Citations

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.

Abstract Background: Ectopic thyroid involves the presence of thyroid tissue in sites other than its normal anatomic location. Dual ectopic thyroid with normally located thyroid gland is extremely rare with only a few cases reported in the literature. Clinical Case: A 24-year-old female presented to the clinic with subclinical hypothyroidism (TSH of 10.54 uIU/ml [ref, 0.27–4.2] and free T4 of 12.96 pmol/L [ref, 12–22]). She noted a gradually enlarging submental mass during the preceding year, which had been present since her adolescent years. Examination was notable for a 2-cm firm, non-tender mass at the submental region that slightly moved with deglutition. The thyroid was not palpable in its normal location. The relaxation phase of the deep tendon reflex was prolonged. Repeat laboratory testing showed persistently elevated TSH of 13.3 uIU/ml and normal free T4 of 13.39 pmol/L. TPO antibody was normal. Thyroid ultrasonography showed a hypoplastic thyroid measuring 2.7 x 0.7 x 0.4 cm on the right and 3.0 x 0.7 x 0.4 cm on the left. A well-circumscribed complex nodule measuring 2.7 x 3.2 x 2.1 cm was noted on the submental region corresponding to the patient’s submental mass. Computed tomography of the neck with contrast showed two hyperdense foci - measuring 3.0 x 2.4 cm at the submental region and 1.4 x 1.2 cm at the base of the tongue. No enhancing thyroid tissue was seen anterior to the thyroid cartilage. 99mTechnetium-pertechnetate scan showed absent focal tracer uptake in the anterior neck and thorax. There were foci of increased tracer activity in the submental and lingual regions. Ultrasound-guided biopsy of the submental area showed cytomorphologic features of a colloid nodule with cystic degeneration (Bethesda Category II). The patient was started on levothyroxine and remained biochemically euthyroid afterwards. The submental neck mass reduced in size. Conclusion: Dual ectopic thyroid with normally located (eutopic) thyroid gland could present with subclinical hypothyroidism. There is no single diagnostic modality that would best identify dual ectopic thyroid; thus, thyroid scan, ultrasonography, CT scan and biopsy are recommended to be used complementarily. For patients with dual ectopic thyroid and hypothyroidism, levothyroxine replacement is recommended to reduce the size of ectopic thyroid and render the patient euthyroid.

Abstract Background: Maturity onset diabetes in young 3 (MODY 3) is caused by mutation of the hepatic nuclear factor 1 alpha (HNF-1A) gene. Craniofacial macrosomia (CFM) is associated with an abnormal development of craniofacial structures during the embryonic period. Maternal diabetes and genetic predisposition have been associated with CFM1. There are rare reports about an association of MODY 3 and CFM. Clinical case: An 11-year-old male patient presented with right side CFM (mild mandibular hypoplasia, internal auditory canal absence, severe pinna hypoplasia, abnormal orbital size and location, O3.M0.E3.N0.S02) noted at 8 months of age. Preoperative examination revealed A1c at 10.9%. After short term intensive insulin therapy, he had standard bread meal test: fasting glucose 8.11 mmol/L, insulin 13.9 mIU/L (3-25), C-peptide 1.25 ng/ml (0.81-3.85); 1 hour glucose 10.05 mmol/L, insulin 27 mIU/L, C-peptide 2.42 ng/ml; 2 hour glucose 8.17 mmol/L, insulin 16.09 mIU/L, C-peptide 2.11 ng/ml. GADA, IAA and ICA were negative. The mother was diagnosed diabetes at age 27years, when the patient was 8-month-old, and received insulin therapy. The mother was blind by age 35years due to diabetic retinopathy and died of DKA at 38-years-old. The patient’s 16-year-old brother had left side CFM (O2.M1.E2.N0.S0) and his OGTT was normal. The father was diagnosed with impaired glucose tolerance. The family had whole genome sequencing by Sanger technique, and resequenced the mutation with side primers. The CGA to CAA mutation was present at the 686 loci of exon 3 of HNF1A gene in the patient and mother. The HNF1A exon 3 mutation of CGA to CAA resulted in the change of arginine to glutamine which by the HGMA database is recognized as a reported MODY3 gene mutation. There was a mutation of G to A in the 4 loci of exon 1 of the insulin coding region in chromosome 11 in both the patient and elder brother. Neither elder brother nor father had the CGA mutation of HNF1A. Conclusion: There has not been a previous report of a relationship between HNF1A and CFM. In this case, the elder brother had CFM without a HNF1A mutation which does not support a connection between CFM and HNF1A. The two brothers both had CFM and insulin coding gene mutations which would represent a new association not previously described. Further testing is needed to confirm a relationship between the two. Reference: 1. Chen Q, Zhao Y, Shen G, Dai J. Etiology and Pathogenesis of Hemifacial Microsomia. J Dent Res 2018; 97(12): 1297-305. 2. Gougoutas AJ, Singh DJ, Low DW, Bartlett SP. Hemifacial microsomia: clinical features and pictographic representations of the OMENS classification system. Plast Reconstr Surg 2007; 120(7): 112e-20e.

