Thyroid Dysfunction and Cardiovascular Events in Patients With Dysglycemia.

OBJECTIVES: Subclinical thyroid disease is the most common form of thyroid dysfunction and may be associated with adverse cardiovascular outcomes in people at high risk for cardiovascular events. Our objective in this study was to assess the association of thyroid function and thyroid hormone replacement with cardiovascular outcomes in high-risk individuals with dysglycemia and additional cardiovascular risk factors. METHODS: The relationship between baseline thyrotropin (TSH) level and incidence of the composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death; an expanded composite of this outcome plus revascularization or hospitalization for heart failure; and mortality was assessed in 8,401 ORIGIN trial participants with a baseline measurement of TSH. The hazard of each outcome according to either baseline levothyroxine use or TSH-defined hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism was estimated before and after adjustment for baseline demographic and clinical characteristics and treatment allocation. RESULTS: Of all participants, 91.5% were euthyroid, 0.8% were hyperthyroid, 5.5% had subclinical hypothyroidism, and 2.2% had overt hypothyroidism. Subclinical hypothyroidism predicted both the expanded cardiovascular outcome (hazard ratio [HR]=1.24, 95% confidence interval [CI] 1.06 to 1.46) and mortality (HR=1.37, 95% CI 1.12 to 1.67), whereas levothyroxine use predicted fewer deaths (HR=0.72, 95% CI 0.56 to 0.94). CONCLUSION: Subclinical hypothyroidism predicts future cardiovascular events and mortality in people with dysglycemia and other cardiovascular risk factors.

Promoting resource stewardship: Reducing inappropriate free thyroid hormone testing.

RATIONALE: Free thyroxine (fT4) and free triiodothyronine (fT3) tests are often ordered when not clinically warranted. Preventing laboratory overuse by reducing inappropriate fT4 and fT3 testing is one strategy to promote resource stewardship. OBJECTIVES: (1) To characterize the frequency of inappropriate fT4 and fT3 testing and (2) to implement a quality improvement strategy aimed at reducing the number of these tests performed. METHODS: Quality improvement tools were used to create sequential change ideas: (1) education of physicians regarding appropriate indications for ordering fT4/fT3 and (2) implementation of a hospital-wide laboratory and forced-function system with a reflex fT4. This study was conducted at an academic ambulatory care hospital in Toronto, Canada. The main outcomes were the differences in weekly median number of thyroid-stimulating hormone, fT4, and fT3 tests performed during the preintervention, education, and reflex periods using the Kruskal-Wallis test and analysis for special cause variation with statistical process control charts. RESULTS: The median number of fT4/fT3 processed per week was significantly reduced from 90/39 at baseline to 78/34 posteducation and 59/14 postreflex (P < .0001). Comparing preintervention to the reflex period, there was 34% reduction in fT4 and 64% reduction in fT3. The number of processed thyroid-stimulating hormone tests was stable with only 2% variation. Statistical process control charts demonstrated special cause variation following implementation of the reflex system for both fT4 and fT3. CONCLUSIONS AND RELEVANCE: Inappropriate testing of free thyroid indices occurs frequently. The implementation of a reflex fT4 strategy after education was feasible in reducing overall testing by 49% and was effective in promoting resource stewardship.

Serial post-surgical stimulated and unstimulated highly sensitive thyroglobulin measurements in low- and intermediate-risk papillary thyroid carcinoma patients not receiving radioactive iodine.

