The type 2 deiodinase ORFa-Gly3Asp polymorphism (rs12885300) influences the set point of the hypothalamus-pituitary-thyroid axis in patients treated for differentiated thyroid carcinoma.

CONTEXT: Iodothyronine deiodinases D1, D2, and D3 play an important role in synthesis and degradation of T(3). The relationship between serum TSH and free T(4) (FT(4)) levels is determined by an individual set point of the hypothalamus-pituitary-thyroid axis. OBJECTIVE: Several polymorphisms have been described in D1 and D2 of which some are associated with serum TSH and iodothyronine levels. In this study we investigate whether polymorphisms of D1 and D2 influence the set point of the hypothalamus-pituitary-thyroid axis. DESIGN: We collected 1905 serum FT(4) and TSH measurements during 11.5 ± 8.8 yr of follow-up in patients treated for differentiated thyroid carcinoma (DTC). We determined these polymorphisms: D1-rs11206244, D1-rs12095080, D2-rs225014, and D2-rs12885300. Effects of these polymorphisms on the set points of the hypothalamus-pituitary-thyroid axis were analyzed with a linear mixed model. SETTING: The study was conducted at Leiden University Medical Center, a tertiary referral center for DTC. PATIENTS: One hundred fifty-one consecutive patients were treated and cured for DTC. MAIN OUTCOME MEASURE: Slopes and intercepts of regression equations representing the relationship between InTSH and FT(4) were measured for all polymorphisms. RESULTS: DTC patients homozygous for the D2-rs12885300 T allele have an altered set point of the hypothalamus-pituitary-thyroid axis. The slope of the regression line (corrected for age, body mass index, and gender) for wild-type patients was -0.32 ± 0.028 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]), the intercept, 4.95. For heterozygous patients, the slope was -0.30 ± 0.028 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]), the intercept, 4.23. The slope of the homozygous patients was -0.35 ± 0.026 (ln[TSH(mU/liter)]/[FT(4)(pmol/liter)]) and the intercept, 6.07 (P = 0.036 compared with wild-type and heterozygous patients). CONCLUSION: Our data suggest that the negative feedback of FT(4) on TSH is weaker in patients homozygous for the D2-rs12885300 T allele than in wild-type and heterozygous subjects.

Short-term overt hypothyroidism induces discrete diastolic dysfunction in patients treated for differentiated thyroid carcinoma.

BACKGROUND: Thyroid hormone has important effects on the cardiovascular system. The consequences of episodes of acute hypothyroidism on cardiac function have been investigated in only a few studies, and their results are inconclusive. Our objective was to investigate the effects of acute hypothyroidism on cardiac function in patients with iatrogenically induced subclinical hyperthyroidism after treatment for differentiated thyroid carcinoma. MATERIAL AND METHODS: Fourteen patients with a history of differentiated thyroid carcinoma on thyroid-stimulating hormone (TSH)-suppressive thyroxine replacement therapy were studied. We assessed cardiac function before, and 1 and 4 weeks after withdrawal of thyroxine substitution. We measured serum levels of free thyroxine, triiodothyronine and TSH and used a new sophisticated Doppler echocardiography technique, tissue Doppler imaging (TDI), to assess detailed and quantitative assessment of systolic and diastolic cardiac function. Echocardiographic parameters in patients were compared to controls. RESULTS: Compared to controls, patients had higher left ventricular mass and wall thickness and decreased diastolic function during TSH-suppressive l-thyroxine substitution therapy. Thyroxine withdrawal resulted in a decrease in both early (E) and late (A) diastolic mitral inflow velocities, without impact on E/A ratio. Using TDI, late diastolic velocity (A') decreased without impact on E'/A' ratio. Left ventricular dimensions, wall thickness and mass did not change during thyroxine withdrawal. CONCLUSIONS: Subclinical hyperthyroidism is accompanied by diastolic dysfunction. Subsequent acute hypothyroidism induces only subtle changes in diastolic function.

Thr92Ala polymorphism in the type 2 deiodinase is not associated with T4 dose in athyroid patients or patients with Hashimoto thyroiditis.

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 Ala(92) 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.

Reduced quality of life in patients with head-and-neck paragangliomas.

OBJECTIVE: The objective of this study was to assess the quality of life (QoL) in patients with head-and-neck paragangliomas ('glomus tumors'). DESIGN: We conducted a case-control study. METHODS: We assessed QoL in 82 patients with head-and-neck paragangliomas using four validated health-related questionnaires: Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index (MFI-20), Short Form-36 (SF-36), and Nottingham Health Profile (NHP). Patient outcomes were compared with controls provided by the patients and with a large age- and sex-adjusted control group. RESULTS: The QoL scores in the paraganglioma patients were significantly reduced in 12 out of the 21 subscales compared with own controls, and in 18 out of the 21 subscales compared with age- and sex-adjusted values derived from the previous studies. In the MFI-20 questionnaire, patients reported more general fatigue, physical fatigue, mental fatigue, and a reduction in activity and motivation. The scores in the NHP showed a difference in energy, emotional reaction, and social isolation. General health perception, pain, and physical functioning were reported to be worse in the paraganglioma patients on the SF-36 scale. Although anxiety and depression did not reveal any significant differences between patients and their own controls, an increased score on both anxiety and depression was seen when compared with the extended control group. Especially, dysphonia contributes to a reduced QoL. CONCLUSION: QoL is considerably reduced in patients with head-and-neck paragangliomas.

Quality of life in patients after long-term biochemical cure of Cushing's disease.

To evaluate the long-term impact of cured Cushing's disease on subjective well-being, we assessed quality of life by validated health-related questionnaires in 58 patients cured from Cushing's disease by transsphenoidal surgery (n = 58), some of whom received additional radiotherapy (n = 11) and/or bilateral adrenalectomy (n = 3). The mean duration of remission was 13.4 +/- 6.7 yr (range of 2-25 yr). Patient data were compared with a control group of 98 healthy subjects with the same age and sex distribution and with age-adjusted reference values available from the literature. General perceived well-being, measured by the Nottingham Health Profile and the Short Form, was reduced compared with controls for all subscales (P < 0.001). Patients with Cushing's disease had worse scores on subscales of fatigue Multidimensional Fatigue Index and anxiety and depression (Hospital Anxiety and Depression Scale). Compared with reference values from the literature, quality of life was also reduced in the patients according to all questionnaires and all items, except pain (Short Form), sleep (Nottingham Health Profile), and reduced activity (Multidimensional Fatigue Index). Despite conventional hormone replacement therapy, hypopituitarism was an important independent predictor of reduced quality of life. Patients without hypopituitarism (n = 28) showed reduced scores on physical items but normal scores on mental items compared with controls. In conclusion, despite long-term cure of Cushing's disease, patients experience a considerable decrease in quality of life, with physical and psychosocial impairments, especially in the presence of hypopituitarism.