High prevalence of frailty in patients with adrenal adenomas and adrenocortical hormone excess: a cross-sectional multi-centre study with prospective enrolment.

OBJECTIVE: Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. DESIGN: Multi-centre, cross-sectional study (March 2019-August 2022). METHODS: Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. RESULTS: Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio-OR 19.2, 95% confidence interval-CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). CONCLUSIONS: Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment.

CONTEXT: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. OBJECTIVE: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. DESIGN AND SETTING: Cross-sectional study conducted in a tertiary medical center. PARTICIPANTS: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). MEASUREMENTS: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). MAIN OUTCOME MEASURES: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. RESULTS: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). CONCLUSIONS: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Incidence of Clinically Relevant Thyroid Cancers Remains Stable for Almost a Century: A Population-Based Study.

OBJECTIVE: To examine the trends in incidence of clinically relevant thyroid cancers within the overall rising incidence of thyroid cancers. PATIENTS AND METHODS: This is a population-based cohort study conducted using the Rochester Epidemiology Project database to identify all new cases of thyroid cancer in Olmsted County, Minnesota, between January 1, 1935, and December 31, 2018. We extracted information about demographics and tumor pathologic type, size, and invasiveness. Clinically relevant cancers included aggressive histology or presence of metastatic disease, size larger than 4 cm, and gross extrathyroidal tumor invasion. RESULTS: Between 1935 and 2018, 596 thyroid cancer cases were diagnosed (mean age, 46.4 years; 72% female; 87% papillary cancers; and median tumor size, 1.5 cm). The sex- and age-adjusted incidence of thyroid cancer increased from 1.3 per 100,000 person-years (p-y) from 1935-1949 to 12.0 per 100,000 p-y in 2010-2018, corresponding to an absolute change per decade of 1.4 (95% CI, 0.7 to 2.2). There was a nonsignificant period absolute change for patients with tumor greater than 4 cm (0.03; 95% CI, -0.2 to 0.3), with evidence of tumor invasion (0.1; 95% CI, -0.1 to 0.4), and with aggressive histology or presence of metastatic disease (0.2; 95% CI, -0.1 to 0.6). Thyroid cancer mortality was unchanged over the observation period. CONCLUSION: Incidence rates of clinically relevant thyroid cancers, as defined by histology, size, and invasiveness, have not changed significantly in 80 years. The rising thyroid cancer incidence is driven by indolent thyroid cancers.

Determinants of Self-reported Health Outcomes in Adrenal Insufficiency: A Multisite Survey Study.

CONTEXT: Current evidence on determinants of adverse health outcomes in patients with adrenal insufficiency (AI) is scarce, especially in regards to AI subtypes. OBJECTIVE: To determine predictors of adverse outcomes in different subtypes of AI. DESIGN AND SETTING: Cross-sectional survey study at 2 tertiary centers. PARTICIPANTS: A total of 696 patients with AI: primary AI (PAI, 42%), secondary AI (SAI, 32%), and glucocorticoid-induced AI (GIAI, 26%). INTERVENTION: Patient-centered questionnaire. MAIN OUTCOME MEASURES: Patients' knowledge, self-management of AI, self-perceived health, and adverse outcomes. RESULTS: The incidence rate of adrenal crisis was 24/100 patient-years with 44% experiencing at least 1 adrenal crisis since diagnosis (59% in PAI vs 31% in SAI vs 37% in GIAI, P < .0001). All patients described high degrees of discomfort with self-management and receiving prompt treatment. Patients with PAI were most likely to develop adrenal crises (adjusted OR 2.8, 95% CI 1.9-4.0) despite reporting better self-perceived health (adjusted OR 3.3, 95% CI 2.1-5.3), understanding of their diagnosis (89% vs 74-81% in other subtypes, P = .002), higher comfort with self-management (62% vs 52-61% in other sub types, P = .005), and higher likelihood to receive prompt treatment for adrenal crises in the emergency department (42% vs 19-30% in other subtypes, P < .0001). CONCLUSIONS: Patients with AI reported high degrees of discomfort with self-management and treatment delays when presenting with adrenal crises. Despite better self-perceived health and understanding of diagnosis, patients with PAI experienced the highest frequency of adrenal crises. A multidimensional educational effort is needed for patients and providers to improve the outcomes of all subtypes of AI.

Treatment of Thyroid Dysfunction and Serum Lipids: A Systematic Review and Meta-analysis.