Abstract Background: Vitamin D deficiency is common in patients presenting with low energy hip fractures. The relationship between Vitamin D levels at the time of a fracture with long term functional outcomes has not been studied. Identifying a benefit to recovery with adequate vitamin D would support supplementation in elderly patients at risk for hip fracture. Methods: A retrospective cohort of patients >/= 50 years, who were treated surgically for low energy hip fracture between July 1 2016 and June 30 2018 were identified. The correlation between Vitamin D levels and functional recovery, assessed using the time up and go (TUG) test, survival at 3 months and 1 year, and readmission within 3 months was examined. The Charlson comorbidity index (CCI) at baseline was also assessed. Results: A total of 216 patients were treated for a hip fracture of which 174 were included with measured baseline Vitamin D levels. A majority were female (112, 64.4%), mean age 79.6 years (+/-11.9), mean Vitamin D level 28.2 ng/ml (+/- 12.4) and mean CCI 5.9 (+/- 2.5). Vitamin D <20 ng/ml was seen in 39 (22.4%) patients and all received appropriate supplementation. 39 (22.4%) individuals died within a year of surgery, among whom 17 (43.6% of 39) passed away within 3 months. 36 (20.7%) were readmitted within 3 months of surgery and 14 (8%) sustained a second fracture within a year. The correlation of Vitamin D levels, taken as a continuous variable, to outcomes, was analyzed using logistic regression. Although not significant, higher Vitamin D was found to be protective against death within 3 months (OR=0.995, p=0.8), but actually increased the odds of death within 1 year (OR=1.008, p=0.62), readmission within 3 months (OR=1.001, p=0.96), second fracture within 1 year (OR=1.017, p=0.33) and failure to recover (OR=1.002, 0.86). After adjusting for age, gender and CCI, Vitamin D levels were non-significantly inversely associated with both TUG 1 and TUG2, with every 1 unit higher Vitamin D associated with a TUG lowered by 0.15 seconds, p=0.42 and 0.44. Vitamin D was poorly correlated to CCI with correlation coefficient of 0.02, p = 0.71. Conclusions: Our results indicate that Vitamin D levels at the time of a hip fracture do not correlate with patients’ functional outcomes. It is possible that replacing vitamin D eliminated the possible negative impact on functional recovery.

Abstract Background: Adrenal adenoma is reported in around 5% of adults undergoing cross-sectional imaging. Although most adenomas are considered non-functioning (NFAT), up to 48% present with mild autonomous cortisol secretion (MACS). Several studies reported increased prevalence and incidence of vertebral fractures in MACS; however conclusions are limited by small sample size, selection bias, inadequate reference population and length of follow up. Objective: To determine the prevalence and incidence of site-specific fragility fractures in a population-based cohort of patients with adrenal adenomas. Methods: Residents of local community with a radiographic diagnosis of adrenal adenoma between 1995 and 2017 were identified using a centralized epidemiologic database and matched with reference subjects for sex and age. All subjects were followed through 2017, until death or migration from the community. MACS was diagnosed based on cortisol level ≥1.8 mcg/dl after overnight 1mg dexamethasone suppression, NFAT based on cortisol level <1.8 mcg/dl, and patients not tested with dexamethasone were considered as adenoma with unknown cortisol secretion (AUCS). Results: Of 1003 patients with adrenal adenomas (581 women (58%), median age of diagnosis 63 years (20–96)), 136 (14%) were diagnosed with NFAT, 86 (9%) with MACS, and 781(78%) with AUCS. At the time of diagnosis, patients had higher BMI (median 30 vs 28 kg/m2, p<0.001), and higher prevalence of tobacco use (70% vs 54%, p<0.001) than reference subjects. Of 154 patients and 113 reference subjects with BMD available at baseline, patients had a higher median BMD at the total hips (0.93 vs 0.89, p=0.02) but similar median BMD at lumbar spine (1.05 vs 1.03, p=0.49) when compared to reference subjects. However, patients had a higher prevalence of fractures than reference subjects (any fracture: 50% vs 42%, p<0.001, vertebral fracture: 6.5% vs 3.7%, P=0.004). When adjusted for age, sex, and prior history of fracture, patients with adenoma had HR of 1.24 (CI 95% 1.04–1.48) for developing a new fracture and HR of 1.18 (CI 95% 0.97–1.44) when also adjusted for BMI and smoking. Subgroup analysis demonstrated that the prevalence of fractures at the time of diagnosis was higher in all 3 subgroups at any fragility fracture site when compared to reference subjects (NFAT: 44% vs 37%, MACS: 48% vs 43%, AUCS: 51% vs 43%); patients with MACS had the highest incidence of new fracture after 5 years of follow up when compared to AUCS and NFAT (cumulative incidence: MACS 25% vs NFAT 19% vs AUCS 16%), though the differences were not significant. Conclusions: Patients with adrenal adenomas have higher prevalence of fractures at the time of diagnosis. During follow up, patients with adenoma have a higher incidence of fractures even when adjusted for sex, age, and prior history of fracture, possibly due to underlying undiagnosed abnormal cortisol secretion.

