Germline Variants in Sporadic Pituitary Adenomas.

Context: Data on germline genetics of pituitary adenomas (PAs) using whole-exome sequencing (WES) are limited. Objective: This study investigated the germline genetic variants in patients with PAs using WES. Methods: We studied 134 consecutive functioning (80.6%) and nonfunctioning (19.4%) PAs in 61 female (45.5%) and 73 male patients (54.5%). Their median age was 34 years (range, 11-85 years) and 31 patients had microadenomas (23.0%) and 103 macroadenomas (77%). None of these patients had family history of PA or a known PA-associated syndrome. Peripheral blood DNA was isolated and whole-exome sequenced. We used American College of Medical Genetics and Genomics (ACMG) criteria and a number of in silico analysis tools to characterize genetic variant pathogenicity levels and focused on previously reported PA-associated genes. Results: We identified 35 variants of unknown significance (VUS) in 17 PA-associated genes occurring in 40 patients (29.8%). Although designated VUS by the strict ACGM criteria, they are predicted to be pathogenic by in silico analyses and their extremely low frequencies in 1000 genome, gnomAD, and the Saudi Genome Project databases. Further analysis of these variants by the Alpha Missense analysis tool yielded 8 likely pathogenic variants in 9 patients in the following genes: AIP:c.767C>T (p.S256F), CDH23:c.906G>C (p.E302D), CDH23:c.1096G>A (p.A366T), DICER1:c.620C>T (p.A207V), MLH1:c.955G>A (p.E319K), MSH2:c.148G>A (p.A50T), SDHA:c.869T>C (p.L290P) and USP48 (2 patients): c.2233G>A (p.V745M). Conclusion: This study suggests that about 6.7% of patients with apparently sporadic PAs carry likely pathogenic variants in PA-associated genes. These findings need further studies to confirm them.

Efficacy and safety of empagliflozin: a "real-world" experience from Saudi Arabia.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are new agents for treating type 2 diabetes. In addition to the glycemic benefits, these agents provide cardiorenal protection in patients with diabetes and without diabetes. There is consistent evidence that these agents increase the risk of genitourinary infections and dehydration, but randomized controlled trials have not included patients from the Middle East. OBJECTIVES: Determine the efficacy and safety of empagliflozin, specifically whether the genitourinary infection risk differs in our population and whether there is an increased risk of dehydration, ketoacidosis, hypoglycemia, and hospitalization with fasting. DESIGN: Retrospective review of medical records. SETTINGS: Department of medicine at tertiary care center. PATIENTS AND METHODS: We reviewed the electronic records of patients with type 2 diabetes who took empagliflozin from 1 December 2018 to 30 November 2019. We collected safety and efficacy data for 12 months from the initiation of treatment. MAIN OUTCOMES MEASURES: Glycemic and weight loss efficacy, risk of hospitalization due to hypoglycemia, dehydration, and genitourinary infections. SAMPLE SIZE: 637 patients. RESULTS: We observed an improvement in glycated hemoglobin, a 4.2% weight loss, improved left ventricular function, stable serum creatinine, and reduced albuminuria. Our patients did not have an increased risk of genitourinary infections, hypoglycemia, dehydration, ketoacidosis, or hospitalizations. Fasting did not increase the incidence of adverse events. CONCLUSIONS: Empagliflozin is safe and effective in our local population. We hypothesize that glycosuria induced by empagliflozin is not the sole contributor to the increased risk of genitourinary infections. Local hygiene and circumcision might reduce this risk. Empagliflozin can be used safely during fasting. LIMITATIONS: Retrospective design. CONFLICT OF INTEREST: None.

Lenvatinib-induced multiorgan adverse events in Hurthle cell thyroid cancer: A case report.