The purpose of this study was to determine the natural temporal trends of serial thyroglobulin (Tg) among low/intermediate-risk PTC patients not receiving radioactive iodine (RAI) using TSH-stimulated Tg (Stim-Tg) and unstimulated highly sensitive Tg (u-hsTg). We prospectively analyzed serial Stim-Tg measurements after total thyroidectomy ± therapeutic central neck dissection among 121 consecutive low/intermediate-risk PTC patients who did not receive RAI, of whom 104 also had serial u-hsTg measurements available. Median follow-up was 6.5 years with Stim-Tg measurements commencing 3 months after surgery and u-hsTg commencing 1.8 years after surgery (when the assay became available). TSH stimulation was performed with 9-day T3 withdrawal, 22-day T4 withdrawal, or using recombinant human TSH (rhTSH). To account for within-patient correlations of repeated Tg measurements, temporal trends in Stim-Tg and u-hsTg were assessed using Generalized Estimating Equations. Stim-Tg models were adjusted for the method of TSH stimulation, whereas the u-hsTg models were adjusted for concurrent TSH level. Linear regression modeling was used to assess the trend in serial Stim-Tg and u-hsTg measurements as a function time from time of surgery throughout the duration of follow-up. The main outcome measured was the change in u-hsTg and Stim-Tg measurements over time. A total of 337 Stim-Tg (2.8/patient) and 602 u-hsTg (5.8/patient) measurements were analyzed. Among the 337 Stim-Tg measurements, Stim-Tg was assessed using rhTSH in 202 (60 %), T4 withdrawal in 41 (12 %), and T3 withdrawal in 94 (28 %) measurements. The overall mean ± 1SD for Stim-Tg and u-hsTg measured was 1.0 ± 1.2 and 0.2 ± 0.1 µg/L, respectively. When adjusted for method of TSH stimulation, serial Stim-Tg measurements did not significantly change over time (all p = NS). The estimated changes in Stim-Tg per year for rhTSH, T4 withdrawal, and T3 withdrawal were 0.01, -0.08, and 0.04 µg/L, respectively. Upon exclusion of 73 patients with an initial undetectable Stim-Tg (n = 48), serial Stim-Tg measurements did not change significantly over time (all p = NS). For these patients, the estimated changes in Stim-Tg per year for rhTSH, T4 withdrawal, and T3 withdrawal were -0.09, -0.10, and 0.01 µg/L, respectively. Serial u-hsTg measurements did not significantly change over time after adjusting for TSH level (p = NS). The estimated change in u-hsTg per year was -0.003 µg/L. No patients had any clinical or imaging evidence of a recurrence during the duration of their follow-up. Among low/intermediate-risk PTC patients not treated with RAI, serial post-surgical Stim-Tg and u-hsTg measurements do not change significantly over a median follow-up of 6.5 years.

Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes.

BACKGROUND AND OBJECTIVES: Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) <20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C <-3.3%/year) and incident advanced CKD (stage ≥3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] <60 ml/min per 1.73 m(2)). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards. RESULTS: Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P<0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P<0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002). CONCLUSIONS: Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.

Post-operative stimulated thyroglobulin and neck ultrasound as personalized criteria for risk stratification and radioactive iodine selection in low- and intermediate-risk papillary thyroid cancer.

The purpose of this study was to demonstrate the utility of a personalized risk stratification and radioactive iodine (RAI) selection protocol (PRSP) using post-operative stimulated thyroglobulin (Stim-Tg) and neck ultrasound in low- and intermediate-risk papillary thyroid carcinoma (PTC) patients. Patients with PTC tumors ≥1 cm were prospectively followed after total thyroidectomy and selective therapeutic central compartment neck dissection. Low/intermediate risk was defined as PTC confined to the thyroid or central (level VI) lymph nodes. Stim-Tg and neck ultrasound were performed approximately 3 months after surgery and used to guide RAI selection. Patients with Stim-Tg < 1 µg/L did not receive RAI, while those with Stim-Tg >5 µg/L routinely did. Those with Stim-Tg 1-5 µg/L received RAI on the basis of several clinical risk factors. Patients were followed for >6 years with serial neck ultrasound and basal/stimulated thyroglobulin. Among the 129 patients, 84 (65 %) had undetectable Stim-Tg after initial surgery, 40 (31 %) had Stim-Tg of 1-5 µg/L, and 5 (4 %) had Stim-Tg >5 µg/L. RAI was administered to 8 (20 %) patients with Stim-Tg 1-5 µg/L and 5 (100 %) with Stim-Tg >5 µg/L. Using this approach, RAI therapy was avoided in 17/20 (85 %) patients with tumors >4 cm, in 72/81 (89 %) patients older than 45 years, and in 6/9 (67 %) patients with central lymph node involvement. To date, 116 (90 %) patients in this cohort have not received RAI therapy with no evidence of residual/recurrent disease, whereas among the 13 patients who received RAI, 1 (8 %) had pathologic residual/recurrence disease. Using the proposed PRSP, RAI can be avoided in the majority of low/intermediate-risk PTC patients. Moreover, traditional risk factors considered to favor RAI treatment were not always concordant with the PRSP and may lead to overtreatment.

