A comparison of cardiovascular disease, cancer, mortality, and Graves' ophthalmopathy following treatment for hyperthyroidism: A Bayesian network meta-analysis.

OBJECTIVES: This network meta-analysis aimed to evaluate the association of anti-thyroid drugs (ATD), radioactive iodine (RAI), and thyroidectomy with subsequent outcomes in patients with newly-diagnosed hyperthyroidism. METHODS: The Ovid Medline, Ovid Embase, and Cochrane Library databases were searched for observational studies and randomized controlled trials. Included studies were published on or before 1st May 2022 involving at least two of the treatments among ATD, RAI, and thyroidectomy for hyperthyroidism. Pairwise comparisons and Bayesian network meta-analysis were used to estimate hazard ratios (HRs) and their credible interval (CrI) of outcomes, including cardiovascular disease (CVD), cancer, overall mortality, and Graves' ophthalmopathy (GO). RESULTS: A total of 22 cohort studies with 131,297 hyperthyroidism patients were included. Thyroidectomy was associated with lower risks of mortality and GO than ATD (HR = 0.54, 95% CrI: 0.31, 0.96; HR = 0.31, 95% CrI: 0.12, 0.64) and RAI (HR = 0.62, 95% CrI: 0.41, 0.95; HR = 0.18, 95% CrI: 0.07, 0.35). RAI had a higher risk of GO (HR = 1.70, 95% CrI: 1.02, 2.99) than ATD treatment. CONCLUSIONS: This Bayesian network meta-analysis indicated that thyroidectomy was associated with lower risks of mortality and GO in newly-diagnosed hyperthyroid patients compared to ATD and RAI. Relative to ATD, RAI therapy increased the risk of GO.

The impact of age on quality of life and frailty outcomes after parathyroidectomy in patients with primary hyperparathyroidism.

OBJECTIVE: Parathyroidectomy (PTx) improves quality of life (QoL) in patients with primary hyperparathyroidism (PHPT). Whether this effect is modified according to the patients' age is unknown. The aim of this study was to evaluate the impact of age on the effect of PTx on QoL and frailty in patients with PHPT, six months post-PTx. METHODS: This was a prospective cohort study, including patients with PHPT, admitted from January 2016 to December 2019, divided into two categories: younger (≤ 65 years old) and older (> 65 years old). QoL was assessed with the Pasieka questionnaire (PAS-Q) two days pre- and six months post-operatively. Frailty was also assessed at the same time intervals, with the Frailty Index (FI). RESULTS: One hundred and thirty-four patients (younger group: 96 patients, mean age 50.4 ± 9.8 years; older group: 38 patients, mean age 72.1 ± 4.9 years) were included. PTx resulted in a significant reduction in PAS-Q score in both groups. Notably, a greater reduction in "mood swings", "irritability", "itchy skin" and "feeling thirsty" PAS-Q domains was observed in the younger group. In contrast, a greater decrease in "bone pain", "tiredness", "weakness", "joint pain", "getting off chair" and "headaches" items was observed in the older group. Moreover, PTx led to a decrease in FI only in this group. CONCLUSIONS: PTx leads to an improvement in QoL both in older (> 65 years) and younger (≤ 65 years) patients with PHPT, attributed to a differential effect on PAS-Q items. Frailty improves only in the older group.

Outcomes of Thyroid Dysfunction in People Aged Eighty Years and Older: An Individual Patient Data Meta-Analysis of Four Prospective Studies (Towards Understanding Longitudinal International Older People Studies Consortium).

