Publications by authors named "Mihail Zilbermint"

36 Publications

Lower hair cortisol among patients with sickle cell disease may indicate decreased adrenal reserves.

Am J Blood Res 2021 15;11(2):140-148. Epub 2021 Apr 15.

Social and Behavioral Research Branch, National Human Genome Research Institute, National Institutes of Health Bethesda, Maryland, USA.

Introduction: Sickle cell disease (SCD) is a chronic illness that presents with a wide range of phenotypic variation. Stress may be a contributing factor to differences that are found in this population.

Objectives: Our objective is to determine the relationship between hair cortisol content (HCC), a biomarker of stress, and other clinical measures in individuals with SCD.

Methods: We collected hair samples and other clinical measures from 73 subjects with SCD (mean age: 39 ± 12 years, 63% female).

Results: HCC was lower among individuals who had greater than 30% hemoglobin S, compared with those who had less than 30% hemoglobin S (W=272.5, P=0.01). Lower HCC was also associated with report of not being on a chronic transfusion program (β=48.34, SE=14.09, P=0.001) and higher ferritin levels (β=-0.006, SE=0.002, P=0.02). Furthermore, HCC was significantly correlated with serum cortisol (r=0.26, P=0.03) and corticosterone (r=0.29, P=0.01). We also observed a consistent pattern of low steroid values among our population.

Conclusion: Our findings suggest that individuals with higher hemoglobin S and ferritin, both markers of severe SCD, may have decreased cortisol levels. This is consistent with the relationship we observed between higher HCC among individuals who are on a chronic blood transfusion program, which typically increases quality of life. Our results suggest that hair cortisol may be an indicator in patients with SCD who could be at risk for developing adrenal insufficiency. We recommend that clinicians treating patients with SCD follow the Endocrine Society guidelines for testing for adrenal insufficiency and treat accordingly.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165714PMC
April 2021

The Endocrine Hospitalist: Enhancing the Quality of Diabetes Care.

J Diabetes Sci Technol 2021 May 6:19322968211007908. Epub 2021 May 6.

Johns Hopkins Community Physicians at Suburban Hospital, Bethesda, MD, USA.

The endocrine hospitalist and inpatient diabetes management team increases access to endocrinology consultations and improves glycemic control and quality metrics such as length of stay and hospital readmission. Enhanced glycemic care is needed in both academic and community hospital settings. Endocrine fellowship programs should implement endocrine hospitalist rotations with emphasis on training endocrine fellows to deliver fast-paced inpatient endocrine care. Entrepreneurship, innovation, and a "start-up" culture within the field of Endocrinology should be encouraged and supported by healthcare systems.
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http://dx.doi.org/10.1177/19322968211007908DOI Listing
May 2021

Retrospective Quality Improvement Study of Insulin-Induced Hypoglycemia and Implementation of Hospital-Wide Initiatives.

J Diabetes Sci Technol 2021 Apr 21:19322968211008513. Epub 2021 Apr 21.

Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Hospitalized patients who are receiving antihyperglycemic agents are at increased risk for hypoglycemia. Inpatient hypoglycemia may lead to increased risk for morbidity, mortality, prolonged hospitalization, and readmission within 30 days of discharge, which in turn may lead to increased costs. Hospital-wide initiatives targeting hypoglycemia are known to be beneficial; however, their impact on patient care and economic measures in community nonteaching hospitals are unknown.

Methods: This retrospective quality improvement study examined the effects of hospital-wide hypoglycemia initiatives on the rates of insulin-induced hypoglycemia in a community hospital setting from January 1, 2016, until September 30, 2019. The potential cost of care savings has been calculated.

