Thyroid dysfunction induced by immune checkpoint inhibitors is associated with a better progression-free survival and overall survival in non-small cell lung cancer: an original cohort study.

BACKGROUND: The objective of this study was to investigate the association between the onset of TD and treatment efficacy in NSCLC patients who initiated anti-PD-1 blockade (Nivolumab®) and to assess the impact of TD severity and subtype on nivolumab efficacy. MATERIALS AND METHODS: This study was performed at a referral oncology center between July 20, 2015 and June 30, 2018. Patients with histologically confirmed stage IIIB/IV NSCLC in progression after one or two lines of treatment and who initiated Nivolumab were included. Thyroid function (TSH ± fT4, fT3) was monitored and patients were classified according to TD status [TD(+) versus TD(-)], severity [moderate thyroid dysfunction: TSH level between 0.1 and 0.4 or 4.0 and 10 mIU/L and severe thyroid dysfunction: TSH ≤ 0.1 or ≥ 10mUI/L) and subtype (isolated hypothyroidism, isolated hyperthyroidism and hyperthyroidism then hypothyroidism)]. Clinical endpoints were overall survival (OS) and progression-free survival (PFS). RESULTS: Among 194 eligible patients, 134 patients (median age, 63 yo; 70.1% male) were included. Forty (29.9%) patients were classified in TD(+) and had a longer OS of 29.8 months (95% CI 18.8-NR) versus 8.1 months (95% CI 5.5-11.5) in TD(-) group (p < 0.001). PFS was also longer (8.7 months (95% CI 5.3-15.1) in TD(+) versus 1.7 months (95% CI 1.6-1.9) in TD(-) group (p < 0.001). In Cox proportional hazards analysis, TD remained an independent predictive factor of OS/PFS. Severity and subtype of TD were not correlated with OS/PFS. CONCLUSIONS: This study suggested that TD induced by Nivolumab appears to be an independent predictive factor of survival, irrespective of TD severity and subtype.

Improved survival in patients with thyroid function test abnormalities secondary to immune-checkpoint inhibitors.

Immune-checkpoint inhibitors (ICI) are monoclonal antibodies which target molecules to enhance antitumor response. Several adverse events have been described and the major ICI-related endocrinopathies are thyroid dysfunction and hypophysitis. Its occurrence has been associated with improved outcomes, but it is still to be proven. We performed a retrospective study of patients treated with ICI between 2014 and 2019 at an oncologic center to characterize thyroid function test abnormalities (TFTA) and to evaluate clinical outcomes. We excluded patients without regular monitoring of thyroid function, with previous thyroid or pituitary disease, previous head/neck radiotherapy and who performed only one ICI cycle. We included 161 of 205 patients treated with pembrolizumab, nivolumab or ipilimumab for several neoplasms, with a median duration of 18.9 weeks (9.1-42.6) of ICI treatment and 49.4 weeks (26.5-75.8) of follow-up. New-onset TFTA was diagnosed in 18% of patients (n = 29), in median at 10.6 weeks (6.1-31.1) of ICI therapy. On the whole, 8.7% had primary hypothyroidism, 4.3% central hypothyroidism, 2.5% biphasic thyroiditis and 2.5% thyrotoxicosis. Patients who experienced primary or central thyroid dysfunction had a significantly improved overall response rate (58.6% vs 34.2%, p = 0.015) and overall survival (3.27 vs 1.76 years, p = 0.030), compared to the control group. The risk of mortality was two times higher for control group (adjusted HR = 2.43, 95% CI 1.13-5.23, p = 0.023). This study recognizes that primary and central thyroid dysfunction can be a predictive clinical biomarker of a better response to ICI across several neoplasms.

Thyroid Disorders and Prognosis in Chronic Heart Failure: A Long-Term Follow-Up Study.