Background: Subclinical and overt thyroid dysfunction is easily detectable, often modifiable, and, in younger age groups, has been associated with clinically relevant outcomes. Robust associations in very old persons, however, are currently lacking. This study aimed to investigate the associations between (sub-)clinical thyroid dysfunction and disability in daily living, cognitive function, depressive symptoms, physical function, and mortality in people aged 80 years and older. Methods: Four prospective cohorts participating in the Towards Understanding Longitudinal International older People Studies (TULIPS) consortium were included. We performed a two-step individual participant data meta-analysis on source data from community-dwelling participants aged 80 years and older from the Netherlands, New Zealand, United Kingdom, and Japan. Outcome measures included disability in daily living (disability in activities of daily living [ADL] questionnaires), cognitive function (Mini-Mental State Examination [MMSE]), depressive symptoms (Geriatric Depression Scale [GDS]), physical function (grip strength) at baseline and after 5 years of follow-up, and all-cause five-year mortality. Results: Of the total 2116 participants at baseline (mean age 87 years, range 80-109 years), 105 participants (5.0%) were overtly hypothyroid, 136 (6.4%) subclinically hypothyroid, 1811 (85.6%) euthyroid, 60 (2.8%) subclinically hyperthyroid, and 4 (0.2%) overtly hyperthyroid. Participants with thyroid dysfunction at baseline had nonsignificantly different ADL scores compared with euthyroid participants at baseline and had similar MMSE scores, GDS scores, and grip strength. There was no difference in the change of any of these functional measures in participants with thyroid dysfunction during five years of follow-up. Compared with the euthyroid participants, no 5-year survival differences were identified in participants with overt hypothyroidism (hazard ratio [HR] 1.0, 95% confidence interval [CI 0.6-1.6]), subclinical hypothyroidism (HR 0.9 [CI 0.7-1.2]), subclinical hyperthyroidism (HR 1.1 [CI 0.8-1.7]), and overt hyperthyroidism (HR 1.5 [CI 0.4-5.9]). Results did not differ after excluding participants using thyroid-influencing medication. Conclusions: In community-dwelling people aged 80 years and older, (sub-)clinical thyroid dysfunction was not associated with functional outcomes or mortality and may therefore be of limited clinical significance.

Incidence and Mortality of Myocardial Infarction and Stroke in Patients with Hyperthyroidism: A Nationwide Cohort Study in Korea.

Background: Hyperthyroidism is associated with various cardiovascular risk factors. However, the relationship between hyperthyroidism and myocardial infarction (MI) or stroke has not been fully elucidated; only a few studies have investigated the association of hyperthyroidism with survival after MI or stroke. Methods: We included 59,021 hyperthyroid patients and a control cohort with 1,180,420 age- and sex-matched subjects from the Korean National Health Insurance database. Blood pressure, body mass index (BMI), glucose and cholesterol levels, and smoking history were obtained during National Health screening examination. We compared the incidence of MI, stroke, and survival after cardiovascular events between subjects with hyperthyroidism and the control cohort. Results: Subjects with hyperthyroidism had higher blood pressure, fasting glucose, and smoking rate, but lower cholesterol levels and a lower obesity rate compared with the control cohort. After adjusting these differences, as well as atrial fibrillation, hyperthyroidism was associated with increased risk of MI and ischemic stroke. Adjusted hazard ratios (HRs) for MI and ischemic stroke with hyperthyroidism was 1.16 [95% confidence interval, CI 1.03-1.30] and 1.12 [CI 1.04-1.20], respectively. In age-, sex-, and BMI-stratified analyses, an increased risk of MI and ischemic stroke remained significant in females, the older age group (≥50 years), and nonobese subjects (BMI <25 kg/m2), but not in males, the younger age group (<50 years), and obese subjects (BMI ≥25 kg/m2). The risk of hemorrhagic stroke was not different between subjects with hyperthyroidism and controls. Adjusted HRs for mortality in subjects with hyperthyroidism who developed MI, ischemic stroke, and hemorrhagic stroke were 1.11 ([CI 0.86-1.43], p = 0.44), 0.89 ([CI 0.75-1.05], p = 0.16), and 1.13 ([CI 0.88-1.47], p = 0.34), respectively. Conclusions: Hyperthyroidism is associated with increased risk of MI and ischemic stroke, independent of cardiovascular risk factors. This association is prominent in subjects with age ≥50 years, in females, and in the nonobese group. Hyperthyroidism did not significantly affect the mortality secondary to cardiovascular events.

Association between mild thyroid dysfunction and clinical outcome in acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: Thyroid hormones profoundly influence the cardiovascular system, but the effects of mild thyroid dysfunction on the clinical outcome of acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) are not well defined. This study aimed to determine the effect of mild thyroid dysfunction on 12-month prognosis in ACS patients undergoing PCI. METHODS: In this prospective cohort study with a 12-month follow-up, 1560 individuals were divided into four groups based on thyroid hormone levels upon admission: euthyroidism (used as a reference group), subclinical hypothyroidism, subclinical hyperthyroidism, and low triiodothyronine syndrome (low T3 syndrome). The outcomes measured were all-cause mortality, cardiac mortality, nonfatal rein-farction, and unplanned repeat revascularization. RESULTS: In this study, the prevalence of mild thyroid dysfunction was 10.8%. Multivariate analysis showed that low T3 syndrome, but not subclinical hypothyroidism or subclinical hyperthyroidism, was associated with a higher rate of all-cause (HR 2.553, 95% CI 1.093-5.964, p = 0.030) and cardiac mortality (HR 2.594, 95% CI 1.026-6.559, p = 0.034), compared with the euthyroidism group. CONCLUSIONS: Mild thyroid dysfunction was frequent in patients with ACS undergoing PCI. Low T3 syndrome was the predominant feature and was associated with 12-month adverse outcomes in these patients.