Results: Among 49 315 total patient days, 2682 days had an instance of hypoglycemia (5.4%). Mean ± SD hypoglycemic patient days/month was 59.6 ± 16.0. The frequency of hypoglycemia significantly decreased from 7.5% in January 2016 to 3.9% in September 2019 ( = .001). Patients with type 2 diabetes demonstrated a significant decrease in the frequency of hypoglycemia (7.4%-3.8%; < .0001), while among patients with type 1 diabetes the frequency trended downwards but did not reach statistical significance (18.5%-18.0%; = 0.08). Based on the reduction of hypoglycemia rates, the hospital had an estimated cost of care savings of $98 635 during the study period.

Conclusions: In a community hospital setting, implementation of hospital-wide initiatives targeting hypoglycemia resulted in a significant and sustainable decrease in the rate of insulin-induced hypoglycemia. These high-leverage risk reduction strategies may be translated into considerable cost savings and could be implemented at other community hospitals.
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http://dx.doi.org/10.1177/19322968211008513DOI Listing
April 2021

Inpatient Insulin Pen Implementation, Waste, and Potential Cost Savings: A Community Hospital Experience.

J Diabetes Sci Technol 2021 Apr 12:19322968211002514. Epub 2021 Apr 12.

Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Insulin pen injectors ("pens") are intended to facilitate a patient's self-administration of insulin and can be used in hospitalized patients as a learning opportunity. Unnecessary or duplicate dispensation of insulin pens is associated with increased healthcare costs.

Methods: Inpatient dispensation of insulin pens in a 240-bed community hospital between July 2018 and July 2019 was analyzed. We calculated the percentage of insulin pens unnecessarily dispensed for patients who had the same type of insulin pen assigned. The estimated cost of insulin pen waste was calculated. A pharmacist-led task force group implemented hospital-wide awareness and collaborated with hospital leadership to define goals and interventions.

Results: 9516 insulin pens were dispensed to 3121 patients. Of the pens dispensed, 6451 (68%) were insulin aspart and 3065 (32%) were glargine. Among patients on insulin aspart, an average of 2.2 aspart pens was dispensed per patient, but only an estimated 1.2 pens/patient were deemed necessary. Similarly, for inpatients prescribed glargine, an average of 2.1 pens/patient was dispensed, but only 1.3 pens/patient were necessary. A number of gaps were identified and interventions were undertaken to reduce insulin pen waste, which resulted in a significant decrease in both aspart (p = 0.0002) and glargine (p = 0.0005) pens/patient over time. Reductions in pen waste resulted in an estimated cost savings of $66 261 per year.

Conclusions: In a community hospital setting, identification of causes leading to unnecessary insulin dispensation and implementation of hospital-wide staff education led to change in insulin pen dispensation practice. These changes translated into considerable cost savings and facilitated diabetes self-management education.
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http://dx.doi.org/10.1177/19322968211002514DOI Listing
April 2021

Effects of a Dedicated Inpatient Diabetes Management Service on Glycemic Control in a Community Hospital Setting.

J Diabetes Sci Technol 2021 May 20;15(3):546-552. Epub 2021 Feb 20.

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA.

Background: Community hospitals account for over 84% of all hospitals and over 94% of hospital admissions in the United States. In academic settings, implementation of an Inpatient Diabetes Management Service (IDMS) model of care has been shown to reduce rates of hyper- and hypoglycemia, hospital length of stay (LOS), and associated hospital costs. However, few studies to date have evaluated the implementation of a dedicated IDMS in a community hospital setting.

Methods: This retrospective study examined the effects of changing the model of inpatient diabetes consultations from a local, private endocrine practice to a full-time endocrine hospitalist on glycemic control, LOS, and 30-day readmission rates in a 267-bed community hospital.

Results: Overall diabetes patient days for the hospital were similar pre- and post-intervention (20,191 vs 20,262); however, the volume of patients seen by IDMS increased significantly after changing models. Rates of hyperglycemia decreased both among patients seen by IDMS (53.8% to 42.5%, < .0001) and those not consulted on by IDMS (33.2% to 29.9%; < .0001). When examined over time, rates of hypoglycemia steadily decreased in the 24 months after dedicated IDMS initiation ( = .02); no such time effect was seen prior to IDMS ( = .34). LOS and 30DRR were not significantly different between IDMS models.