BACKGROUND: Thyroid disorders may have a negative impact on the prognosis of patients affected by chronic heart failure (CHF). OBJECTIVE: The aim of the current study was to evaluate the prognostic role of all thyroid disorders over a long term follow-up in a single centre large sample of CHF outpatients. METHODS: In all patients, the function of the thyroid was evaluated at the enrolment and during the follow- up. On the basis of free triiodothyronine (T3), free thyroxine (fT4) and thyroid-stimulating hormone (TSH) serum levels, patients were classified into one of the following four categories: euthyroid subjects, patients affected by hypothyroidism, low T3 (LT3) syndrome and hyperthyroidism. During the follow-up, death for all causes was assessed as primary end-point, whereas time to the first hospitalization for heart failure worsening was the secondary end-point analyzed. RESULTS: Among 762 patients, 190 patients were affected by hypothyroidism (Hypo). LT3 syndrome was diagnosed in 15 patients and 59 patients were affected by hyperthyroidism (Hyper). During a long term follow-up (5.1±3.7 years), 303 patients died. Patients with Hypo showed an increased risk of death as well as of hospitalization due to heart failure worsening at univariate regression analysis. At multivariate regression analysis, Hypo remained associated with hospitalization after correction for age >75 years, ischemic aetiology, diabetes, therapy with ACE-inhibitors or ARBs, therapy with betablockers and with aldosterone antagonists, NYHA class 3, systolic arterial pressure <95 mmHg, left ventricular ejection fraction <30%, estimated glomerular filtration rate <60 ml/min, hyponatremia and NTproBNP> 1000 pg/ml. At multivariate analysis, the independent association with death was significant only for the subgroup of patients with TSH >10 mIU/L. LT3 was independently associated with both heart failure hospitalization and death, whereas Hyper was not associated with any of the two considered end-points. CONCLUSION: Hypo is associated with a worse prognosis over a long-term follow-up. The association with heart failure hospitalization is not dependent on the baseline TSH levels, whereas the association with death is significant only when TSH >10 mIU/L. Finally, Hyper does not have any association with a worse prognosis.

Thyroid disorders in programmed death 1 inhibitor-treated patients: Is previous therapy with tyrosine kinase inhibitors a predisposing factor?

BACKGROUND: Programmed death 1 (PD-1) inhibitors are frequently associated with thyroid-related adverse events (TAEs), but many aspects remain unclear. This study aims to evaluate the incidence and characteristics of such events and to find any predictive factor for its development. METHODS: We retrospectively analysed data from patients with advanced solid tumours (non-small-cell lung carcinoma, renal cell carcinoma, metastatic melanoma) treated with PD-1 inhibitors (nivolumab, pembrolizumab) in Oncology Unit B, Policlinico Umberto I of Rome, from June 2015 to December 2018. All patients underwent baseline thyroid function evaluations repeated monthly. RESULTS: The cohort consisted of 126 patients (66.7% male, mean age 66.4 ± 9.7 years). One hundred and seven received nivolumab and 19 pembrolizumab. Twenty-three per cent of patients experienced TAEs (mainly CTCAE grade 1), with hypothyroidism in 15.1% (subclinical: 11.9%, overt: 3.2%) and hyperthyroidism in 8.0% (subclinical: 4.8%, overt: 3.2%). Median time to TAE onset was 8.7 ± 6.8 weeks (10.4 ± 7.6 weeks for hypothyroidism, 5.4 ± 3.0 weeks for hyperthyroidism). Most TAEs (89.7%) appeared within the first 3 months, none after 8 months. Most hypothyroid patients (63.2%) had previously been treated with a tyrosine kinase inhibitor (TKI). Logistic regression analysis showed that pretreatment with a TKI was a major predisposing factor for the development of hypothyroidism (OR 9.2, 95% CI: 1.4-59.9, P = .020). CONCLUSIONS: TAEs are common during anti-PD-1 therapy and usually occur within the first 3 months of treatment. This is the first study evaluating the impact of previous oncologic therapies on TAEs, identifying TKI as a major risk factor for the development of hypothyroidism in patients treated with anti-PD-1.

Sample Timing, Diagnosis of Subclinical Thyroid Dysfunction and Mortality in Acute Myocardial Infarction: ThyrAMI1 Study.

OBJECTIVE: The objective of this study was to determine the impact of blood sample timing on the diagnosis of subclinical thyroid dysfunction (SCTD) and mortality in patients with acute myocardial infarction (AMI). PATIENTS, DESIGN, AND MAIN OUTCOME MEASURES: Patients with AMI had thyroid function evaluated on admission between December 2014 and December 2016 and those with abnormal serum thyrotropin (TSH) had repeat thyroid function assessed at least a week later. The association between sample timing and SCTD was evaluated by logistic regression analysis. Secondary outcomes were confirmation of SCTD on repeat testing and all-cause mortality up to June 2018. RESULTS: Of the 1806 patients [29.2% women, mean (± standard deviation) age of 64.2 (±12.1) years] analyzed, the prevalence of subclinical hypothyroidism (SCH) was 17.2% (n = 311) and subclinical hyperthyroidism (SHyper) was 1.2% (n = 22) using a uniform TSH reference interval. The risk of being diagnosed with SCTD varied by sample timing in fully-adjusted models. The risk of SCH was highest between 00.01 and 06.00 hours and lowest between 12.01 and 18.00 hours, P for trend <.001, and risk of SHyper was highest between 12.01 hours and 18.00 hours and lowest between 00.01 hours and 06.00 hours. Furthermore, time of the initial sample was associated with the risk of remaining in a SCH state subsequently. Mortality in SCH patients was not elevated when a uniform TSH reference interval was utilized. However, when time period-specific TSH reference ranges were utilized, the mortality risk was significantly higher in SCH patients with HR (95% CI) of 2.26 (1.01-5.19), P = .04. CONCLUSIONS: Sample timing impacts on the diagnosis and prognosis of SCH in AMI patients. If sample timing is not accounted for, SCH is systemically misclassified, and its measurable influence on mortality is lost.