Abstract Background: Adrenal insufficiency (AI) is a chronic disorder necessitating life-long replacement. Patients’ quality of life and health outcomes depend on knowledge and comfort level with self-management. Objective: To determine patients’ knowledge in regards to diagnosis and management, estimate burden of disease and to identify predictors of adverse outcomes in patients with AI Methods: Survey study of patients with AI evaluated at two tertiary medical centers between 2015 and 2019. Collected variables included data on circumstances of AI diagnosis, symptoms, management, burden of disease, and overall well-being. Results: Among 785 patients (mean age at diagnosis 44.2 ± 18.0, 64% women, and 92% Caucasian), 310 (40%) had primary AI (PAI), 255 (33%) had secondary AI (SAI) not related to glucocorticoid use, and 211 (27%) had steroid-induced AI (SIAI). Patients were diagnosed with AI after presenting with symptoms for a median of 1 year (0-6), 28% with symptoms lasting >2 years, 44% visiting emergency room (ER) at least once prior to diagnosis. A third of patients reported a discordant diagnosis from their medical record. Baseline glucocorticoid replacement therapy included hydrocortisone (HC) in 447 (59%), median of 20 mg (IQR 15 - 25mg), prednisone in 190 (25%), median of 5 mg (IQR 4 - 7.5mg), other regimens in 38 (5%), and no steroids in the remainder (85, 11%); 197 (26%) patients reported daily equivalent HC dose of >25 mg. Overall, 549 (73%) of patients reported use of stress dose steroids at least once per year, higher in patients taking HC >25 mg/day (3.2 vs 2.7 times per year if HC<25mg/day, p=0.01). Improper use of stress steroids was reported in 193, 25% patients. Patients taking HC>25 mg /day reported a higher number of adrenal crises (1.6 vs 1.3 in patients on HC<25 mg/day, p=0.04). Among 314 (41%) patients who reported ER visits due to adrenal crisis, only a third received prompt glucocorticoids. One third of patients described their general health as fair or poor. Predictors of negative perceptions of overall health included SIAI (OR 6.2 and 2.5, vs PAI and SAI respectively), poor understanding of diagnosis (OR 2.6), daily HC>25 mg (OR 2.1), and presence of at least one adrenal crisis (OR 2.3) (p<0.001 for all). Conclusion: Patients with AI experience delay in diagnosis, and a third do not fully understand their diagnosis. In addition to patient education, interventions to improve general health and outcomes may include selecting a physiological glucocorticoid replacement therapy, prevention of adrenal crisis, and improving ER care.