Conclusions: Implementation of an endocrine hospitalist-based IDMS at a community hospital was associated with significantly decreased hyperglycemia, while avoiding concurrent increases in hypoglycemia. Further studies are needed to investigate whether these effects are associated with improvements in clinical outcomes, patient or staff satisfaction scores, or total cost of care.
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http://dx.doi.org/10.1177/1932296821993198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120056PMC
May 2021

The Financial Impact of an Inpatient Diabetes Management Service.

Curr Diab Rep 2021 01 15;21(2). Epub 2021 Jan 15.

Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Suite 333, Baltimore, MD, 21287, USA.

Context: Diabetes is a leading metabolic disorder with a substantial cost burden, especially in inpatient settings. The complexity of inpatient glycemic management has led to the emergence of inpatient diabetes management service (IDMS), a multidisciplinary team approach to glycemic management.

Objective: To review recent literature on the financial and clinical impact of IDMS in hospital settings.

Methods: We searched PubMed using a combination of controlled vocabulary and keyword terms to describe the concept of IDMS and combined the search terms with a comparative effectiveness filter for costs and cost analysis developed by the National Library of Medicine.

Findings: In addition to several improved clinical endpoints such as glycemic management outcomes, IDMS implementation is associated with hospital cost savings through decreased length of stay, preventing hospital readmissions, hypoglycemia reduction, and optimizing resource allocation. There are other downstream potential cost savings in long-term patient health outcomes and avoidance of litigation related to suboptimal glycemic management.

Conclusion: IDMS may play an important role in helping both academic and community hospitals to improve the quality of diabetes care and reduce costs. Clinicians and policymakers can utilize existing literature to build a compelling business case for IDMS to hospital administrations and state legislatures in the era of value-based healthcare.
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http://dx.doi.org/10.1007/s11892-020-01374-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810108PMC
January 2021

Development and Validation of a Machine Learning Model to Predict Near-Term Risk of Iatrogenic Hypoglycemia in Hospitalized Patients.

JAMA Netw Open 2021 01 4;4(1):e2030913. Epub 2021 Jan 4.

Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Importance: Accurate clinical decision support tools are needed to identify patients at risk for iatrogenic hypoglycemia, a potentially serious adverse event, throughout hospitalization.

Objective: To predict the risk of iatrogenic hypoglycemia within 24 hours after each blood glucose (BG) measurement during hospitalization using a machine learning model.

Design, Setting, And Participants: This retrospective cohort study, conducted at 5 hospitals within the Johns Hopkins Health System, included 54 978 admissions of 35 147 inpatients who had at least 4 BG measurements and received at least 1 U of insulin during hospitalization between December 1, 2014, and July 31, 2018. Data from the largest hospital were split into a 70% training set and 30% test set. A stochastic gradient boosting machine learning model was developed using the training set and validated on internal and external validation.

Exposures: A total of 43 clinical predictors of iatrogenic hypoglycemia were extracted from the electronic medical record, including demographic characteristics, diagnoses, procedures, laboratory data, medications, orders, anthropomorphometric data, and vital signs.

Main Outcomes And Measures: Iatrogenic hypoglycemia was defined as a BG measurement less than or equal to 70 mg/dL occurring within the pharmacologic duration of action of administered insulin, sulfonylurea, or meglitinide.