Subclinical thyroid dysfunction and cardiovascular consequences: An alarming wake-up call?

Subclinical thyroid dysfunction (STD), presenting as subclinical hypothyroidism (SHypo) or subclinical hyperthyroidism (SHyper), defined as abnormal serum thyrotropin (TSH) and normal free thyroid hormones, is associated with increased cardiovascular (CV) risk and mortality. Depending on the degree of such dysfunction, atherosclerosis, coronary artery disease, heart failure and cardiac arrhythmias, predominantly atrial fibrillation, characterize both disorders and increase CV and total mortality compared to euthyroid persons. There are some differences in the mechanisms involved in the increased CV risk incurred by each type of STD, with more traditional CV risk factors clustered in SHypo than in SHyper, while the role of the TSH or its absence thereof, together with the respective, even subtle, changes incurred in thyroid hormone concentrations, seem to adversely influence the CV system in both types of STD. There is evidence that treatment of STD confers potential benefits by reducing CV events, however, no consensus has been reached due to lack of randomized controlled studies. Nevertheless, due to accumulating evidence from observational studies, many authorities agree that individuals with severe SHypo (TSH > 10 mIU/L) or grade 2 SHyper (TSH < 0.1 mIU/L) should receive treatment, mostly for the increased risk of CV morbidity and mortality. The evidence reviewed herein should alert and help the clinician to wake up to these two potentially alarming conditions of STD as they may confer serious CV complications, while their treatment appears quite beneficial.

Subclinical thyroid dysfunction is associated with adverse prognosis in heart failure patients with reduced ejection fraction.

BACKGROUND: Subclinical thyroid dysfunction whose typical patterns include subclinical hypothyroidism and subclinical hyperthyroidism, has been indicated to be associated with an increased risk of heart failure (HF). However, the relationship between subclinical thyroid dysfunction and the clinical outcomes of HF patients is uncertain. This meta-analysis was conducted to assess the association between subclinical thyroid dysfunction and the clinical outcomes of HF patients. METHODS: Pubmed, Embase, Web of Science and Cochrane Central Register of Clinical Trials were searched for eligible studies published up to August 1, 2018 which reported the association between subclinical thyroid dysfunction and the clinical outcomes of HF patients. The pooled hazard ratio (HR) with the corresponding 95% confidence interval (CI) was used to assess the association. RESULTS: Fourteen studies met the eligibility criteria and a total of 21,221 patients with heart failure were included in the meta-analysis. Compared with HF patients with euthyroidism, the pooled HR of subclinical hypothyroidism for all-cause mortality was 1.45 (95% CI 1.26-1.67) in a randomized effects model with mild heterogeneity (I2 = 40.1, P = 0.073). The pooled HR of subclinical hypothyroidism for cardiac death and/or hospitalization was 1.33 (1.17-1.50) in a randomized effects model with moderate heterogeneity (I2 = 69.4, P < 0.001). Subclinical hyperthyroid can increase the risk of all-cause mortality without heterogeneity (HR 1.31, 95% CI 1.10-1.55, I2 = 25.5%, P = 0.225) but have no influence on the risk of cardiac death and/or hospitalization (HR 1.03, 95% CI 0.87-1.23, I2 = 0.0%, P = 0.958). These significant adverse associations were also retained in subgroup analysis. Sensitivity analysis demonstrated the stability of the results of our meta-analysis. CONCLUSIONS: Both subclinical hypothyroidism and subclinical hyperthyroidism are associated with adverse prognosis in patients with HF. Subclinical thyroid dysfunction may be a useful and promising predictor for the long-term prognosis in HF patients.

Thyroid Status and Death Risk in US Veterans With Chronic Kidney Disease.