Abstract OBJECTIVE: Low dose dexamethasone suppression testing (DST) is standard of care in patients with adrenal incidentalomas or suspected endogenous hypercortisolism. False positive total serum cortisol (TC) results occur due to poor absorption, rapid metabolism or estrogen use. Free serum cortisol (FC) measurement is an alternative, but optimal cut-offs are unknown. We aimed to establish the optimal serum dexamethasone concentrations (DEXA) to interpret TC and FC results and identify reasons for discrepancies between TC and FC values in healthy male and female (with and without oral contraceptive therapy, OCT) subjects. METHODS: Single center prospective study of healthy subjects >17 years old undergoing assessment with DST between 2016 and 2019. Measurement of FC and DEXA was performed by tandem mass spectrometry and TC by immune-enzymatic assay at 8 AM following overnight administration of 1 mg dexamethasone at 11pm. Subjects were excluded if they had a known adrenal adenoma, any form of endogenous cortisol excess, or exogenous steroid use. RESULTS: DST was performed in 165 healthy volunteers, median age of 29.5 (18-74) years; 53 men (32%) and 112 (67%) women, median BMI 25 (18-42) kg/m2, 47 (42%) of which were taking OCT (median daily ethinyl-estradiol dose of 30 (20-35) mcg). The median DEXA was 0.34 (0.09-1.12) mcg/dl, median TC was 0.8 (0.25-15.7) mcg/dl and median FC was 24 (4-714) ng/ml. TC and FC measurements were highly correlated (r2=0.89, p<0.0001). The median FC/TC was 3% (0.3-6.7), lowest in women on OCT (median 2.5% vs 3.3% in women not on OCT and men, p<0.0001). TC>1.8 mcg/dl was demonstrated in 18 (11%) healthy subjects (men: 3/53, 5.7% vs women not on OCT: 3/65, 4.6% and women on OCT: 12/47, 25.5%, p=0.0007). Excluding women on OCT, the proportion of subjects with TC>1.8 was higher when DEXA was <0.2mcg/dl (4/15, 27%) vs when DEXA was >0.2mcg/dl (2/101, 2%),(p<0.0001). After excluding 24 (14%) healthy subjects with DEXA <0.2 mcg/dl, in the remaining 142 subjects (51 (35%) men, 54 (38%) women not on OCT and 39 (27%) women on OCT), median TC was 0.75 (0.25-4.6) mcg/dl and median FC was 23 (4-103) ng/ml). Significant differences were noted in both TC and FC following DST within subgroups: men vs women not on OCT vs women on OCT, TC: 0.6 vs 0.7 vs 1.3 mcg/dl, (p<0.0001) and FC: median 20 vs 22 vs 31 ng/ml, (p<0.0001). All men and all women not on OCT demonstrated post-DST FC <50 ng/ml (97.5% cutoff of 47 and 37), while women on OCT demonstrated post-DST FC <50 in 80% and FC<75 in 95%. CONCLUSION: Post-DST TC>1.8 mcg/dl was demonstrated in 11% of all healthy subjects, of which 1 in 4 were women on OCT and 1 in 4 had DEXA<0.2 mcg/dl. Simultaneous measurement of serum DEXA during DST may be valuable when false positive results are suspected. Despite a lower FC/TC ratio in women on OCT, post-DST FC cutoffs were higher in women on OCT. Measurement of FC after DST may be helpful in some but not all women on OCT.

Abstract Background: Hypophosphatemia has been recognized as one of the side effect of intravenous ferric carboxymaltose infusion. This effect is thought to be secondary to fibroblast growth factor 23 (FGF 23) mediated renal phosphate wasting and associated with calcitriol deficiency and secondary hyperparathyroidism. Clinical Case: A 76 years old male patient with medical problems including hypertension, type 2 diabetes mellitus, hyperlipidemia, paroxysmal atrial fibrillation, nephrolithiasis, spinal stenosis and chronic anemia was referred to endocrinology clinic for osteoporosis management. Bone density scan showed left femur neck T-score of -2.5 and L1-L4 lumbar spine T-score of 1.4. He reported pain on back and bilateral posterior thighs, difficulty with ambulation which were partly attributed to severe spinal stenosis that he was planned to have surgery for. Muscle strength was normal on examination. Laboratory studies were obtained for osteoporosis work up and showed: Calcium: 8.9 mg/dL (8.8-10.2 mg/dL), Creatinine: 0.77 mg/dL (0.74-1.35 mg/dL), GFR: 88 mL/min/BSA, Albumin 4.5 g/dL (3.5-5.0 g/dL), 25-Hydroxy vitamin D: 26 ng/mL, Magnesium 1.8 mg/dL (1.7-2.3 mg/mL), 1,25 Dihydroxy Vitamin D 24 pg/mL (18-64 pg/mL), Phosphorus: 1 mg/dL (2.5-4.5 mg/dL), PTH 163 pg/mL (15-65 pg/mL), Hemoglobin 12.9 mg/dL (13.2-16.6 mg/dL). Due to hypophosphatemia tumor induced osteomalacia diagnosis was entertained and further work up was considered in this regard however later noted that patient received ferric carboxymaltose 750 mg infusion two times within last 3 weeks for iron deficiency anemia. Hemoglobin level was 8.6 mg/dL before the infusions. After oral phosphate replacement the phosphate level improved to 2.4 mg/dL. Serum FGF 23 level was measured and it was normal at 108 RU/mL (<180 RU/mL). He was then started on bisphosphonate treatment for osteoporosis. Conclusion: Hypophosphatemia and secondary hyperparathyroidism can be seen after ferric carboxymaltose infusion due to FGF-23 mediated mechanism. In literature various presentations were reported from transient- asymptomatic hypophosphatemia to severe acute symptomatic hypophosphatemia along with persistent hypophosphatemia with osteomalacia and fragility fractures due to recurrent ferric carboxymaltose infusions. Thus, one should keep this possible side effect in mind during evaluation of hypophosphatemia and osteoporosis. References: 1. Wolf M, Chertow GM, Macdougall IC, Kaper R, Krop J, Strauss W. Randomized trial of intravenous iron-induced hypophosphatemia. JCI Insight. Dec 6 2018;3(23):e124486 2. Fang W, McMahon LP, Bloom S, Garg M. Symptomatic severe hypophosphatemia after intravenous ferric carboxymaltose. JGH Open. October 2019, volume 3, issue 5, P 438-440