Results: This cohort study included 54 978 admissions (35 147 inpatients; median [interquartile range] age, 66.0 [56.0-75.0] years; 27 781 [50.5%] male; 30 429 [55.3%] White) from 5 hospitals. Of 1 612 425 index BG measurements, 50 354 (3.1%) were followed by iatrogenic hypoglycemia in the subsequent 24 hours. On internal validation, the model achieved a C statistic of 0.90 (95% CI, 0.89-0.90), a positive predictive value of 0.09 (95% CI, 0.08-0.09), a positive likelihood ratio of 4.67 (95% CI, 4.59-4.74), a negative predictive value of 1.00 (95% CI, 1.00-1.00), and a negative likelihood ratio of 0.22 (95% CI, 0.21-0.23). On external validation, the model achieved C statistics ranging from 0.86 to 0.88, positive predictive values ranging from 0.12 to 0.13, negative predictive values of 0.99, positive likelihood ratios ranging from 3.09 to 3.89, and negative likelihood ratios ranging from 0.23 to 0.25. Basal insulin dose, coefficient of variation of BG, and previous hypoglycemic episodes were the strongest predictors.

Conclusions And Relevance: These findings suggest that iatrogenic hypoglycemia can be predicted in a short-term prediction horizon after each BG measurement during hospitalization. Further studies are needed to translate this model into a real-time informatics alert and evaluate its effectiveness in reducing the incidence of inpatient iatrogenic hypoglycemia.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.30913DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794667PMC
January 2021

Volumetric Modeling of Adrenal Gland Size in Primary Bilateral Macronodular Adrenocortical Hyperplasia.

J Endocr Soc 2021 Jan 29;5(1):bvaa162. Epub 2020 Oct 29.

Section on Endocrinology & Genetics (SEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.

Context: Radiological characterization of adrenal size in primary bilateral macronodular adrenocortical hyperplasia (PBMAH) has not been previously investigated.

Objective: We hypothesized that volumetric modeling of adrenal gland size may correlate with biochemical disease severity in patients with PBMAH. Secondary analysis of patients with concurrent primary aldosteronism (PA) was performed.

Design: A retrospective cross-sectional analysis of 44 patients with PBMAH was conducted from 2000 to 2019.

Setting: Tertiary care clinical research center.

Patients: Patients were diagnosed with PBMAH based upon clinical, genetic, radiographic and biochemical characteristics.

Intervention: Clinical, biochemical, and genetic data were obtained. Computed tomography scans were used to create volumetric models by manually contouring both adrenal glands in each slice using Vitrea Core Fx v6.3 software (Vital Images, Minnetonka, Minnesota).

Main Outcome And Measures: 17-hydroxycorticosteroids (17-OHS), genetics, and aldosterone-to-renin ratio (ARR) were retrospectively obtained. Pearson test was used for correlation analysis of biochemical data with adrenal volume.

Results: A cohort of 44 patients with PBMAH was evaluated, with a mean age (±SD) of 53 ± 11.53. Eight patients met the diagnostic criteria for PA, of whom 6 (75%) were Black. In the Black cohort, total adrenal volumes positively correlated with midnight cortisol (R = 0.76,  = 0.028), urinary free cortisol (R = 0.70,  = 0.035), and 17-OHS (R = 0.87,  = 0.0045), with a more pronounced correlation with left adrenal volume alone. 17-OHS concentration positively correlated with total, left, and right adrenal volume in patients harboring pathogenic variants in (R = 0.72,  = 0.018; R = 0.65,  = 0.042; and R = 0.73,  = 0.016, respectively).

Conclusions: Volumetric modeling of adrenal gland size may associate with biochemical severity in patients with PBMAH, with particular utility in Black patients.
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http://dx.doi.org/10.1210/jendso/bvaa162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716656PMC
January 2021

Diabetes and climate change.

J Community Hosp Intern Med Perspect 2020 Sep 3;10(5):409-412. Epub 2020 Sep 3.

Johns Hopkins Community Physicians at Suburban Hospital, Suburban Hospital, Bethesda, MD, USA.

Background: Diabetes mellitus, a looming crisis, is approaching worldwide epidemic proportions. In 2018, 34.2 million Americans, or 10.5% of the population had diabetes. Climate change, and in particular rising global temperatures, may exacerbate various health issues, including diabetes and ultimately lead to increased mortality.

Objectives: To identify the impact of climate change on diabetes.