Thyroidectomy Complications in Patients with Diabetes Mellitus.

OBJECTIVE: To (1) analyze postoperative thyroidectomy outcomes in patients with diabetes mellitus (DM), who are prone to deleterious effects of glucose dysmetabolism, and (2) apply findings to optimize perioperative management of diabetics requiring thyroid surgery. STUDY DESIGN: Retrospective database analysis. SETTING: University hospital. SUBJECTS AND METHODS: The National Inpatient Sample was queried using International Classification of Diseases, Ninth Revision, Clinical Modification and Procedure Coding System (PCS) codes for patients with benign or malignant thyroid disease who underwent thyroid surgery between 2002 and 2013. An analysis of demographics, comorbidities, and postoperative outcomes was conducted between a DM vs non-DM cohort using bivariate and multivariate techniques. RESULTS: In total, 103,842 cases met inclusion criteria; 14.2% were diabetics. Diabetics had significantly higher rates of baseline comorbid chronic pulmonary disease, hypertension, obesity, and anemia. Following thyroidectomy, patients with DM were more likely to have vocal cord paresis or paralysis compared to non-DM patients (2.0% vs 1.3%; P < .001). However, when adjusting for demographics and comorbidities, there was no significant difference in this complication between the 2 groups. Diabetics had independently higher rates of cardiac, pulmonary, and urinary complications, as well as transfusion, reintubation, and in-hospital mortality. Diabetics had longer hospital stays (2.76 vs 1.97; P < .001) with higher incurred hospital charges (32,921 vs 25,198; P < .001). CONCLUSION: Although DM often confers metabolic and ischemic derangements secondary to hyperglycemia such as neuropathy, this comorbidity was not independently associated with higher rates of vocal cord paresis or paralysis following thyroid surgery. However, DM predicted other adverse outcomes, including greater cardiac, pulmonary, and urinary complications, as well as transfusion, reintubation, and in-hospital mortality.

Urinary Iodine Concentration and Mortality Among U.S. Adults.

BACKGROUND: Iodine deficiency has long been recognized as an important public health problem. Global approaches such as salt iodization that aim to overcome iodine deficiency have been successful. Meanwhile, they have led to excessive iodine consumption in some populations, thereby increasing the risks of iodine-induced thyroid dysfunction, as well as the comorbidities and mortality associated with hypothyroidism and hyperthyroidism. This study aimed to elucidate whether iodine intake is associated with mortality among U.S. adults. METHODS: This was an observational study to estimate mortality risks according to urinary iodine concentration (UIC) utilizing a nationally representative sample of 12,264 adults aged 20-80 years enrolled in the National Health and Nutrition Examination Survey (NHANES) III. Crude and multivariable Cox proportional hazards regression models were employed to investigate the association between UIC (<50, 50-99, 100-299, 300-399, and ≥400 µg/L) and mortalities (all-cause, cardiovascular, and cancer). In sensitivity analyses, the study adjusted for total sodium intake and fat/calorie ratio in addition to other potential confounders. Stratum-specific analyses were also conducted to estimate the effects of UIC on mortality according to age, sex, race/ethnicity, and estimated glomerular filtration rate category. RESULTS: Over a median follow-up of 19.2 years, there were 3159 deaths from all causes. Participants with excess iodine exposure (UIC ≥400 µg/L) were at higher risk for all-cause mortality compared to those with adequate iodine nutrition (hazard ratio = 1.19 [confidence interval 1.04-1.37]). Elevated hazard ratios of cardiovascular and cancer mortality were also found, but the confidence interval of the effect estimates included the null value for both outcomes. Low UIC was not associated with increased mortality. Restricted cubic spline models showed similar results for all outcomes. The results did not change substantially after adjusting for total sodium intake and fat/calorie ratio. None of the potential interactions were statistically significant on a multiplicative scale. CONCLUSION: Higher all-cause mortality among those with excess iodine intake compared to individuals with adequate iodine intake highlights the importance of monitoring population iodine status. Further studies with longitudinal measures of iodine status are needed to validate these results and to assess the potential risks excess iodine intake may have on long-term health outcomes.

Octogenarians have worse clinical outcomes after thyroidectomy.

