by Taqman assay. Univariate regression analysis was performed to determine the relation between T4 dosages and the D2‐Thr92Ala polymorphism corrected for age, gender, BMI and serum TSH levels.
Results Both in DTC patients and Hashimoto patients, no association was observed between serum thyroid hormone levels or T4 dosages in presence of the D2‐Thr92Ala polymorphism. Categorization of DTC patients according to degree of TSH suppression did not change these results.
Conclusion The D2‐Thr92Ala polymorphism is not associated with thyroid hormone levels or T4 dose in patients treated for DTC or Hashimoto thyroiditis.
Summary
Objective
SDHD mutations predispose carriers to hereditary paraganglioma syndrome. The objective of this study was to assess the genotype–phenotype correlation of a large Dutch cohort of SDHD ...mutation carriers and evaluate potential differences in clinical phenotypes due to specific SDHD gene mutations.
Design
Retrospective, descriptive single‐centre study.
Patients
All consecutive SDHD mutation carriers followed at the Department of Endocrinology of the Leiden University Medical Center were included.
Measurements
Subjects were investigated according to structured protocols used for standard care, including repetitive biochemical and radiological screening for paragangliomas.
Results
Two hundred and one SDHD mutation carriers with a mean age at presentation of 42·6 ± 14·4 years and a mean follow‐up of 5·8 ± 5·4 years were evaluated. Eighty‐one percent carried the SDHD c.274G>T (p.Asp92Tyr) mutation and 13% the SDHD c.416T>C (p.Leu139Pro) mutation. No differences in clinical phenotype between these two specific SDHD mutations were found. Ninety‐one percent developed one or multiple paragangliomas in the head and neck region (HNPGLs), of which the carotid body tumour was the most prevalent (85%). Eighteen carriers developed pheochromocytomas, fifteen sympathetic paragangliomas and nine carriers (4%) suffered from malignant paraganglioma. By end of follow‐up, sixteen SDHD mutation carriers (8%) displayed no biochemical or radiological evidence of manifest disease.
Conclusions
The two main Dutch SDHD founder mutations do not differ in clinical expression. SDHD mutations are associated with the development of multiple HNPGLs and predominantly benign disease.
The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial ...developmental milestones in long-term survivors of childhood DTC.
Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (
= 30). A comparison group non-affected with cancer (
= 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used.
We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (
= 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales.
Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.
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