Kaur, Ravinder Jeet

Abstract 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.

Background: Suboptimal glycemic control is associated with maternal and neonatal morbidity and mortality in pregnancy complicated by type 1 diabetes (T1D). Prospective analysis of continuous glucose monitoring (CGM) metrics, insulin pump settings, and insulin delivery can better characterize the changes in glycemic levels and insulin use throughout pregnancy with T1D. Materials and Methods: Prescribed parameters, insulin delivery, carbohydrate intake, and CGM data for 25 pregnant women with T1D from three U.S. sites were collected. Participants enrolled before 17 weeks gestation and used personal insulin pumps and study CGM. Mean daily total, basal, and bolus insulin doses (units/kg), CGM time in range (TIR: 63–140 mg/dL), and pump-entered carbohydrates were analyzed for every 2-week gestational interval. Linear mixed-effects regression models were used to evaluate changes across gestational ages compared to 12–14 weeks. Results: Basal insulin was higher during weeks 6–12 and 24–40. Daily bolus and total insulin were higher during weeks 20–40. Pump parameters were adjusted to intensify insulin therapy from 22 weeks onward. Average TIR across pregnancy was 59% ± 14%. Between 18 and 30 weeks, TIR was significantly lower, and time above range was significantly higher compared to the reference biweek. Time below target was lower between 22 and 34 weeks. Seven participants achieved >70% recommended TIR for pregnancy. Participants with maternal complications or infant neonatal intensive care unit admissions had lower TIR. Conclusion: While insulin dosing changed significantly with advancing gestation, most participants did not achieve >70% TIR. Customized anticipatory pump setting adjustments and automated systems aimed toward the designated TIR are needed to improve outcomes for this population. NCT03761615

Abstract Context While adrenal adenomas have been linked with cardiovascular morbidity in convenience samples of patients from specialized referral centers, large-scale population-based data are lacking. Objective To determine the prevalence and incidence of cardiometabolic disease and assess mortality in a population-based cohort of patients with adrenal adenomas. Design Population-based cohort study. Setting Olmsted County, Minnesota, USA. Patients Patients diagnosed with adrenal adenomas without overt hormone excess and age- and sex-matched referent subjects without adrenal adenomas. Main outcome measure Prevalence, incidence of cardiometabolic outcomes, mortality. Results (Adrenal adenomas were diagnosed in 1004 patients (58% women, median age 63 years) from 1/01/1995 to 12/31/2017. At baseline, patients with adrenal adenomas were more likely to have hypertension [adjusted odds ratio (aOR) 1.96, 95% CI 1.58-2.44], dysglycemia (aOR 1.63, 95% CI 1.33-2.00), peripheral vascular disease (aOR 1.59, 95% CI 1.32-2.06), heart failure (aOR 1.64, 95% CI 1.15-2.33), and myocardial infarction (aOR 1.50, 95% CI 1.02-2.22) compared to referent subjects. During median follow-up of 6.8 years, patients with adrenal adenomas were more likely than referent subjects to develop de novo chronic kidney disease [adjusted hazard ratio (aHR) 1.46, 95% CI 1.14-1.86], cardiac arrhythmia (aHR 1.31, 95% CI 1.08-1.58), peripheral vascular disease (aHR 1.28, 95% CI 1.05-1.55), cardiovascular events (aHR 1.33, 95% CI 1.01-1.73), and venous thromboembolic events (aHR 2.15, 95% CI 1.48-3.13). Adjusted mortality was similar between the 2 groups. Conclusion Adrenal adenomas are associated with an increased prevalence and incidence of adverse cardiometabolic outcomes in a population-based cohort.