BACKGROUND: The rising proportion of older adults in the US population coupled with an increased prevalence of nodular thyroid disease will result in more thyroidectomies being performed. The aim of this study is to evaluate the clinical outcomes among older adults (age ≥65) undergoing thyroidectomy compared to younger adults (18-64). METHODS: This was a population-based study of adult thyroidectomy patients using the Premier Healthcare Database, 2005-2014. Discharge status, hospital length of stay (LOS), morbidity, and total patient charge were compared between younger adults and older adults in three different age groups: ≥65, ≥70, and ≥80 years old. RESULTS: Among 75,141 thyroidectomy patients, 15,805 (21.0%) patients were ≥65 years, 8834 (11.8%) were ≥70 years, and 1613 (2.2%) were ≥80 years. Patients ≥80 years were 2.6 times (aOR:2.58, 95%CI: 1.72-3.86; p < 0.001) more likely to be discharged to a home health organization than to be discharged to their residence and 1.6 times (aOR:1.61, 95%CI: 1.30-2.00; p < 0.001) more likely to have at least one complication. CONCLUSIONS: Age ≥80 is an independent predictor of worse clinical outcomes after thyroidectomy.

Outcome After Radiation Therapy for Langerhans Cell Histiocytosis Is Dependent on Site of Involvement.

PURPOSE: To characterize the efficacy and safety of radiation therapy in a contemporary Langerhans cell histiocytosis (LCH) cohort and to explore whether there are sites at higher risk for local recurrence. PATIENTS AND METHODS: Between 1995 and 2015 we identified 39 consecutive LCH patients who were treated primarily with radiation therapy. Patients were staged by single/multisystem involvement and established risk organ criteria. In 46 irradiated lesions, clinical and radiologic responses were evaluated at multiple time points after radiation therapy. Patient demographics, treatment, and local failure were compared by site of lesion. RESULTS: Median age at radiation therapy was 35 years (range, 1.5-67 years). Twelve patients had multisystem involvement, and of those, 5 patients had disease in organs considered to be high risk. The following sites were irradiated: bone (31), brain (6), skin (3), lymph node (3), thyroid (2), and nasopharynx (1). Median dose was 11.4 Gy (range, 7.5-50.4 Gy). At a median follow-up of 45 months (range, 6-199 months), local recurrence or progression was noted in 5 of 46 lesions (11%). There were no local failures of the 31 bone lesions evaluated, whereas the 3-year freedom from local failure in the 15 non-bone lesions was 63% (95% confidence interval 32-83%; P=.0008). Local failures occurred in 2 of 3 skin lesions, in 2 of 6 brain lesions, and 1 of 3 lymph node lesions. Deaths were recorded in 5 of 39 patients (13%), all of whom were adults with multisystem disease. CONCLUSION: Radiation therapy is a safe and effective measure for providing local control of LCH involving the bone. Whereas bone lesions are well controlled with low doses of radiation, disease in other tissues, such as the skin and brain, may require higher doses of radiation or additional treatment modalities.

THYROID AND AGING.

OBJECTIVE: Review physiologic thyroid function changes with aging and emphasize careful interpretation of tests in the aging population. METHODS: Literature review. RESULTS: Using age-specific thyroid-stimulating hormone (TSH) reference ranges should minimize or avoid the unnecessary diagnosis of thyroid disease in elderly patients. Subclinical thyroid dysfunction and abnormal TSH with normal thyroid levels may improve with time, so careful monitoring of thyroid function is recommended. Overt thyroid disease should always be treated. CONCLUSION: Clinical judgement is always warranted to decide how and when to treat subclinical thyroid disease in the elderly. ABBREVIATIONS: FT4 = free thyroxine; rT3 = reverse triiodothyronine; T3 = triiodothyronine; T4 = thyroxine; TFT = thyroid function test; TSH = thyroid-stimulating hormone.

Unstable Thyroid Function in Older Adults Is Caused by Alterations in Both Thyroid and Pituitary Physiology and Is Associated with Increased Mortality.