Induction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies.

CONTEXT: Immunotherapies against immune checkpoints that inhibit T cell activation [cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1)] are emerging and promising treatments for several metastatic malignancies. However, the precise adverse effects of these therapies on thyroid gland function have not been well described. CASE DESCRIPTION: We report on 10 cases of painless thyroiditis syndrome (PTS) from a novel etiology, following immunotherapy with anti-PD-1 monoclonal antibodies (mAb) during treatment for metastatic malignancies. Six patients presented with transient thyrotoxicosis in which thyrotropin binding inhibitory immunoglobulins (TBII) were absent for all, whereas four patients had evidence of positive antithyroid antibodies. All thyrotoxic patients required temporary beta-blocker therapy and had spontaneous resolution of thyrotoxicosis with subsequent hypothyroidism. Four patients presented with hypothyroidism without a detected preceding thyrotoxic phase, occurring 6-8 weeks after initial drug exposure. All of these patients had positive antithyroid antibodies and required thyroid hormone replacement therapy for a minimum of 6 months. CONCLUSIONS: Patients receiving anti-PD-1 mAb therapy should be monitored for signs and symptoms of PTS which may require supportive treatment with beta-blockers or thyroid hormone replacement. The anti-PD-1 mAb is a novel exogenous cause of PTS and provides new insight into the possible perturbations of the immune network that may modulate the development of endogenous PTS, including cases of sporadic and postpartum thyroiditis.

Structure-function relationship between corneal nerves and conventional small-fiber tests in type 1 diabetes.

OBJECTIVE: In vivo corneal confocal microscopy (IVCCM) has been proposed as a noninvasive technique to assess small nerve fiber structural morphology. We investigated the structure-function relationship of small fibers in diabetic sensorimotor polyneuropathy (DSP). RESEARCH DESIGN AND METHODS: Ninety-six type 1 diabetic subjects with a spectrum of clinical DSP and 64 healthy volunteers underwent IVCCM examinations to determine corneal nerve structure, including corneal nerve fiber length (CNFL), fiber density (CNFD), branch density (CNBD), and fiber tortuosity (CNFT). Small nerve fiber function was assessed by cooling detection thresholds (CDTs), axon reflex-mediated neurogenic vasodilatation in response to cutaneous heating by laser Doppler imaging flare technique (LDIFLARE), and heart rate variability (HRV). Linear associations between structural and functional measures in type 1 diabetic subjects were determined using Spearman correlation coefficients and linear regression analysis. RESULTS: Of the type 1 diabetic subjects, with a mean age of 38.2 ± 15.5 years and a mean HbA1c of 7.9 ± 1.4%, 33 (34%) had DSP according to the consensus definition. Modest correlations were observed between CNFL, CNFD, and CNBD and all functional small-fiber tests (rs = 0.25 to 0.41; P ≤ 0.01 for all comparisons). For example, quantitatively every 1 mm/mm(2) lower CNFL was associated with a 0.61°C lower CDT, a 0.07 cm(2) lower LDIFLARE area, and a 1.78% lower HRV. No significant associations were observed for CNFT and the functional small-fiber measures. CONCLUSIONS: Small nerve fiber structural morphology assessed by IVCCM correlated well with functional measures of small nerve fiber injury. In particular, CNFL, CNFD, and CNBD demonstrated clear structure-function relationships.

The impact of common variation in the definition of diabetic sensorimotor polyneuropathy on the validity of corneal in vivo confocal microscopy in patients with type 1 diabetes: a brief report.

The consensus definition for diabetic sensorimotor polyneuropathy allows for subtle variation in specific diagnostic criteria. In 89 type 1 diabetes participants, we found that common variations in these criteria do not impact the diagnostic validity of corneal nerve fiber length, a parameter of corneal in vivo confocal microscopy.

Predictive value of metastatic cervical lymph node ratio in papillary thyroid carcinoma recurrence.