Abstract Introduction: Pancreas Transplantation (PT) improves quality of life in Type 1 Diabetes (T1D) patients but limited longitudinal data are available regarding comprehensive metabolic assessment and lifestyle. Our objective was to comprehensively assess T1D patients who underwent PT (PTA and SPK) ≥ 1 year prior on two separate visits 1 year apart. Methodology: We studied 12 PT recipients ≥1 year post PT. Two assessments 1 year apart included comprehensive assessment of graft function using standard mixed meal tolerance test (MMTT), Continuous Glucose Monitoring (CGM) for 1 week, body composition using DEXA scan, physical activity using ActiGraph for 1 week and dietary assessment by VIOCARE®. Results: PT recipients (9F) were 55.5± 9.7 years old, 91.7 % Caucasian with 34.9 ± 12.3 years of diabetes, 6.7 ± 5.2 years (range-1.3–17.6 years) after PT. Ten participants underwent Pancreas Transplantation alone and two received Simultaneous Pancreas Kidney transplantation. Visit 1(V1) showed HbA1c 5.5 ± 0.7%, Fructosamine 238.4 ± 25.6 mcmol/L, BMI 31.2 ± 6.7 kg/m2, fasting plasma glucose (FPG) 95.2 ± 19.4mg/dL and C-peptide 2.6 ± 1.0 ng/ml and visit 2 (V2) HbA1c 5.5 ± 0.6%, Fructosamine 244.4 ± 41.3 mcmol/L, BMI 29.9 ± 5.1kg/m2, FPG 95.4 ± 27.7mg/dL, and C-peptide 2.5 ± 0.8 ng/ml (p-value not significant). One week CGM (n=9) showed excellent glucose control at both visits with mean glucose 117.8 ± 7.0 vs.112 ± 6.2 mg/dl and 96.3 ± 3.6 vs. 96.9±2.8 % time in target range (70-180mg/dl). Time >180mg/dl and >250mg/dl were 2.7 ± 3.0 vs. 1.3±1.7 % (p=0.0413) and 0.2 ± 0.6 vs. 0.1 ± 0.1 % respectively. Mild CGM hypoglycemia (<70 mg/dl) was observed during both visits (1.0 ± 1.0 vs. 1.7± 2 %). CV was 21.1 ± 5.5 and 20.1 ± 4.8 %. Eight recipients underwent MMTT and showed excellent response to Boost® with no significant difference between visits with exception of insulin concentrations at 60 mins (increased from V1) and 90 mins (decreased from V1) (p=0.0424 and 0.0235). DEXA (n=10) revealed similar total % mean fat, and fat distribution in arms, legs and trunk. ActiGraph (n=10) showed similar physical activity during both visits with 16761 ± 5176 and 14499 ± 4192 average steps/day respectively. Mean MET score was 1.6 ± 0.4 and 1.6 ± 0.2 indicating light intensity activity during both periods. Total mean sedentary bouts increased over 1 year (49.6 ± 39.1 vs. 60.8 ± 43.7, p=0.0038). Dietary assessment in 11 recipients showed no significant difference in dietary intake with calories intake 1.3± 0.4 vs. 1.2±0.5 daily Harris-Benedict and macronutrient intake with fat of 36.7 ± 4.3 % and 36.5 ± 5.7 %, CHO of 45.7 ± 5.5 % and 45.7 ± 5.5 % and Omega-3 of 0.1 ± 0.1 g and 0.05 ± 0.1 g respectively. Conclusion: PT recipients have excellent glucose control and pancreas graft function 1 or more years after PT when assessed over successive 2 years with suboptimal body composition and dietary intake and above average physical activity.