BACKGROUND: The management of metastatic progressive radioiodine-resistant differentiated thyroid cancer remains challenging for clinicians. The availability of tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, within the last decade has expanded treatment options; however, these lead to significant adverse effects, which may curtail their use. CASE SUMMARY: We report the case of a 47-year-old female with Hurthle cell thyroid cancer who underwent total thyroidectomy followed by radioiodine ablation. During follow-up, she developed noniodine-avid renal and pulmonary metastases. With respect to her pre-existing diabetes, hypertension, and polycystic kidney disease, the tumor board decided against performing renal metastasectomy because of the risk of future renal decline requiring dialysis. Metastases were treated using sorafenib, which provided stability followed by progression within a year. We switched to lenvatinib, which led to disease regression. However, the patient experienced severe adverse effects, including cardiomyopathy, bicytopenia, renal impairment, and the rarely reported nephrotic syndrome. Renal metastasis is a rare manifes-tation of Hurthle cell thyroid cancer with only two reported cases in literature. We report the experience of our first case of renal metastasis and its treatment with TKIs. This case serves as a reminder of the adverse drug reactions associated with TKI use. CONCLUSION: We advocate close monitoring of patients' hematological and renal profiles as well as their cardiac status using an echocardiogram.

The Impact of COVID-19 Viral Infection on the Hypothalamic-Pituitary-Adrenal Axis.

OBJECTIVE: To study the adrenocortical response to an acute coronavirus disease-2019 (COVID-19) infection. METHODS: Morning plasma cortisol, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate levels were measured in 28 consecutive patients with COVID-19 (16 men, 12 women, median age 45.5 years, range 25-69 years) on day 1 to 2 of hospital admission. These tests were repeated twice in 20 patients and thrice in 15 patients on different days. The hormone levels were correlated with severity of the disease. RESULTS: The median morning cortisol level was 196 (31-587) nmol/L. It was <100 nmol/L in 8 patients (28.6%), <200 nmol/L in 14 patients (50%), and <300 nmol/L in 18 patients (64.3%). The corresponding ACTH values had a median of 18.5 ng/L (range 4-38 ng/L), and the ACTH level was <10 ng/L in 7 patients (26.9%), <20 ng/L in 17 patients (60.7%), and <30 ng/L in 23 patients (82.1%). The repeated testing on different days showed a similar pattern. Overall, if a cutoff level of <300 nmol/L is considered abnormal in the setting of acute disease, 9 patients (32%) had cortisol levels below this limit, regardless of whether the test was done only once (3 patients) or 3 times (6 patients). When the disease was more severe, the patients had lower cortisol and ACTH levels, suggesting a direct link between the COVID-19 infection and impaired glucocorticoid response. CONCLUSION: Unexpectedly, the adrenocortical response in patients with COVID-19 infection was impaired, and a significant percentage of the patients had plasma cortisol and ACTH levels consistent with central adrenal insufficiency.

Comparing the utility of 30- and 60-minute cortisol levels after the standard short synacthen test to determine adrenal insufficiency: A retrospective cross-sectional study.

Short Synacthen test (SST) involves measuring the baseline, 30-, and 60-minute serum cortisol levels, after injecting 250 µg of synthetic adrenocorticotropic hormone or Synacthen (ACTH). This study aimed to review the current clinical practice of performing SST to establish a standardized test protocol and to additionally test the hypothesis regarding performing the 60-minute cortisol test alone and the dependence of overall SST result on baseline cortisol level.Patients >14 years who underwent SST from January 2010 to December 2017 were included. Pearson's chi-square cross-tabulation was used to identify individuals with inconsistent 30- and 60-minute serum cortisol test results. Logistic regression analysis was performed to predict normal responses based on the baseline cortisol value.Of the 965 patients identified from pharmacy, medical, and laboratory records, 849 were included. Mean baseline, 30-, and 60-minute cortisol levels after ACTH injection were 394 ±â€Š286.58, 722 ±â€Š327.11, and 827 ±â€Š369.30 nmol/L, respectively. Overall, 715 (84%) and 134 (16%) patients had normal and abnormal responses, respectively. Primary and secondary adrenal insufficiency was diagnosed in 10% and 35%, respectively, while ACTH levels were not measured in 55% of the patients. Overall, 9.49% (n = 72) of the patients had a suboptimal response at 30 minutes, but reached the threshold value of 550 nmol/L at 60 minutes. This particular subgroup's mean change (240 nmol/L) in cortisol level from baseline to 30-minute was higher than that observed in patients with abnormal response at both time-points (mean change, 152 nmol/L). No patient with 30-minute optimal responses had 60-minute suboptimal responses. The baseline serum cortisol threshold of ≥226 nmol/L had 80% sensitivity, 71% specificity, and 93% positive predictive value for detecting a normal SST (P-value < .0001).Relying on a 60-minute cortisol level can identify all normal and abnormal responses, while relying on 30-minute cortisol level alone may produce false-positives. Additionally, a baseline cortisol level of ≥226 nmol/L is a reliable threshold for determining adequate adrenal function, particularly with a low pretest hypoadrenalism probability.