BACKGROUND: The purpose of this study was to determine whether the proportion of metastatic cervical lymph nodes resected (metastatic lymph node ratio [MLNR]) predicted papillary thyroid carcinoma (PTC) recurrence, and whether MLNR could alter the predictive ability of TNM nodal classification for recurrence in PTC. METHODS: We conducted a retrospective review of patients with PTC who underwent a total or near-total thyroidectomy with at least 1 lymph node removed at our institution. RESULTS: Of 253 patients, 35 (13.8%) developed recurrent disease. The total MLNR (ratio between total metastatic lymph nodes and total number of lymph nodes resected) independently predicted PTC recurrence (odds ratio [OR], 1.024; 95% confidence interval [CI], 1.010-1.039; p = .001). In receiver operating characteristic (ROC) curve analysis, TNM nodal classification with total MLNR had greater accuracy in predicting PTC recurrence than did TNM nodal classification alone (0.726 and 0.675, respectively). CONCLUSION: MLNR is an independent predictor of PTC recurrence and enhances the predictive value of TNM nodal classification.

Heart rate variability and sensorimotor polyneuropathy in type 1 diabetes.

OBJECTIVE: Reduced heart rate variability (HRV) is classically viewed as an early phenomenon in diabetic sensorimotor polyneuropathy (DSP). We aimed to determine the characteristics of HRV across the spectrum of clinical DSP in type 1 diabetes. RESEARCH DESIGN AND METHODS: Eighty-nine diabetic subjects and 60 healthy volunteers underwent assessment of RR interval variation (RR(var)) during deep breathing and clinical and electrophysiological examination. We examined the distribution of age-standardized RR(var) across the spectrum of clinical DSP, identified variables associated with RR(var) in multivariate regression, and compared RR(var) with validated measures of neuropathy. RESULTS: Age-standardized RR(var) had a significant, step-wise, inverse relationship with ordinal categories of increasing DSP severity (ß = -5.4, P < 0.0001) among subjects with diabetes. Case subjects with DSP had substantially lower age-standardized RR(var) compared with diabetic control subjects without DSP (ß = -5.2, P < 0.01), although there was substantial overlap of RR(var) between diabetic case subjects and control subjects and the healthy volunteer cohort. In multivariate analysis, advanced age was independently associated with lower RR(var) in both healthy volunteers and diabetic subjects, whereas higher glycated hemoglobin A(1c) and systolic blood pressure were independently associated with lower RR(var) in diabetic subjects. RR(var) had a significant association with validated measures of large and small fiber neuropathy. CONCLUSIONS: HRV may be a biomarker for clinical DSP and is associated cross-sectionally with both early and late measures of neuropathy. The low HRV observed in some control subjects without DSP and in most case subjects with severe DSP may signify that HRV has different prognostic implications in these groups, requiring further longitudinal study.

Detection of diabetic sensorimotor polyneuropathy by corneal confocal microscopy in type 1 diabetes: a concurrent validity study.

OBJECTIVE: We aimed to determine the corneal confocal microscopy (CCM) parameter that best identifies diabetic sensorimotor polyneuropathy (DSP) in type 1 diabetes and to describe its performance characteristics. RESEARCH DESIGN AND METHODS: Concurrent with clinical and electrophysiological examination for classification of DSP, CCM was performed on 89 type 1 diabetic and 64 healthy subjects to determine corneal nerve fiber length (CNFL), density, tortuosity, and branch density. Area under the curve (AUC) and optimal thresholds for DSP identification in those with diabetes were determined by receiver operating characteristic (ROC) curve analysis. RESULTS: DSP was present in 33 (37%) subjects. With the exception of tortuosity, CCM parameters were significantly lower in DSP case subjects. In ROC curve analysis, AUC was greatest for CNFL (0.88) compared with fiber density (0.84, P = 0.0001), branch density (0.73, P < 0.0001), and tortuosity (0.55, P < 0.0001). The threshold value that optimized sensitivity and specificity for ruling in DSP was a CNFL of ≤14.0 mm/mm(2) (sensitivity 85%, specificity 84%), associated with positive and negative likelihood ratios of 5.3 and 0.18. An alternate approach that used separate threshold values maximized sensitivity (threshold value ≥15.8 mm/mm(2), sensitivity 91%, negative likelihood ratio 0.16) and specificity (≤11.5 mm/mm(2), specificity 93%, positive likelihood ratio 8.5). CONCLUSIONS: Among CCM parameters, CNFL best discriminated DSP cases from control subjects. A single threshold offers clinically acceptable operating characteristics, although a strategy that uses separate thresholds to respectively rule in and rule out DSP has excellent performance while minimizing unclassified subjects. We hypothesize that values between these thresholds indicate incipient nerve injury that represents those individuals at future neuropathy risk.