BACKGROUND: Average thyrotropin (TSH) levels are known to be higher in older adults when measured in cross-sectional populations. Possible etiologies include differential survival, neutral aging changes, or increased disease prevalence at older ages. This study aimed to elucidate the mechanisms underlying changing thyroid function during aging, and to determine the association of changes with survival, by analyzing the individual thyroid axis over time. METHODS: Individual patterns of changing TSH and free thyroxine (fT4) were determined in 640 participants in the Baltimore Longitudinal Study of Aging who had at least three measures of serum TSH and fT4, not on medications, over an average of seven years of follow-up. Participants with changing phenotypes were identified based on quintiles for both slopes. Those with alterations in primary thyroid gland function demonstrated intact negative feedback (rising TSH with declining fT4 or declining TSH with rising fT4). Other participants had a parallel rise or fall of TSH and fT4 levels, consistent with pituitary dysfunction. Predictors of phenotype were analyzed by logistic regression. Differential survival between thyroid aging phenotypes was analyzed using multivariate Cox regression. RESULTS: While the majority of participants at all ages had stable thyroid function, changes were more common among older adults, with 32.3% of those aged >80 years but only 9.5% of those aged <60 years demonstrating thyroid function changes in the highest and lowest quintiles. Regression to the mean accounts for some of the changes, for example increased baseline TSH was associated with a falling TSH pattern (odds ratio = 1.4 [confidence interval 1.1-1.7] per 1 mIU/L). Importantly, changing thyroid function in either the upper or lower quintiles of slope for TSH and fT4 was associated with increased risk of death compared to stable thyroid status (hazard ratio = 5.4 [confidence interval 3.1-9.5]). CONCLUSIONS: Changing thyroid hormone function is increasingly common at older ages and is associated with decreased survival. Nonetheless, the tendency for abnormal thyroid function tests to resolve, along with altered pituitary responsiveness underlying some TSH elevations, suggests that an elevated TSH level should be not assumed to represent subclinical hypothyroidism in older adults. Thus, caution is appropriate when determining the need for thyroid hormone supplements in older adults.

Association of Otolaryngology Resident Duty Hour Restrictions With Procedure-Specific Outcomes in Head and Neck Endocrine Surgery.

Importance: Graduate medical education has undergone a transformation from traditional long work hours to a restricted plan to allow adequate rest for residents. The initial goal of this restriction is to improve patient outcomes. Objective: To determine whether duty hour restrictions had any impact on surgery-specific outcomes by analyzing complications following thyroid and parathyroid procedures performed before and after duty hour reform. Design, Setting, and Participants: Retrospective cross-sectional analysis of the National Inpatient Sample (NIS).The NIS was queried for procedure codes associated with thyroid and parathyroid procedures for the years 2000 to 2002 and 2006 to 2008. Hospitals were divided based on teaching status into 3 groups: nonteaching hospitals (NTHs), teaching hospitals without otolaryngology programs (THs), and teaching hospitals with otolaryngology programs (THs-OTO). Main Outcomes and Measures: Procedure-specific complication rates, length of stay, and mortality rates were collected. SAS statistical software (version 9.4) was used for analysis with adjustment using Charlson comorbidity index. Results: Total numbers of head and neck endocrine procedures were 34 685 and 39 770 (a 14.7% increase), for 2000 to 2002 and 2006 to 2008, respectively. THs-OTO contributed a greater share of procedures in 2006 to 2008 (from 18% to 25%). With the earlier period serving as the reference, length of stay remained constant (2.1 days); however, total hospital charges increased (from $12 978 to $23 708; P < .001). Rates of postoperative hematoma (odds ratio [OR], 1.21; 95% CI, 1.06-1.38), hypoparathyroidism (OR, 1.27; 95% CI, 1.06-1.52), and unintentional vessel lacerations (OR, 1.36; 95% CI, 1.02-1.83) increased overall with NTHs (OR, 1.26; 95% CI, 1.04-1.52), THs (OR, 1.65; 95% CI, 1.15-2.37), and THs-OTO (OR, 1.98; 95% CI, 1.09-3.61) accounting for these differences, respectively. Overall mortality decreased (OR, 0.66; 95% CI, 0.47-0.94) following a decrease in the TH-OTO mortality rate (OR, 0.34; 95% CI, 0.12-0.93). Conclusions and Relevance: While recurrent laryngeal nerve injury, hematoma formation, and hypoparathyroidism did not change, length of stay and mortality improved within THs-OTO following head and neck endocrine procedures after implementation of duty hour regulations. This finding refutes the concern that duty hour restrictions result in poorer overall outcomes. Less time available to develop technical competence may play a factor in some outcomes in lieu of recurrent laryngeal nerve injury increasing within THs and accidental injury to vessels, organs, or nerves and hypocalcemia increasing within THs-OTO. Furthermore, head and neck endocrine cases increased at THs with otolaryngology programs.

The influence of comorbidities on mortality in sarcoidosis: a observational prospective cohort study.

AIM: The aim of this study was to identify the frequency and prevalence of comorbidities in sarcoid patients and to assess their influence on overall mortality in the cohort of patients with sarcoidosis. MATERIALS AND METHODS: A cohort of 557 patients with histologically confirmed sarcoidosis diagnosed between 2007 and 2011 and a group of non-sarcoid controls were observed. All patients were carefully observed for comorbidities and mortality. RESULTS: 291 males (52.2%) and 266 females (47.8%) with mean age 48.4 ± 12.0 years in sarcoidosis group and a group of 100 controls with mean age (49.25 ± 10.3) were observed. The mean number of comorbidities in both groups was similar (0.9 ± 0.99 vs 0.81 ± 0.84 NS). The frequency of thyroid disease was significantly higher in sarcoidosis group comparing to controls at the time of diagnosis (OR = 3.62 P = 0.0144). During the observation period (median 58.0 months), 16 patients died (2.9%). The mean number of comorbidities was significantly higher in the groups of non-survivors as compared to survivors (2.8 ± 1.0, vs 0.8 ± 0.9), P < 0.0001. CONCLUSION: The comorbidity burden has strong impact on mortality in sarcoidosis. Thyroid diseases are more frequent in sarcoidosis than in non-sarcoid controls.