CONTEXT: Hyperthyroidism is associated with low levels of cholesterol and triglycerides, and hypothyroidism is associated with hypercholesterolemia and hypertriglyceridemia. OBJECTIVE: The aim of this systematic review was to investigate the impact of therapy for overt and subclinical hyper- and hypothyroidism on serum lipids. DATA SOURCES: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, and Scopus from 1970 through April 5, 2018. STUDY SELECTION: Pairs of independent reviewers selected randomized and observational studies evaluating lipid parameters in patients undergoing treatment for hyper- or hypothyroidism. DATA EXTRACTION: Pairs of independent reviewers extracted data and appraised studies. DATA SYNTHESIS: Treatment of overt hyperthyroidism showed a significant increase in total cholesterol (TC) by 44.50 mg/dL (95% confidence interval [CI]: 37.99, 51.02), low-density lipoprotein cholesterol (LDL-C) by 31.13 mg/dL (95% CI: 24.33, 37.93), high-density lipoprotein cholesterol (HDL-C) by 5.52 mg/dL (95% CI: 1.48, 9.56), apolipoprotein A (Apo A) by 15.6 mg/dL (95% CI: 10.38, 20.81), apolipoprotein B (apo B) by 26.12 mg/dL (95% CI: 22.67, 29.57), and lipoprotein (Lp[a]) by 4.18 mg/dL (95% CI: 1.65, 6.71). There was no significant change in triglyceride (TG) levels. Treatment of subclinical hyperthyroidism did not change any lipid parameters significantly. Levothyroxine therapy in overt hypothyroidism showed a statistically significant decrease in TC by -58.4 mg/dL (95% CI: -64.70, -52.09), LDL-C by -41.11 mg/dL (95% CI: -46.53, -35.69), HDL-C by -4.14 mg/dL (95% CI: -5.67, -2.61), TGs by -7.25 mg/dL (95% CI: -36.63, 17.87), apo A by -12.59 mg/dL (95% CI: -17.98, -7.19), apo B by -33.96 mg/dL (95% CI: 41.14, -26.77), and Lp(a) by -5.6 mg/dL (95% CI: -9.06, -2.14). Levothyroxine therapy in subclinical hypothyroidism showed similar changes but with a smaller magnitude. The studies contained varied population characteristics, severity of thyroid dysfunction, and follow-up duration. CONCLUSIONS: Treatment of overt but not subclinical hyperthyroidism is associated with worsening of the lipid profile. Levothyroxine therapy in both overt and subclinical hypothyroidism leads to improvement in the lipid profile, with a smaller magnitude of improvement in subclinical hypothyroidism.

Evaluation of Medical Surveillance and Incidence of Post-September 11, 2001, Thyroid Cancer in World Trade Center-Exposed Firefighters and Emergency Medical Service Workers.

Importance: Elevated incidence rates of thyroid cancer among World Trade Center (WTC)-exposed individuals may be associated with the identification of asymptomatic cancers during medical surveillance. Objective: To examine the association between WTC exposure and thyroid cancer among Fire Department of the City of New York (hereafter, Fire Department) rescue/recovery workers as well as the association with medical surveillance. Design, Setting, and Participants: This closed-cohort study classified the method of detection (asymptomatic and symptomatic) of thyroid cancers in 14 987 men monitored through the Fire Department-WTC Health Program diagnosed from September 12, 2001, to December 31, 2018. Age-, sex-, and histologic-specific Fire Department incidence rates were calculated and compared with demographically similar men in Olmsted County, Minnesota, from the Rochester Epidemiology Project using age-standardized rates, relative rates (RRs), and 95% CIs. The secondary analysis was restricted to papillary carcinomas. Exposures: World Trade Center exposure was defined as rescue/recovery work at the WTC site from September 11, 2001, to July 25, 2002. Main Outcomes and Measures: The outcomes evaluated comprised (1) number of incident thyroid cancers and their detection method categorizations in the Fire Department and Rochester Epidemiology Project cohorts; (2) Fire Department, Rochester Epidemiology Project, and Surveillance, Epidemiology, and End Results-21 age-standardized incidence rates of thyroid cancer; and (3) RRs comparing Fire Department and Rochester Epidemiology Project overall and by detection method categorization. Results: Seventy-two post-9/11 Fire Department cases of thyroid cancer were identified. Among the 65 cases (90.3%) with a categorized detection method, 53 cases (81.5%) were asymptomatic and 12 cases (18.5%) were symptomatic. Median (interquartile range) age at diagnosis was 50.2 (44.0-58.6) vs 46.6 (43.9-52.9) years for asymptomatic vs symptomatic cases. Associated primarily with asymptomatic cancers, the overall age-standardized incidence of Fire Department thyroid cancers (24.7; 95% CI, 17.4-52.3) was significantly higher than the Rochester Epidemiology Project (10.4; 95% CI, 8.5-12.7) and Surveillance, Epidemiology, and End Results-21 (9.1; 95% CI, 9.0-9.1) per 100 000 person-years. Furthermore, the RR of thyroid cancer among symptomatic men in Fire Department cases was not significantly different from that of men in the Rochester Epidemiology Project (0.8; 95% CI, 0.4-1.5); however, the rate of asymptomatic cancers was more than 3-fold that of the Rochester Epidemiology Project rate (RR, 3.1; 95% CI, 2.1-4.7). Conclusions and Relevance: Excess asymptomatic thyroid cancer in Fire Department WTC-exposed rescue/recovery workers is apparently attributable to the identification of occult lesions during medical surveillance. Among WTC-exposed cohorts and the general population, these findings appear to have important implications for how thyroid cancer incidence rates are interpreted and how diagnoses should be managed.