Methods: A systematic literature review of Pubmed (MEDLINE database of references and abstracts on life sciences and biomedical topics from the USA National Library of Medicine at the National Institutes of Health) and Scopus (Elsevier's abstract and citation database) with the following terms: 'diabetes' [AND] 'climate change'.

Results: The following risk factors for diabetes due to climate change were identified and discussed: extreme temperatures (heat), the risk of hospitalization, shortage of medical and food supplies and urbanization.

Conclusions: Diabetes and climate change are interconnected. Extreme weather events and rising temperatures may increase morbidity and mortality in patients living with diabetes, especially in those with cardiovascular complications. Failure to mitigate climate change and the diabetes epidemic threatens the lives of many people in the U.S. and beyond.
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http://dx.doi.org/10.1080/20009666.2020.1791027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671730PMC
September 2020

Nivolumab-induced autoimmune diabetes mellitus and hypothyroidism in a patient with rectal neuroendocrine tumor.

J Community Hosp Intern Med Perspect 2020 Aug 2;10(4):338-339. Epub 2020 Aug 2.

Johns Hopkins Community Physicians, Bethesda, MD, USA.

We present a rare case of autoimmune diabetes mellitus and hypothyroidism in an elderly man initiated on nivolumab two months prior to admission for treatment of a high-grade neuroendocrine rectal tumor. This patient presented to a local community hospital with one-week history of severe nausea, thirst, and bilateral leg edema. Biochemical studies confirmed the diagnosis of diabetic ketoacidosis in the setting of autoimmune diabetes mellitus and primary hypothyroidism, likely due to nivolumab use. This case illustrates an acute complication due to secondary diabetes mellitus in the setting of a novel anticancer agent. There are three key takeaways for physicians managing patients on nivolumab. First, there should be a discussion of the benefits and risks of immunomodulatory therapy. Second, patients should be tested for immunological and other markers before being started on checkpoint inhibitors. Third, oncologists must be aware of the signs and symptoms of life-threatening hyperglycemia and severe hypothyroidism. Additional studies are needed to identify those patients at highest risk for autoimmune complications.
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http://dx.doi.org/10.1080/20009666.2020.1771126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7427449PMC
August 2020

Hospital Diabetes Meeting 2020.

J Diabetes Sci Technol 2020 09 12;14(5):928-944. Epub 2020 Aug 12.

Mills-Peninsula Medical Center, San Mateo, CA, USA.

Patients with diabetes may experience adverse outcomes related to their glycemic control when hospitalized. Continuous glucose monitoring systems, insulin-dosing software, enhancements to the electronic health record, and other medical technologies are now available to improve hospital care. Because of these developments, new approaches are needed to incorporate evolving treatments into routine care. With the goal of educating healthcare professionals on the most recent practices and research for managing diabetes in the hospital, Diabetes Technology Society hosted the Virtual Hospital Diabetes Meeting on April 24-25, 2020. Because of the coronavirus disease 2019 (COVID-19) pandemic, the meeting was restructured to be held virtually during the national lockdown to ensure the safety of the participants and allow them to remain at their posts treating COVID-19 patients. The meeting focused on (1) inpatient management and perioperative care, (2) diabetic ketoacidosis and hyperglycemic hyperosmolar state, (3) computer-guided insulin dosing, (4) and diabetes, (5) technology, (6) hypoglycemia, (7) data and cybersecurity, (8) special situations, (9) glucometrics and insulinometrics, and (10) quality and safety. This meeting report contains summaries of each of the ten sessions. A virtual poster session will be presented within two months of the meeting.
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http://dx.doi.org/10.1177/1932296820939626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477766PMC
September 2020

Inpatient Diabetes Management During the COVID-19 Crisis: Experiences From Two Community Hospitals.

J Diabetes Sci Technol 2020 Jul 2;14(4):780-782. Epub 2020 Jun 2.

Johns Hopkins University Carey Business School, Baltimore, MD, USA.