Abstract Background: Adrenal adenomas have been linked with cardiovascular morbidity in selected patient populations from specialized referral centers. Population-based data examining the association of adrenal adenomas with cardiometabolic outcomes are lacking. Aim: To determine the incidence of cardiometabolic outcomes in a population-based cohort of patients with adrenal adenomas. Methods: We conducted a population-based cohort study of patients diagnosed with adrenal adenomas while living in a defined community from 1995–2017. Eligible patients were retrospectively identified by a medical records linkage system and confirmed on chart review. Adenomas were classified as mild autonomous cortisol secretion (MACS) if the serum cortisol concentration was >1.8 mcg/dL after 1 mg overnight dexamethasone suppression test (DST), nonfunctioning adrenal tumor (NFAT) if serum cortisol after DST was ≤1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if DST was not performed. Patients with overt hormone excess were excluded. Cardiometabolic outcomes were assessed at the time of adrenal adenoma diagnosis. Patients were then followed until death, migration out of the community, or through December 31, 2017. Incident outcomes were assessed starting at 1 year following the diagnosis and excluded those with the outcome of interest at baseline, except for myocardial infarction (MI) and coronary intervention, which were adjusted for in the analysis. Results: were compared to 1:1 age and sex-matched referent subjects without adrenal adenomas from the same community. Results: Adrenal adenomas were diagnosed in 1004 patients with 141 (14%) NFAT, 81 (8%) MACS, and 782 (78%) AUCS. The median age of diagnosis was 63 years (range, 20–96), and 582 (58%) were women. The baseline data was previously presented and showed higher prevalence of hypertension, diabetes, peripheral vascular disease (PVD), and heart failure (HF) in the adenoma group, after adjusting for BMI and tobacco use. During a median follow-up of 6.8 years (range, 0–22), patients with adrenal adenomas were more likely than referent subjects to develop new-onset dyslipidemia (HR 1.31, 95% CI 1.03–1.67), diabetes (HR 1.68, 95% CI 1.28–2.22), chronic kidney disease (HR 1.77, 95% CI 1.39–2.25), atrial fibrillation (HR 1.32 (1.03–1.70), PVD (HR 1.61, 95% CI 1.24–2.09), and HF (HR 1.46, 95% CI 1.15–1.85). In addition, the adenoma group had higher risk for incident MI (HR 1.62, 95% CI 1.16–2.25) and coronary intervention (HR 1.70, 95% CI 1.25–2.31). Conclusions: Adrenal adenomas are associated with increased incidence of adverse cardiometabolic outcomes in this population-based cohort study. While these results are potentially explained by different degrees of cortisol excess, the majority of patients received suboptimal hormone evaluation, suggesting a knowledge gap in the workup of adrenal adenomas in the broader medical community.

Abstract Background: Adrenal adenomas are incidentally diagnosed in 7% of adults undergoing abdominal imaging. Mild autonomous cortisol secretion is present in 50% of adrenal adenomas, and even “nonfunctioning” adrenal adenomas demonstrate abnormal steroid profile. We aimed to 1) investigate the prevalence of mental and sleep disorders in patients with adrenal adenomas and to 2) determine the risk of mental and sleep disorders after the diagnosis of adrenal adenoma in patients compared to the referent subjects from the same population Methods: Using a medical records linkage system, we identified adult patients living in the Olmsted County, MN diagnosed with an adrenal adenoma during 1995–2017. Patients with overt hormone excess were excluded. Every patient with adenoma was matched by sex and age to a referent subject from the same population. Subjects were followed until death or end of the study. Mental health related comorbidities and sleep disorders were assessed at baseline and during follow up. Results: Our cohort included 1004 patients with adrenal adenomas and 1004 referent subjects (58% women, median age of 63 years). Patients were more likely to smoke (70% vs 54%, p <0.001) and had a higher BMI (30 kg/m2 vs 28 kg/m2, p < 0.001). Within 5 years prior to the index date (diagnosis of adenoma), and after adjusting for BMI and smoking, patients demonstrated a higher prevalence of depression (Odds ratio, OR of 1.3 (CI95% 1.1–1.6), p=0.02), anxiety (OR of 1.4 (CI95% 1.1–1.8, p=0.003), substance abuse disorders (OR of 2.4 (CI 95% 1.7–3.4), p<0.001), but not insomnia (OR of 1.2 (CI95% 0.9–1.7) and sleep related breathing disorders (OR of 1.3 (CI 95% 0.9–1.7). During follow-up, starting 1 year after the diagnosis, patients demonstrated a higher risk of new onset depression (HR of 1.9, CI95%1.5–2.4), anxiety (HR of 1.5,CI95% 1.2–1.9), schizophrenia (HR of 1.7, CI95% 1.2–2.4), and substance abuse disorders (HR of 1.6, CI95% 1.2–2.0). Risk of sleep disorders 1 year after diagnosis was also high for insomnia (HR of 1.4, CI95% 1.1–1.9), sleep-related breathing disorders (HR of 1.8, CI95% 1.4–2.3), hypersomnias of central origin (HR of 2.0, CI95%1.04–3.96), parasomnias (HR of 2.4, CI95%1.2–4.7), and sleep-related movement disorders(HR of 1.9, CI95%1.3–2.6). Conclusion: Patients with adenomas are at increased risk for mental and sleep disorders, possibly explained by the underlying subtle cortisol secretion. Further prospective studies with an in-depth characterization of both hormonal secretion and mental/sleep disorders are needed. Reversibility or improvement of mental health and sleep disorders with adrenalectomy should be investigated.