Drivers of the Decision to Biopsy and Follow-Up of Small Suspicious Thyroid Nodules.

OBJECTIVE: In 2015, the updated American Thyroid Association (ATA) guidelines recommended observation for suspicious subcentimeter thyroid nodules, based on their indolent course. We aimed to evaluate the frequency of biopsy in suspicious thyroid nodules since the introduction of these guidelines, including factors contributing to clinical decision-making in a tertiary care center. METHODS: We conducted a retrospective study of patients in the Mayo Clinic, Rochester, Minnesota, with new, subcentimeter suspicious thyroid nodules (by report or by sonographic features) between March, 2015, and November, 2017, not previously biopsied. RESULTS: We identified 141 nodules in 129 patients: mean age 58.1±14.1 years, 74% female, 87% Caucasian. The frequency of biopsy in suspicious thyroid nodules was 39%. Ultrasound features that were the strongest predictors for biopsy on multivariate analysis included: nodule volume (odds ratio [OR] 37.3 [7.5-188.7]), radiology recommendation for biopsy (OR 2.6 [1.8-3.9]) and radiology report of the nodule as "suspicious" (OR 2.1 [1.4-3.2]). Patient's age and degree of comorbidities did not change the likelihood for biopsy, nor did it vary by clinician type or how the nodule was initially found (incidentally or not incidentally). Among 86 nodules that were not biopsied, 41% had no specific follow-up recommendations. CONCLUSION: One third of suspicious thyroid nodules underwent biopsy since the release of updated ATA guidelines. Factors driving thyroid biopsy seem to be associated with nodule characteristics but not with patient factors including age and comorbidities. Further studies and development of decision aides may be helpful in providing individualized approaches for suspicious thyroid nodules. ABBREVIATIONS: ATA = American Thyroid Association; OR = odds ratio.

Current and Emerging Treatment Strategies for Graves' Orbitopathy.

Graves' orbitopathy is a debilitating disorder which occurs in patients with autoimmune thyroid disease, mainly Graves' disease, and adds layers of complexity to management of both conditions. We conducted a comprehensive review of literature for publications relating to established and new management options for Graves' orbitopathy and have summarized key articles in this review. Initial evaluation of patients with Graves' disease should also include clinical evaluation for orbitopathy. If eye disease is present, patients are best managed by a multi-specialty team including an endocrinologist and ophthalmologist. All patients with Graves' orbitopathy benefit from risk factor modification and normalization of thyroid function tests. Patients with active, mild disease generally benefit from local therapies and selenium, while patients with moderate-to-severe disease usually require the addition of intravenous glucocorticoid therapy. If there is an inadequate response to glucocorticoid therapy, several second-line therapies have been investigated for use, including orbital radiotherapy (with additional glucocorticoids), rituximab, cyclosporine, mycophenolate mofetil, and methotrexate. Use of new biologic agents, mainly teprotumumab and tocilizumab, have demonstrated impressive reductions in disease activity and severity. If these results are confirmed, the treatment paradigm is likely to change in the future. Finally, there are several novel immunotherapies being investigated for Graves' disease, which may have treatment implications for Graves' orbitopathy as well. Overall, there are many encouraging advances in the therapy of Graves' orbitopathy that are making the future more promising for patients suffering from this disease.

Physician perspectives on de-intensifying diabetes medications.

Guidelines for diabetes care recommend that physicians select individualized glycemic goals based on life expectancy, diabetes duration, comorbidity, and resources/support. When patients have stable hemoglobin A1C (HbA1C) levels, guidelines lack recommendations on when diabetes medications should be de-intensified.To understand physicians' perspectives on de-intensifying diabetes medications in patients with type 2 diabetes.Cross-sectional survey, (February-June, 2015).Academic medical center and suburban integrated health system.Primary care and endocrinology physicians.Physicians' self-reported: awareness, agreement, and frequency of individualizing HbA1C goals; practice of de-intensifying diabetes medications; HbA1C values at which physicians de-intensify diabetes medications; and other patient factors physicians consider when de-intensifying diabetes medications.Response rate was 73% (156/213). Most physicians (78%) responded they were familiar with recommendations to individualize HbA1C goals. For patients with stable HbA1C levels, 80% of physicians reported they had initiated conversations about stopping medications; however, physicians differed in predefined HbA1C levels used to initiate conversations (HbA1C < 5.7%: 14%; HbA1C < 6.0%: 31%; HbA1C < 6.5%: 22%; individualized level: 21%). In multiple logistic regression, women physicians (odds ratio [OR] 3.0; confidence interval [CI] 1.1-8.2; P = 0.03) and physicians practicing fewer than 20 years (OR 2.8; CI 1.01-7.7; P = 0.048) were more likely to report de-intensifying diabetes medications.Individualizing glycemic goals and de-intensifying treatments are concepts well accepted by physicians in our sample. However, physicians vary considerably in reporting how they carry out recommendations to individualize and may be missing opportunities to stop or taper diabetes medications based on patients' individualized glycemic goals.