Two-step thyroid screening strategy in the critical patient.

BACKGROUND: Thyroid function biochemical tests are known for their usefulness in prognosis of long-term critical patients, although current data are controversial regarding the clinical benefit of both free triiodothyronine and thyroxine as prognostic thyroid markers during the first 48h after Intensive Care Unit (ICU) admission. METHODS: The aim of this study was to evaluate the usefulness of two strategies for thyroid function assessment in the first 48h after admission at the ICU. The usefulness of a two-step biochemical thyroid strategy (initial isolated TSH determination, followed by subsequent fT4 and fT3) was compared with a complete one-step biochemical profile (TSH+fT4+fT3). RESULTS: No significant differences were found between the rates of thyroid dysfunction detection when using both strategies (2.8% vs. 2.4%; p=0.71). Using the two-step strategy and a 2.5µUI/mL cut-off value for TSH, sensitivity and negative predictive value were 100%. Among patients with an altered fT3 only, mortality was 14% if TSH≤2.5µUI/mL, whereas it was 7% if TSH>2.5µUI/mL (p=0.008). CONCLUSIONS: For patients with critical illness, the early two-step thyroid screening strategy (starting with an isolated TSH determination between 24 and 48h after admission) led to a saving of 50% in fT4 and fT3 tests, with a false-negative rate of 1.3%. This represents an improved diagnostic approach, hence avoiding the performance of unnecessary complementary biochemical measurements.

Association between thyroid dysfunction and venous thromboembolism in the elderly: a prospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) and subclinical thyroid dysfunction (SCTD) are both common in elderly patients. SCTD has been related to a hypercoagulable state and an increased thromboembolic risk. However, prospective data on the relationship between SCTD and VTE are lacking. OBJECTIVES: To investigate the relationship between SCTD and recurrent VTE (rVTE), all-cause mortality, and thrombophilic biomarkers. Patients Elderly patients with VTE were studied. METHODS: In a prospective multicenter cohort, thyroid hormones and thrombophilic biomarkers were measured 1 year after acute VTE, as both may be influenced by acute thrombosis. We defined subclinical hypothyroidism (SHypo) as elevated thyroid-stimulating hormone (TSH) levels (4.50-19.99 mIU L(-1) ), and subclinical hyperthyroidism (SHyper) as TSH levels of < 0.45 mIU L(-1) , both with normal free thyroxine levels. Outcomes were incidence of rVTE and overall mortality during follow-up starting after the 1-year blood sampling. RESULTS: Of 561 participants (58% with anticoagulation), 6% had SHypo and 5% had SHyper. After 20.8 months of mean follow-up, 9% developed rVTE and 10% died. The rVTE incidence rate was 7.2 (95% confidence interval [CI] 2.7-19.2) per 100 patient-years in SHypo participants, 0.0 (95% CI 0.0-7.6) in SHyper participants, and 5.9 (95% CI 4.4-7.8) in euthyroid participants. In multivariate analyses, the sub-hazard ratio for rVTE was 0.00 (95% CI 0.00-0.58) in SHyper participants and 1.50 (95% CI 0.52-4.34) in SHypo participants as compared with euthyroid participants, without increased levels of thrombophilic biomarkers. SHyper (hazard ratio [HR] 0.80, 95% CI 0.23-2.81) and SHypo (HR 0.99, 95% CI 0.30-3.29) were not associated with mortality. CONCLUSION: In elderly patients, SHyper may be associated with lower rVTE risks. SHypo showed a non-statistically significant pattern of an association with rVTE, without increased mortality or differences in thrombophilic biomarkers.

Thyroid Status, Cardiac Function, and Mortality in Patients With Idiopathic Dilated Cardiomyopathy.