Objective Several small studies reported increased prevalence and incidence of asymptomatic vertebral fractures in patients with non-functioning adrenal adenomas and adenomas with mild autonomous cortisol secretion. However, the risk of symptomatic fractures at vertebrae, and at other sites remains unknown. Our objective was to determine the prevalence and incidence of symptomatic site-specific fractures in patients with adrenal adenomas. Design Population-based cohort study, Olmsted County, Minnesota, USA, 1995–2017. Methods Participants were the patients with adrenal adenoma and age/sex-matched referent subjects. Patients with overt hormone excess were excluded. Main outcomes measures were prevalence and incidence of bone fractures. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years (20–96). At the time of diagnosis, patients had a higher prevalence of previous fractures than referent subjects (any fracture: 47.9% vs 41.3%, P = 0.003, vertebral fracture: 6.4% vs 3.6%, P = 0.004, combined osteoporotic sites: 16.6% vs 13.3%, P = 0.04). Median duration of follow-up was 6.8 years (range: 0–21.9 years). After adjusting for age, sex, BMI, tobacco use, prior history of fracture, and common causes of secondary osteoporosis, patients with adenoma had hazard ratio of 1.27 (95% CI: 1.07–1.52) for developing a new fracture during follow up when compared to referent subjects. Conclusions Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis and increased risk to develop new fractures when compared to referent subjects.

Abstract Background: Benign adrenal tumors are frequently diagnosed on imaging and may pose health risks to patients regardless of functional status. Both non-functioning adrenal tumors (NFAT) and tumors with mild autonomous cortisol secretion (MACS) have been associated with increased cardiovascular events and risk factors. However, limited data exist on the association of adrenal adenomas with cardiometabolic outcomes in the population-based setting. Aim: 1) To determine the prevalence of cardiovascular co-morbidities and events and 2) to assess mortality in a population-based cohort of patients with adrenal adenomas. Methods: We identified adult patients living in the community diagnosed with an adrenal tumor from 1995-2017 using a medical records linkage system. Adrenal tumors were classified as MACS if cortisol was ≥1.8mcg/dL after 1 mg dexamethasone suppression test, NFAT if cortisol was <1.8 mcg/dL, and adenoma with unknown cortisol secretion (AUCS) if dexamethasone suppression test was not performed. Cardiovascular co-morbidities and events were assessed at baseline. Patients were then followed until death, migration out of the community, or through December 31, 2018. Results were compared to age and sex matched reference subjects without adrenal tumors and adjusted for tobacco use and BMI. Results: A total of 1,003 patients had adrenal adenomas with 136 (14%) NFAT, 86 (9%) MACS, and 781 (78%) AUCS. The median age of diagnosis was 63 years (range, 20-96) and 581 (58%) were women. At baseline, patients with adrenal adenomas were more likely to have hypertension (92% vs 81%, p<0.001), overweight/obesity (89% vs 82%, p<0.001), pre-diabetes/diabetes (82% vs 70%, p<0.001), dyslipidemia (89% vs 82%, p<0.001), and chronic kidney disease (11% vs 7%, p=0.004) than age and sex matched reference subjects. Myocardial infarctions (13% vs 8%, p <0.001), coronary intervention (9% vs 6%, p= 0.007), heart failure (12% vs 6%, p<0.001), peripheral vascular disease (26% vs 15%, p<0.001), and thromboembolic disease (7% vs 3%, p<0.001) were more prevalent in patients with adrenal adenomas, whereas overall survival was lower compared to reference subjects (60% vs 65%, p value = 0.013). Subgroup analysis (adjusted for age, sex, BMI, and smoking) demonstrated prevalence of cardiovascular events including peripheral vascular disease was highest in those with MACS (44.7%), followed by AUCS (40.1%), and then NFAT (36.6%), although differences between groups were not significant. Overall survival was lower in patients with MACS (62%) and AUCS (59%) compared to NFAT (71%), p<0.001. Conclusions: Adrenal adenomas are associated with significantly higher prevalence of cardiovascular risk factors and morbidity at the time of diagnosis and with increased morality during follow-up. Results are potentially related to abnormal cortisol secretion but are limited by suboptimal evaluation for hormone excess.