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http://dx.doi.org/10.1177/1932296820930268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673178PMC
July 2020

The Association of ARMC5 with the Renin-Angiotensin-Aldosterone System, Blood Pressure, and Glycemia in African Americans.

J Clin Endocrinol Metab 2020 08;105(8)

The Ohio State University, Columbus, Ohio.

Context: Armadillo repeat containing 5 (ARMC5) on chromosome 16 is an adrenal gland tumor suppressor gene associated with primary aldosteronism, especially among African Americans (AAs). We examined the association of ARMC5 variants with aldosterone, plasma renin activity (PRA), blood pressure, glucose, and glycosylated hemoglobin A1c (HbA1c) in community-dwelling AAs.

Methods: The Jackson Heart Study is a prospective cardiovascular cohort study in AAs with baseline data collection from 2000 to 2004. Kernel machine method was used to perform a single joint test to analyze for an overall association between the phenotypes of interest (aldosterone, PRA, systolic and diastolic blood pressure [SBP, DBP], glucose, and HbA1c) and the ARMC5 single nucleotide variants (SNVs) adjusted for age, sex, BMI, and medications; followed by Baysian Lasso methodology to identify sets of SNVs in terms of associated haplotypes with specific phenotypes.

Results: Among 3223 participants (62% female; mean age 55.6 (SD ± 12.8) years), the average SBP and DBP were 127 and 76 mmHg, respectively. The average fasting plasma glucose and HbA1c were 101 mg/dL and 6.0%, respectively. ARMC5 variants were associated with all 6 phenotypes. Haplotype TCGCC (ch16:31476015-31476093) was negatively associated, whereas haplotype CCCCTTGCG (ch16:31477195-31477460) was positively associated with SBP, DBP, and glucose. Haplotypes GGACG (ch16:31477790-31478013) and ACGCG (ch16:31477834-31478113) were negatively associated with aldosterone and positively associated with HbA1c and glucose, respectively. Haplotype GCGCGAGC (ch16:31471193-ch16:31473597(rs114871627) was positively associated with PRA and negatively associated with HbA1c.

Conclusions: ARMC5 variants are associated with aldosterone, PRA, blood pressure, fasting glucose, and HbA1c in community-dwelling AAs, suggesting that germline mutations in ARMC5 may underlie cardiometabolic disease in AAs.
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http://dx.doi.org/10.1210/clinem/dgaa290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7308077PMC
August 2020

Effects of the low carbohydrate, high fat diet on glycemic control and body weight in patients with type 2 diabetes: experience from a community-based cohort.

BMJ Open Diabetes Res Care 2020 03;8(1)

Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

Objective: The optimal diet to improve glycemia in patients with type 2 diabetes remains unclear. Low carbohydrate, high fat (LCHF) diets can improve glycemic control, but have not been investigated in real-world settings.

Research Design And Methods: We investigated effects of the LCHF diet compared with usual care in a community-based cohort of patients with type 2 diabetes by performing a retrospective study of 49 patients who followed the LCHF diet for ≥3 months, and compared glycemic outcomes with age-matched and body mass index (BMI)-matched controls who received usual care (n=75). The primary outcome was change in A1C from baseline to the end of follow-up.

Results: Compared with the usual care group, the LCHF group showed a significantly greater reduction in A1C (-1.29% (95% CI -1.75 to -0.82; p<0.001)) and body weight (-12.8 kg (95% CI -14.7 to -10.8; p<0.001) at the end of follow-up after adjusting for age, sex, baseline A1C, BMI, baseline insulin dose. Of the patients initially taking insulin therapy in the LCHF group, 100% discontinued it or had a reduction in dose, compared with 23.1% in the usual care group (p<0.001). The LCHF group also had significantly greater reduction in fasting plasma glucose (-43.5 vs -8.5 mg/mL; p=0.03) compared with usual care.