Application of post-surgical stimulated thyroglobulin for radioiodine remnant ablation selection in low-risk papillary thyroid carcinoma.

BACKGROUND: We present our ongoing experience in the use of postsurgical stimulated serum thyroglobulin (Stim-Tg) to assist in radioiodine remnant ablation (RRA) decision-making. METHODS: Patients with low-risk well-differentiated thyroid carcinoma (WDTC) with undetectable anti-Tg antibodies were prospectively followed after total thyroidectomy and therapeutic central compartment neck dissection, when indicated.Stim-Tg was performed 3 months postoperatively and used to base RRA selection. RESULTS: Of 104 patients, 59 patients (56.7%) had an undetectable Stim-Tg after thyroidectomy, 35 (33.7%) had Stim-Tg values of 1-5 microg/L, and 10 (9.6%) had Stim-Tg values >5 microg/L. RRA was administered to 1 patient (1.7%) with undetectable Stim-Tg, 6 patients (17.1%) with Stim-Tg1-5 microg/L, and 9 patients (90%) with Stim-Tg >5 microg/L, for a total of 16 patients (15.4%) receiving RRA. When compared to current RRA selection guidelines, the proposed protocol achieved a significantly lower RRA administration rate. CONCLUSION: Stim-Tg measurement performed several months after total thyroidectomy is a useful objective parameter in assisting RRA decision-making for patients with low-risk WDTC. (

Influence of age and primary tumor size on the risk for residual/recurrent well-differentiated thyroid carcinoma.

BACKGROUND: Though age and primary tumor size predict cancer-specific survival in well-differentiated thyroid carcinoma (WDTC), their influence on residual/recurrent disease has not been elucidated. METHODS: In a retrospective study, residual/recurrent disease was defined by the surrogate outcome of positive (>or=2 microg/L) follow-up stimulated thyroglobulin after surgery and radioactive remnant ablation. Age, primary tumor size, and clinical staging systems were examined in the context of stimulated thyroglobulin outcome. RESULTS: A total of 246 patients were followed up for a mean of 5.8 years. No significant difference in age (t(239) = 0.61, p > .05) or tumor size (t(237) = 0.16, p > .05) was found among patients with positive follow-up stimulated thyroglobulin compared with those with negative results. pTNM staging failed to demonstrate significant, stage-dependent increase in the percentage of patients with positive stimulated thyroglobulin, chi(2)(2, N = 229) = 0.17, p > .05, unlike staging based solely on surgical pathology, chi(2)(2, N = 241) = 34.97, p < .001. CONCLUSION: Age, primary tumor size, and pTNM staging do not predict risk for residual/recurrent WDTC, whereas extrathyroidal extension at initial surgery is predictive.

Prognostic value of postsurgical stimulated thyroglobulin levels after initial radioactive iodine therapy in well-differentiated thyroid carcinoma.

BACKGROUND: In well-differentiated thyroid carcinoma, predictors of future positivity of stimulated thyroglobulin (>2 microg/L) after initial radioactive iodine treatment are not known. METHODS: In a retrospective study, we used logistic regression analysis to determine whether postoperative stimulated thyroglobulin measurements and pathologic stage independently predict future stimulated thyroglobulin positivity. RESULTS: We followed 141 patients with well-differentiated thyroid carcinoma for a median of 35 months; follow-up stimulated thyroglobulin measurements were positive in 20.6% (29/141). The natural logarithm of the postsurgical stimulated thyrogolobulin was independently associated with a positive stimulated thyroglobulin at long-term follow-up (odds ratio [OR], 4.44; 95% confidence interval [CI], 2.33-8.45; p < .001); there was a trend for a positive association of TNM stage with positive follow-up stimulated thyroglobulin (p = .054). Lymph node positivity predicted a positive stimulated thyroglobulin in papillary cancer. CONCLUSIONS: Stimulated thyroglobulin measurements prior to initial radioactive iodine treatment independently predict future stimulated thyroglobulin positivity in well-differentiated thyroid carcinoma.