OBJECTIVE: Given that patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) have a disproportionately higher prevalence of hypothyroidism compared with their non-CKD counterparts, we sought to determine the association between thyroid status, defined by serum thyrotropin (TSH) levels, and mortality among a national cohort of patients with NDD-CKD. PATIENTS AND METHODS: Among 227,422 US veterans with stage 3 NDD-CKD with 1 or more TSH measurements during the period October 1, 2004, to September 30, 2012, we first examined the association of thyroid status, defined by TSH categories of less than 0.5, 0.5 to 5.0 (euthyroidism), and more than 5.0 mIU/L, with all-cause mortality. We then evaluated 6 granular TSH categories: less than 0.1, 0.1 to less than 0.5, 0.5 to less than 3.0, 3.0 to 5.0, more than 5.0 to 10.0, and more than 10.0 mIU/L. We concurrently examined thyroid status, thyroid-modulating therapy, and mortality in sensitivity analyses. RESULTS: In expanded case-mix adjusted Cox analyses, compared with euthyroidism, baseline and time-dependent TSH levels of more than 5.0 mIU/L were associated with higher mortality (adjusted hazard ratios [aHRs] [95% CI], 1.19 [1.15-1.24] and 1.23 [1.19-1.28], respectively), as were baseline and time-dependent TSH levels of less than 0.5 mIU/L (aHRs [95% CI], 1.18 [1.15-1.22] and 1.41 [1.37-1.45], respectively). Granular examination of thyroid status showed that incrementally higher TSH levels of 3.0 mIU/L or more were associated with increasingly higher mortality in baseline and time-dependent analyses, and TSH categories of less than 0.5 mIU/L were associated with higher mortality (reference, 0.5-<3.0 mIU/L) in baseline analyses. In time-dependent analyses, untreated and undertreated hypothyroidism and untreated hyperthyroidism were associated with higher mortality (reference, spontaneous euthyroidism), whereas hypothyroidism treated-to-target showed lower mortality. CONCLUSION: Among US veterans with NDD-CKD, high-normal TSH (≥3.0 mIU/L) and lower TSH (<0.5 mIU/L) levels were associated with higher death risk. Interventional studies identifying the target TSH range associated with the greatest survival in patients with NDD-CKD are warranted.

All-cause and cardiovascular mortality risk after surgery versus radioiodine treatment for hyperthyroidism.

BACKGROUND: Little is known about the long-term side-effects of different treatments for hyperthyroidism. The few studies previously published on the subject either included only women or focused mainly on cancer outcomes. This register study compared the impact of surgery versus radioiodine on all-cause and cause-specific mortality in a cohort of men and women. METHODS: Healthcare registers were used to find hyperthyroid patients over 35 years of age who were treated with radioiodine or surgery between 1976 and 2000. Comparisons between treatments were made to assess all-cause and cause-specific deaths to 2013. Three different statistical methods were applied: Cox regression, propensity score matching and inverse probability weighting. RESULTS: Of the 10 992 patients included, 10 250 had been treated with radioiodine (mean age 65·1 years; 8668 women, 84·6 per cent) and 742 had been treated surgically (mean age 44·1 years; 633 women, 85·3 per cent). Mean duration of follow-up varied between 16·3 and 22·3 years, depending on the statistical method used. All-cause mortality was significantly lower among surgically treated patients, with a hazard ratio of 0·82 in the regression analysis, 0·80 in propensity score matching and 0·85 in inverse probability weighting. This was due mainly to lower cardiovascular mortality in the surgical group. Men in particular seemed to benefit from surgery compared with radioiodine treatment. CONCLUSION: Compared with treatment with radioiodine, surgery for hyperthyroidism is associated with a lower risk of all-cause and cardiovascular mortality in the long term. This finding was more evident among men.

Is it possible to improve prognostic value of NCCN-IPI in patients with diffuse large B cell lymphoma? The prognostic significance of comorbidities.