CONTEXT: Previous studies claiming a relationship between thyroid dysfunction and poor prognosis of heart failure (HF) had a major limitation in that they included patients with different etiologies. OBJECTIVE: With complete information of thyroid function profile from 458 consecutive patients with idiopathic dilated cardiomyopathy, we tested the hypothesis that thyroid status can independently influence mortality in patients with HF. Design, Patients, and Outcome Measure: The original cohort consisted of 572 consecutive patients with idiopathic dilated cardiomyopathy, and 458 patients remained at the end of follow-up. All patients took thyroid function tests and other regular examinations in hospital. The risk of mortality was evaluated based on free T3, TSH, and the whole thyroid function profile, respectively. RESULTS: The most frequent thyroid dysfunction was subclinical hypothyroidism (n = 41), followed by subclinical hyperthyroidism (n = 35), low-T3 syndrome (n = 17), and hypothyroidism (n = 12). Logistic analysis showed log-TSH and free T3 as independent predictors of exacerbated cardiac function (New York Heart Association stages III-IV vs New York Heart Association stages I-II). During the follow-up (17 ± 8 mo), 111 cumulative deaths occurred. Hypothyroidism was the strongest predictor of mortality [hazard ratio (HR) 4.189; 95% confidence interval (CI) 2.118-8.283)], followed by low-T3 syndrome (HR 3.147; 95% CI 1.558-6.355) and subclinical hypothyroidism (HR 2.869; 95% CI 1.817-4.532). Subclinical hyperthyroidism showed no significant impact. CONCLUSIONS: We found a clear association between thyroid dysfunction and increased risk of mortality in idiopathic dilated cardiomyopathy with HF. These results suggest that monitoring thyroid function in HF patients is necessary, and further studies on the treatment of HF with thyroid dysfunction are needed.

Medical morbidities in endometrial cancer patients.

OBJECTIVES: The aim of this study was to evaluate the prevalence and types of medical morbidities in Thai endometrial cancer (EMC) patients and their impact on treatment outcomes. METHODS: The EMC patients treated in the institution from 1995 to 2012 and with available medical history were identified. Data collected were age; medical morbidities; tumor stage, histopathology, and grade; adjuvant therapy; living status; and cause of death. RESULTS: Of the 335 EMC patients included in the study, 77.3% had early-stage diseases, and 46.6% received adjuvant therapy. A total of 220 patients (65.7%) had medical morbidities. Median age of patients with medical morbidities was significantly higher than those without: 59 years (range, 30-84 years) versus 52 years (range, 30-86 years) (P < 0.001). One or more components of metabolic syndrome were the most common: 10.9% had all 4 components, 30.0% had three, and 31.4% had two. Thyroid dysfunction, as the second most common, was found in 8.2%. From a median follow-up of 56.5 months (0.07-234.04 months), 18.5% were dead: 11.6% from EMC, 4.8% from medical conditions, and 2.1% from other causes. Survival of the patients who had or had no medical morbidities was not significantly different: 5-year overall survival and 5-year cancer-specific survival were 84.7% (95% confidence interval [CI], 79.6%-89.8%) versus 84.0% (95% CI, 76.9%-91.0%) (P = 0.918) and 87.3% (95% CI, 82.6%-92.0%) versus 89.3% (95% CI, 83.2%-95.3%) (P = 0.986), respectively. CONCLUSION: This was the first large analysis in South-East Asia showing common incidence of medical morbidities in EMC patients. One or more components of metabolic syndrome were the most common. Some medical illnesses were the causes of death. Comprehensive and continual medical care for EMC patients is important.

Duration of thyroid dysfunction correlates with all-cause mortality. the OPENTHYRO Register Cohort.

INTRODUCTION AND AIM: The association between thyroid dysfunction and mortality is controversial. Moreover, the impact of duration of thyroid dysfunction is unclarified. Our aim was to investigate the correlation between biochemically assessed thyroid function as well as dysfunction duration and mortality. METHODS: Register-based follow-up study of 239,768 individuals with a serum TSH measurement from hospitals and/or general practice in Funen, Denmark. Measurements were performed at a single laboratory from January 1st 1995 to January 1st 2011. Cox regression was used for mortality analyses and Charlson Comorbidity Index (CCI) was used as comorbidity score. RESULTS: Hazard ratios (HR) with 95% confidence intervals (CI) for mortality with decreased (<0.3 mIU/L) or elevated (>4.0 mIU/L) levels of TSH were 2.22; 2.14-2.30; P<0.0001 and 1.28; 1.22-1.35; P<0.0001, respectively. Adjusting for age, gender, CCI and diagnostic setting attenuated the risk estimates (HR 1.23; 95% CI: 1.19-1.28; P<0.0001, mean follow-up time 7.7 years, and HR 1.07; 95% CI: 1.02-1.13; P = 0.004, mean follow-up time 7.2 years) for decreased and elevated values of TSH, respectively. Mortality risk increased by a factor 1.09; 95% CI: 1.08-1.10; P<0.0001 or by a factor 1.03; 95% CI: 1.02-1.04; P<0.0001 for each six months a patient suffered from decreased or elevated TSH, respectively. Subdividing according to degree of thyroid dysfunction, overt hyperthyroidism (HRovert 1.12; 95% CI: 1.06-1.19; P<0.0001), subclinical hyperthyroidism (HRsubclinical 1.09; 95% CI: 1.02-1.17; P = 0.02) and overt hypothyroidism (HRovert 1.57; 95% CI: 1.34-1.83; P<0.0001), but not subclinical hypothyroidism (HRsubclinical 1.03; 95% CI: 0.97-1.09; P = 0.4) were associated with increased mortality. CONCLUSIONS AND RELEVANCE: In a large-scale, population-based cohort with long-term follow-up (median 7.4 years), overt and subclinical hyperthyroidism and overt but not subclinical hypothyroidism were associated with increased mortality. Excess mortality with increasing duration of decreased or elevated serum TSH suggests the importance of timely intervention in individuals with thyroid dysfunction.