A Life-Changing Moment in a Patient with Type 1 Diabetes: Insulin Holiday.

BACKGROUND: The diagnosis of type 1 diabetes can be a life-changing moment for our patients particularly having to live with the idea of taking insulin all their life and the barriers it can bring about. CASE REPORT: We report a patient with ten years of autoimmune type 1 diabetes treated with insulin. He was able to stop insulin in favour of oral diabetes agents after dynamic endocrine tests confirmed micro insulin secretion despite autoimmunity. Our case demonstrates that a detailed history and thorough investigations adopting a holistic approach can sometimes change the course of disease management and can leave a positive impact on the life of our patients. CONCLUSION: Patients with partial retention of beta-cell function in type 1 diabetes can temporarily stop insulin safely with ongoing surveillance.

Rivaroxaban Experience at Tertiary Care Centre in Saudi Arabia:A Retrospective Observational Study.

BACKGROUND: Atrial fibrillation (AF) and Venous Thromboembolism (VTE) are significant causes of morbidity and mortality. Direct oral anticoagulants (DOACs) are as effective as vitamin K antagonists (VKAs) with a propensity to cause less major bleeding. This study aimed to assess the safety and effectiveness of rivaroxaban in routine clinical practice in a large tertiary referral center in Saudi Arabia. MATERIALS AND METHODS: In this study, patients who received rivaroxaban at a tertiary referral hospital were included in this study. All adverse events were recorded, including major bleeding, non-major bleeding events, symptomatic thromboembolic events (deep vein thrombosis, pulmonary embolism) and all-cause death. RESULTS: A total of 509 patients were prescribed rivaroxaban during the study period. The most common indication for rivaroxaban was non-valvular AF (65.3%) and VTE (34.7%). The mean age was 60.4 ± 16.4 years, and 50.8% were female. The median CHA2DS2-Vasc score was 2.1 in patients on rivaroxaban for non-valvular AF. Bleeding occurred in 72 (14.1%) patients, of which 20 (3.9%) had major bleeds. Thrombosis events occurred in 13 (2.5%) patients in the overall cohort. Fourteen (2.7%) patients died during the study, including a case of fatal bleeding secondary to rivaroxaban. CONCLUSION: This study describes the use of rivaroxaban in a broad patient population in clinical practice in the Middle East. The overall bleeding and thrombosis rates in this study were comparable to those seen in major clinical trials.

Recurrent neutropenia due to dopamine agonists in a patient with microprolactinoma.

OBJECTIVE: The objective of our case report is to increase the awareness of neutropenia as a rare but potentially serious adverse outcome of commonly used dopamine agonists for the treatment of prolactinomas. METHODS: This report reviews the clinical history, diagnosis, investigations, and drug treatment of our patient. RESULTS: Neutropenia was recurrent after changing to various different dopamine agonists necessitating surgical treatment of a prolactinoma. CONCLUSION: This case serves a reminder of this adverse drug reaction. Considering the significant impact and potentially a life threatening outcome, we advocate routine monitoring of full blood count prior to and during the treatment with dopamine agonists.