The prognostic value of the International Prognostic Index (IPI) has been re-evaluated in the rituximab-treated diffuse large B cell lymphoma (DLBCL) patients. Accordingly, National Comprehensive Cancer Network-IPI (NCCN-IPI) has been introduced to estimate prognosis of DLBCL patients. However, comorbidities that frequently affect elderly DLBCL patients were not analyzed. The aim of this study was to evaluate the prognostic significance of comorbidities using Charlson Comorbidity Index (CCI) in 962 DLBCL patients. According to CCI, majority of patients (73.6%) did not have any comorbidity, while high CCI (≥ 2) was observed in 71/962 (7.4%) patients, and in 55/426 (12.9%) of the elderly patients aged ≥ 60 years. When the CCI was analyzed in a multivariate model along with the NCCN-IPI parameters, it stood out as a threefold independent risk factor of a lethal outcome. Also, we have developed a novel comorbidity-NCCN-IPI (cNCCN-IPI) by adding additional 3 points if the patient had a CCI ≥ 2. Four risk groups emerged with the following patient distribution in low, low-intermediate, high-intermediate, and high group: 3.4, 34.3, 49.4, and 12.5%, respectively. The prognostic value of the new cNCCN-IPI was 2.1% improved compared to that of the IPI, and 1.3% improved compared to that of the NCCN-IPI (p < 0.05). This difference was more pronounced in elderly patients, in whom the cNCCN-IPI showed a 5.1% better discriminative power compared to that of the IPI, and 3.6% better compared to the NCCN-IPI. The NCCN-IPI enhanced by the CCI and combined with redistributed risk groups is better for differentiating risk categories in unselected DLBCL patients, especially in the elderly.

Excess Mortality in Treated and Untreated Hyperthyroidism Is Related to Cumulative Periods of Low Serum TSH.

Introduction and Aim: Cumulative time-dependent excess mortality in hyperthyroid patients has been suggested. However, the effect of antithyroid treatment on mortality, especially in subclinical hyperthyroidism, remains unclarified. We investigated the association between hyperthyroidism and mortality in both treated and untreated hyperthyroid individuals. Patients and Methods: Register-based cohort study of 235,547 individuals who had at least one serum thyroid-stimulating hormone (TSH) measurement in the period 1995 to 2011 (7.3 years median follow-up). Hyperthyroidism was defined as at least two measurements of low serum TSH. Mortality rates for treated and untreated hyperthyroid subjects compared with euthyroid controls were calculated using multivariate Cox regression analyses, controlling for age, sex, and comorbidities. Cumulative periods of decreased serum TSH were analyzed as a time-dependent covariate. Results: Hazard ratio (HR) for mortality was increased in untreated [1.23; 95% confidence interval (CI), 1.12 to 1.37; P < 0.001], but not in treated, hyperthyroid patients. When including cumulative periods of TSH in the Cox regression analyses, HR for mortality per every 6 months of decreased TSH was 1.11 (95% CI, 1.09 to 1.13; P < 0.0001) in untreated hyperthyroid patients (n = 1137) and 1.13 (95% CI, 1.11 to 1.15; P < 0.0001) in treated patients (n = 1656). This corresponds to a 184% and 239% increase in mortality after 5 years of decreased TSH in untreated and treated hyperthyroidism, respectively. Conclusions: Mortality is increased in hyperthyroidism. Cumulative periods of decreased TSH increased mortality in both treated and untreated hyperthyroidism, implying that excess mortality may not be driven by lack of therapy, but rather inability to keep patients euthyroid. Meticulous follow-up during treatment to maintain biochemical euthyroidism may be warranted.

Acute cardiovascular events and all-cause mortality in patients with hyperthyroidism: a population-based cohort study.

OBJECTIVE: Several studies have shown an increased risk for cardiovascular disease (CVD) in hyperthyroidism, but most studies have been too small to address the effect of hyperthyroidism on individual cardiovascular endpoints. Our main aim was to assess the association among hyperthyroidism, acute cardiovascular events and mortality. DESIGN: It is a nationwide population-based cohort study. Data were obtained from the Danish Civil Registration System and the Danish National Patient Registry, which covers all Danish hospitals. We compared the rate of all-cause mortality as well as venous thromboembolism (VTE), acute myocardial infarction (AMI), ischemic and non-ischemic stroke, arterial embolism, atrial fibrillation (AF) and percutaneous coronary intervention (PCI) in the two cohorts. Hazard ratios (HR) with 95% confidence intervals (95% CI) were estimated. RESULTS: The study included 85 856 hyperthyroid patients and 847 057 matched population-based controls. Mean follow-up time was 9.2 years. The HR for mortality was highest in the first 3 months after diagnosis of hyperthyroidism: 4.62, 95% CI: 4.40-4.85, and remained elevated during long-term follow-up (>3 years) (HR: 1.35, 95% CI: 1.33-1.37). The risk for all examined cardiovascular events was increased, with the highest risk in the first 3 months after hyperthyroidism diagnosis. The 3-month post-diagnosis risk was highest for atrial fibrillation (HR: 7.32, 95% CI: 6.58-8.14) and arterial embolism (HR: 6.08, 95% CI: 4.30-8.61), but the risks of VTE, AMI, ischemic and non-ischemic stroke and PCI were increased also 2- to 3-fold. CONCLUSIONS: We found an increased risk for all-cause mortality and acute cardiovascular events in patients with hyperthyroidism.