Thyroid-stimulating hormone and clinical outcomes: the CORONA trial (controlled rosuvastatin multinational study in heart failure).

OBJECTIVES: This study sought to examine the association between thyroid status and clinical outcomes in patients in the CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure) study. BACKGROUND: Hypo- and hyperthyroidism were associated with worse clinical outcomes in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial). METHODS: In CORONA, 4,987 patients underwent baseline thyroid-stimulating hormone (TSH) measurement, 237 of which (4.8%) were receiving thyroid replacement therapy (TRT). Patients were classified as euthyroid (TSH: 0.3 to 5.0 µU/ml, and no TRT), hyperthyroid (<0.3 µU/ml and no TRT), or hypothyroid (>5.0 µU/ml and no TRT). The outcome composites of cardiovascular (CV) death or hospitalization for heart failure (HF), the components of this composite, and all-cause death were compared among hyperthyroid, hypothyroid, and euthyroid states, using multivariable models adjusting for previously reported prognostic variables. RESULTS: A total of 91.3% of patients were euthyroid, 5.0% were hypothyroid, and 3.7% were hyperthyroid. Compared with euthyroid patients, hypothyroid patients were more likely to have a history of stroke, had worse renal function and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, were more likely to be treated with an antiarrhythmic drug (or have an implantable cardioverter defibrillator), and were less likely to smoke or be treated with a beta-blocker or angiotensin-converting enzyme inhibitor/angiotensin receptor blocker. In univariate analyses, hypothyroidism was associated with an increased risk of the composite outcome of CV death or HF hospitalization (hazard ratio: 1.29; 95% confidence interval: 1.07 to 1.57; p = 0.008), as well as all-cause death (HR: 1.36; 95% confidence interval: 1.03 to 1.76; p = 0.004). However, after adjustment for other known predictors of outcome, the associations were weakened, and when NT-proBNP was added to the models, the association between hypothyroidism and all outcomes was eliminated. CONCLUSIONS: Thyroid status is not an independent predictor of outcome in heart failure with reduced ejection fraction. (Controlled Rosuvastatin Multinational Study in Heart Failure [CORONA]; NCT00206310).

Thyroid function in heart failure and impact on mortality.

OBJECTIVES: The aim of this study was to investigate whether patients with systolic heart failure (HF) and abnormal thyroid function are at increased risk for death. BACKGROUND: Thyroid hormone homeostasis is vital to the optimal functioning of the cardiovascular system, but an independent prognostic effect of thyroid abnormalities in patients with HF has not been established. METHODS: In SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial), which randomized patients with ischemic or nonischemic HF to placebo or amiodarone or implantable cardioverter-defibrillator therapy, thyroid-stimulating hormone (TSH) was measured at baseline and at 6-month intervals throughout the 5-year study. RESULTS: Of 2,225 patients, the majority (87%) had normal TSH levels (0.3 to 5.0 µU/ml) at baseline, 12% had values suggestive of hypothyroidism, and 1% had values consistent with hyperthyroidism. Compared with euthyroid patients, those hypothyroid at baseline were older and included more women and Caucasians (all p values <0.05). Over the median follow-up period of 45.5 months, among patients euthyroid at baseline, 89 developed abnormally low TSH levels, and 341 developed abnormally high values. Patients randomized to amiodarone (median dose 300 mg) had an elevated risk for developing abnormal TSH levels compared with implantable cardioverter-defibrillator therapy or placebo (p < 0.0001). Patients with baseline or new-onset abnormal thyroid function had a higher mortality than those with normal thyroid function, even after controlling for other known mortality predictors (hazard ratio: 1.58; 95% confidence interval: 1.29 to 1.94; p < 0.0001 for hypothyroid; hazard ratio: 1.85; 95% confidence interval: 1.21 to 2.83; p = 0.0048 for hyperthyroid). Implantable cardioverter-defibrillator benefit did not vary with thyroid function. CONCLUSIONS: Abnormal thyroid function in patients with symptomatic HF and ejection fractions ≤35% is associated with significantly increased risk for death, even after controlling for known mortality predictors.