Conclusions: In a community-based cohort of type 2 diabetes, the LCHF diet was associated with superior A1C reduction, greater weight loss and significantly more patients discontinuing or reducing antihyperglycemic therapies suggesting that the LCHF diet may be a metabolically favorable option in the dietary management of type 2 diabetes.
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http://dx.doi.org/10.1136/bmjdrc-2019-000980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7103851PMC
March 2020

Mosaicism for KCNJ5 Causing Early-Onset Primary Aldosteronism due to Bilateral Adrenocortical Hyperplasia.

Am J Hypertens 2020 02;33(2):124-130

Section on Genetics & Endocrinology, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA.

Background: Somatic variants in KCNJ5 are the most common cause of primary aldosteronism (PA). There are few patients with PA in whom the disease is caused by germline variants in the KCNJ5 potassium channel gene (familial hyperaldosteronism type III-FH-III).

Methods: A 5-year-old patient who developed hypertension due to bilateral adrenocortical hyperplasia (BAH) causing PA had negative peripheral DNA testing for any known genetic causes of PA. He was treated medically with adequate control of his PA but by the third decade of his life, due to worsening renal function, he underwent bilateral adrenalectomy.

Results: Focused exome sequencing in multiple nodules of his BAH uncovered a "hot-spot" pathogenic KCNJ5 variant, while repeated Sanger sequencing showed no detectable DNA defects in peripheral blood and other tissues. However, whole exome, "deep" sequencing revealed that 0.23% of copies of germline DNA did in fact carry the same KCNJ5 variant that was present in the adrenocortical nodules, suggesting low level germline mosaicism for this PA-causing KCNJ5 defect.

Conclusions: Thus, this patient represents a unique case of BAH due to a mosaic KCNJ5 defect. Undoubtedly, his milder PA compared with other known cases of FH-III, was due to his mosaicism. This case has a number of implications for the prognosis, treatment, and counseling of the many patients with PA due to BAH that are seen in hypertension clinics.
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http://dx.doi.org/10.1093/ajh/hpz172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204147PMC
February 2020

ARMC 5 Variants and Risk of Hypertension in Blacks: MH- GRID Study.

J Am Heart Assoc 2019 07 3;8(14):e012508. Epub 2019 Jul 3.

1 Section on Endocrinology and Genetics Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health Bethesda MD.

Background We recently found that ARMC 5 variants may be associated with primary aldosteronism in blacks. We investigated a cohort from the MH - GRID (Minority Health Genomics and Translational Research Bio-Repository Database) and tested the association between ARMC 5 variants and blood pressure in black s. Methods and Results Whole exome sequencing data of 1377 black s were analyzed. Target single-variant and gene-based association analyses of hypertension were performed for ARMC 5, and replicated in a subset of 3015 individuals of African descent from the UK Biobank cohort. Sixteen rare variants were significantly associated with hypertension ( P=0.0402) in the gene-based (optimized sequenced kernel association test) analysis; the 16 and one other, rs116201073, together, showed a strong association ( P=0.0003) with blood pressure in this data set. The presence of the rs116201073 variant was associated with lower blood pressure. We then used human embryonic kidney 293 and adrenocortical H295R cells transfected with an ARMC 5 construct containing rs116201073 (c.*920T>C). The latter was common in both the discovery ( MH - GRID ) and replication ( UK Biobank) data and reached statistical significance ( P=0.044 [odds ratio, 0.7] and P=0.007 [odds ratio, 0.76], respectively). The allele carrying rs116201073 increased levels of ARMC5 mRNA , consistent with its protective effect in the epidemiological data. Conclusions ARMC 5 shows an association with hypertension in black s when rare variants within the gene are considered. We also identified a protective variant of the ARMC 5 gene with an effect on ARMC 5 expression confirmed in vitro. These results extend our previous report of ARMC 5's possible involvement in the determination of blood pressure in blacks.
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http://dx.doi.org/10.1161/JAHA.119.012508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662143PMC
July 2019

Retrospective study of inpatient diabetes management service, length of stay and 30-day readmission rate of patients with diabetes at a community hospital.