Thyroid Functional Disease and Mortality in a National Peritoneal Dialysis Cohort.

CONTEXT AND OBJECTIVE: End-stage renal disease patients have a higher risk of thyroid disease compared with those without kidney disease. Although thyroid dysfunction is associated with higher death risk in the general population and those undergoing hemodialysis, little is known about the effect of thyroid disease upon mortality in patients treated with peritoneal dialysis (PD). DESIGN, SETTING, PARTICIPANTS, AND MAIN OUTCOME: We examined the association of thyroid status, assessed by serum TSH, with all-cause mortality among PD patients from a large national dialysis organization who underwent one or more TSH measurements over 5 years (January 2007 to December 2011). Thyroid status was categorized as overt-hyperthyroid, subclinical-hyperthyroid, low-normal, high-normal, subclinical-hypothyroid, and overt-hypothyroid range (TSH < 0.1, 0.1­<0.5, 0.5­<3.0, 3.0­<5.0, 5.0­<10.0, and ≥10.0 mIU/L, respectively). We examined the association between TSH and mortality using case mix­adjusted time-dependent Cox models to assess short-term thyroid function­mortality associations and to account for changes in thyroid function over time. RESULTS: Among 1484 patients, 7 and 18% had hyperthyroidism and hypothyroidism, respectively, at baseline. We found that both lower and higher time-dependent TSH levels were associated with higher mortality (reference: TSH, 0.5-<3.0 mIU/L): adjusted hazard ratios (95% confidence intervals) 2.09 (1.08-4.06), 1.53 (0.87-2.70), 1.05 (0.75-1.46), 1.63 (1.11-2.40), and 3.11 (2.08-4.63) for TSH levels, <0.1, 0.1-<0.5, 0.5-<3.0, 3.0-<5.0, 5.0-<10.0, and ≥10.0 mIU/L, respectively. CONCLUSION: Time-dependent TSH levels < 0.1 mIU/L and ≥ 5.0 mIU/L were associated with higher mortality, suggesting hyper- and hypothyroidism carry short-term risk in PD patients. Additional studies are needed to determine mechanisms underlying the thyroid dysfunction-mortality association, and whether normalization of TSH with treatment ameliorates mortality in this population.

Association Between Serum Thyrotropin Levels and Mortality Among Euthyroid Adults in the United States.

BACKGROUND: Low thyroid function within the euthyroid range, as well as overt and subclinical hypothyroidism, reportedly increases the risk of cardiovascular disease and mortality. However, the association between low normal thyroid function and mortality remains controversial. This study was performed to elucidate the association between low normal thyroid function and all-cause and/or cause-specific mortalities among U.S. adults. METHODS: A prospective cohort study was conducted using a nationally representative sample of 12,584 U.S. adults aged ≥20 years with thyrotropin (TSH) levels within the reference range from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994). Associations between TSH tertiles (high, medium, and low normal TSH groups) and mortalities (all-cause, cardiovascular, and cancer) were investigated using multivariable Cox models. Stratum-specific analyses were estimated within subgroups defined according to sex (male or female) and baseline age (age <60 years or age ≥60 years). Further, the same analysis was conducted using continuous NHANES 2001-2002, 2007-2008, and 2009-2010 cohorts, which included data on free thyroxine levels. RESULTS: The median follow-up period was 19.1 years, with 3395 all-cause deaths. A significantly higher risk of all-cause mortality (adjusted hazard ratio [HR] 1.27; [confidence interval (CI) 1.10-1.47]), and cardiovascular mortality (HR 1.30 [CI 1.02-1.67]), and cancer mortality (HR 1.43 [CI 1.01-2.01]) was observed in the high normal TSH group than in the medium normal TSH group. Additionally, the low normal TSH group had an increased risk of all-cause mortality. In stratum-specific analyses, a significant association was found between high normal TSH levels and all-cause mortality among males, females, and participants <60 years. Continuous NHANES cohorts demonstrated a non-significant increase in the HR for all-cause mortality in the high normal TSH group. CONCLUSIONS: High normal TSH levels compared with medium normal TSH levels were associated with increased risk of all-cause, cardiovascular, and cancer mortalities over a long-term follow-up period among U.S. adults. This study indicates that the reference range for TSH levels may require re-evaluation.