Abstract Background: Unlike with solid organ cancers, little data is available on how diabetes mellitus (DM) and hematologic malignancies interact to affect survival and glycemic control. We examined the impact of DM on survival in patients with leukemia and the effect of leukemia on glycemic control. Materials and Methods: Patients with leukemia with and without DM were matched 1:1 (2007–2017), 70 matched pairs (total N=140 pts) were included in the analysis. We compared characteristics between cases and controls and assessed survival with the Kaplan-Meier method and Cox proportional hazards model. Mixed models compared hemoglobin A1c (HbA1c) and glucose levels over time. Results: The median age of patients at diagnosis was 56 (18–94); 60% were male and 89% had acute leukemia. Among those with DM, HbA1c was only recorded in 25 of 70 patients during the year following cancer diagnosis and was 6.8%. There was no change in HbA1c values over time in these DM patients. Mean glucose was significantly different between DM and non-DM patients (p<0.001). Time (days since leukemia diagnosis) was significant (p<0.001) and there was a significant interaction effect (p=0.01). Glucose values increased in the DM patients during the year following diagnosis, while remaining stable in those without DM. Median follow-up time was 23.2 months. Three-year survival was estimated at 46% for DM patients versus 45% in non-DM pts by Kaplan Meier method (p=0.79). Hazard ratio (stratification for matched pairs) was 1.05 (95% CI: 0.57 - 1.94; p=0.88). Three-year relapse-free survival was estimated at 34% for DM patients versus 43% for non-DM patients (p=0.58). Hazard ratio (stratification for matched pairs) = 1.10 (95% CI: 0.61–1.98; p=0.76). Conclusions: DM did not adversely impact survival in patients with leukemia. Leukemia and its treatment did not affect glycemic control. This should be reassuring to hematologists and endocrinologists who treat patients with leukemia and diabetes.

Abstract Background: We have previously examined the link between diabetes mellitus (DM) and malignancy with respect to mortality, but little is known about how the cancer affects glycemic control. Therefore, the aim of this study was to evaluate metabolic parameters in patients with cancer with and without DM. Methods: We selected 1404 patients with newly diagnosed prostate, breast, lung, colorectal, and pancreatic cancer from the institutional cancer registry from 2010–2015. Records were selected and matched 2:1 cancer without DM (n=936) and cancer and concurrent DM patients (n=468). Patients were matched by year of diagnosis, age, gender, and cancer type. Metabolic parameters during the year after cancer diagnosis were examined using linear mixed models with fixed effects for time, cancer type, DM status and individual-specific random effect allowing each patient to have a different intercept. Results: Prostate cancer accounted for the majority of cases (n=199), followed by lung cancer (n=91), breast cancer (n=71), colorectal cancer (n=54), and pancreas cancer (n=53). Mean overall hemoglobin A1c (HbA1c) was 6.9 (1.2)%. Pancreas cancer patients had higher HbA1c overall (p=0.02). There was no change in HbA1c one year post cancer diagnosis (p=0.28). Mean glucose in non-DM was 108(18) mg/dL and 146 (45) mg/dL in DM pts. Lung and pancreas cancer patients had higher glucose values overall (p<0.001). Time (p<0.001), DM (p<0.001) and time * DM (p=0.02) were significant in a mixed model. A decrease in glucose over the year was observed in DM patients across all cancer types. Conclusions: A diagnosis of malignancy does not worsen glycemic control within the first year of cancer diagnosis. This should be reassuring to endocrinologists and oncologists who treat patients with DM and cancer. Longer term studies, and analysis in larger and more diverse patients groups are needed.