Risk Factors for Hip Fracture in Older Men: The Osteoporotic Fractures in Men Study (MrOS).

Almost 30% of hip fractures occur in men; the mortality, morbidity, and loss of independence after hip fractures are greater in men than in women. To comprehensively evaluate risk factors for hip fracture in older men, we performed a prospective study of 5994 men, primarily white, age 65+ years recruited at six US clinical centers. During a mean of 8.6 years of 97% complete follow-up, 178 men experienced incident hip fractures. Information on risk factors including femoral neck bone mineral density (FNBMD) was obtained at the baseline visit. Cox proportional hazards models were used to calculate the hazard ratio (HR) with 95% confidence intervals; Fine and Gray models adjusted for competing mortality risk. Older age (≥75 years), low FNBMD, currently smoking, greater height and height loss since age 25 years, history of fracture, use of tricyclic antidepressants, history of myocardial infarction or angina, hyperthyroidism or Parkinson's disease, lower protein intake, and lower executive function were all associated with an increased hip fracture risk. Further adjustment for competing mortality attenuated HR for smoking, hyperthyroidism, and Parkinson's disease. The incidence rate of hip fracture per 1000 person-years (PY) was greatest in men with FNBMD T-scores <-2.5 (white women reference database) who also had 4+ risk factors, 33.4. Men age ≥80 years with 3+ major comorbidities experienced hip fracture at rates of 14.52 versus 0.88 per 1000 PY in men age <70 years with zero comorbidities. Older men with low FNBMD, multiple risk factors, and multimorbidity have a high risk of hip fracture. Many of these assessments can easily be incorporated into routine clinical practice and may lead to improved risk stratification. © 2016 American Society for Bone and Mineral Research.

Subclinical Thyroid Disease and Mortality in the Elderly: A Retrospective Cohort Study.

OBJECTIVE: The association between subclinical hypothyroidism and hyperthyroidism and mortality in the elderly is poorly defined. This study was designed to evaluate the association between subclinical hypothyroidism and subclinical hyperthyroidism and mortality in the elderly and to define the thyroid-stimulating hormone values associated with excess mortality in the elderly. METHODS: We performed a retrospective cohort study with a review of a computerized database of a large health care organization. Patients aged more than 65 years evaluated in the years 2002 to 2012 with documented normal free T4 values were included in the analysis. All cases of known thyroid disease or cases in which thyroid medications were dispensed were excluded. Analysis was performed only on individuals who were not treated for hyperthyroidism or hypothyroidism during the follow-up period. Subjects were divided into 3 groups based on thyroid-stimulating hormone values: normal (normal thyroid-stimulating hormone), subclinical hypothyroidism (thyroid-stimulating hormone >4.2 mIU/L), and subclinical hyperthyroidism (thyroid-stimulating hormone <0.35 mIU/L). All-cause mortality hazard ratio (HR) was compared among the 3 groups, and a subanalysis according to thyroid-stimulating hormone values was performed in those with subclinical hypothyroidism and subclinical hyperthyroidism. RESULTS: A final analysis was performed on 17,440 individuals with subclinical thyroid disease (538 with subclinical hyperthyroidism [3.1%], 1956 with subclinical hypothyroidism [11.2%], 14,946 normal cases [85.7%], average age of 83 years, 10,289 were women) who were followed up for 10 years. Both subclinical hypothyroidism (HR, 1.75; confidence interval [CI], 1.63-1.88) and subclinical hyperthyroidism (HR, 2.33; CI, 2.08-2.63) were associated with significantly increased mortality, and this association persisted on multivariate analysis (subclinical hypothyroidism HR, 1.68; CI, 1.56-1.8, subclinical hyperthyroidism HR, 1.93; CI, 1.7-2.17). Crude mortality was elevated at 1, 2, and 5 years, but this association seemed to decrease as time from initial analysis increased (most significant association at 1 year). Thyroid-stimulating hormone values greater than 6.38 mIU/L were associated with the highest mortality in those with subclinical hypothyroidism after multivariate adjustment (HR, 1.708; CI, 1.38-2.12), whereas in subclinical hyperthyroidism, no threshold for increased mortality was identified. Mortality was higher. CONCLUSIONS: Both subclinical hypothyroidism and subclinical hyperthyroidism are associated with increased mortality in the elderly. A threshold thyroid-stimulating hormone value (>6.35 mIU/L) exists for increased mortality in subclinical hypothyroidism, but not in subclinical hyperthyroidism.

Cinacalcet, Fibroblast Growth Factor-23, and Cardiovascular Disease in Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) Trial.

BACKGROUND: Patients with kidney disease have disordered bone and mineral metabolism, including elevated serum concentrations of fibroblast growth factor-23 (FGF23). These elevated concentrations are associated with cardiovascular and all-cause mortality. The objective was to determine the effects of the calcimimetic cinacalcet (versus placebo) on reducing serum FGF23 and whether changes in FGF23 are associated with death and cardiovascular events. METHODS AND RESULTS: This was a secondary analysis of a randomized clinical trial comparing cinacalcet to placebo in addition to conventional therapy (phosphate binders/vitamin D) in patients receiving hemodialysis with secondary hyperparathyroidism (intact parathyroid hormone ≥300 pg/mL). The primary study end point was time to death or a first nonfatal cardiovascular event (myocardial infarction, hospitalization for angina, heart failure, or a peripheral vascular event). This analysis included 2985 patients (77% of randomized) with serum samples at baseline and 2602 patients (67%) with samples at both baseline and week 20. The results demonstrated that a significantly larger proportion of patients randomized to cinacalcet had ≥30% (68% versus 28%) reductions in FGF23. Among patients randomized to cinacalcet, a ≥30% reduction in FGF23 between baseline and week 20 was associated with a nominally significant reduction in the primary composite end point (relative hazard, 0.82; 95% confidence interval, 0.69-0.98), cardiovascular mortality (relative hazard, 0.66; 95% confidence interval, 0.50-0.87), sudden cardiac death (relative hazard, 0.57; 95% confidence interval, 0.37-0.86), and heart failure (relative hazard, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS: Treatment with cinacalcet significantly lowers serum FGF23. Treatment-induced reductions in serum FGF23 are associated with lower rates of cardiovascular death and major cardiovascular events. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00345839.

Arrhythmia and thyroid dysfunction.

CONTEXT: Arrhythmia is a major cause of morbidity and mortality in Europe and in the United States. The aim of this review article was to assess the results of the prospective studies that evaluated the risk of arrhythmia in patients with overt and subclinical thyroid disease and discuss the management of this arrhythmia. EVIDENCE ACQUISITION: A literature search was carried out for reports published with the following terms: thyroid, hypothyroidism, hyperthyroidism, subclinical hyperthyroidism, subclinical hypothyroidism, levothyroxine, triiodothyronine, antithyroid drugs, radioiodine, deiodinase, atrial flutter, supraventricular arrhythmia, ventricular arrhythmia, ventricular tachycardia, ventricular fibrillation, torsade de pointes, amiodarone and atrial fibrillation. The investigation was restricted to reports published in English. EVIDENCE ANALYSIS: The outcome of this analysis suggests that patients with untreated overt clinical or subclinical thyroid dysfunction are at increased risk of arrhythmia. Hyperthyroidism increased atrial arrhythmia; however, hypothyroidism increased ventricular arrhythmia. CONCLUSION: The early recognition and effective treatment of thyroid dysfunction in patients with arrhythmia is mandatory because the long-term prognosis of arrhythmia may be improved with the appropriate treatment of thyroid dysfunction.

Cardiac death risk in diabetic haemodialysis patients increased due to thyroid problems.

A prospective study found that diabetic haemodialysis patients' subclinical hyperthyroidism and euthyroid sick syndrome might increase the risk of sudden cardiac-related deaths. Dr Christiane Drechsler, of University Hospital Würzburg in Würzburg, Germany, and colleagues conducted a study that included 1000 patients undergoing haemodialysis for diabetes. Of those patients, 78.1% had euthyroidism, 13.7% had subclinical hyperthyroidism, 1.6% had subclinical hypothyroidism and 5.4% had euthyroid sick syndrome.