J Community Hosp Intern Med Perspect 2019 Apr 12;9(2):64-73. Epub 2019 Apr 12.

Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

: Hospitalized patients with diabetes are at risk of complications and longer length of stay (LOS). Inpatient Diabetes Management Services (IDMS) are known to be beneficial; however, their impact on patient care measures in community, non-teaching hospitals, is unknown. : To evaluate whether co-managing patients with diabetes by the IDMS team reduces LOS and 30-day readmission rate (30DR). : This retrospective quality improvement cohort study analyzed LOS and 30DR among patients with diabetes admitted to a community hospital. The IDMS medical team consisted of an endocrinologist, nurse practitioner, and diabetes educator. The comparison group consisted of hospitalized patients with diabetes under standard care of attending physicians (mostly internal medicine-trained hospitalists). The relationship between study groups and outcome variables was assessed using Generalized Estimating Equation models. : 4,654 patients with diabetes (70.8 ± 0.2 years old) were admitted between January 2016 and May 2017. The IDMS team co-managed 18.3% of patients, mostly with higher severity of illness scores (p < 0.0001). Mean LOS in patients co-managed by the IDMS team decreased by 27%. Median LOS decreased over time in the IDMS group (p = 0.046), while no significant decrease was seen in the comparison group. Mean 30DR in patients co-managed by the IDMS decreased by 10.71%. Median 30DR decreased among patients co-managed by the IDMS (p = 0.048). : In a community hospital setting, LOS and 30DR significantly decreased in patients co-managed by a specialized diabetes team. These changes may be translated into considerable cost savings.
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http://dx.doi.org/10.1080/20009666.2019.1593782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6484466PMC
April 2019

Genetics of Hypertension in African Americans and Others of African Descent.

Int J Mol Sci 2019 Mar 2;20(5). Epub 2019 Mar 2.

Section on Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, BG 31 RM 2A46, 31 Center Dr, Bethesda, MD 20892, USA.

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (), Armadillo Repeat Containing 5 (), G Protein-Coupled Receptor Kinase 4 ), and Calcium Voltage-Gated Channel Subunit Alpha1 D (). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.
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http://dx.doi.org/10.3390/ijms20051081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429313PMC
March 2019

To Give or Not to Give: The Challenge of Pharmaceutical Coupons.

J Clin Ethics Winter 2018;29(4):319-322

Johns Hopkins Carey Business School, Baltimore, Maryland USA.

Diabetes is epidemic and many people cannot afford insulin, a lifesaving medication, as its price has increased by almost 160 percent in the past five years.1 To help subsidize the cost of insulin, one of the staff members at my hospital would like to give patients copayment coupons provided to her by pharmaceutical companies. I advised my colleague to stop distributing these branded coupons, as they promote particular pharmaceutical companies. This practice is not consistent with the policy on interaction with industry established by the Johns Hopkins Health System. Yet at the same time, I want my patients to be able to afford their insulin so they can treat their diabetes. I truly believe in utilitarianism. Would temporarily subsidizing patients' insulin make me and my staff better healthcare providers? Would this minimize my patients' financial burden? Would giving away medications coupons help pharmaceutical companies influence me as a prescriber? This challenge created a personal internal debate and profound moral distress.
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April 2019

Mini-review of hair cortisol concentration for evaluation of Cushing syndrome.

Expert Rev Endocrinol Metab 2018 09 20;13(5):225-231. Epub 2018 Sep 20.

c Section on Endocrinology and Genetics , Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health , Bethesda , MD , USA.

Introduction: The diagnosis of endogenous Cushing syndrome is often challenging and requires multiple repeated blood, urine, and saliva tests to detect elevated cortisol levels. Hair cortisol concentration has been described as a marker of long-term exposure to systemic cortisol in patients with Cushing syndrome. Like hemoglobin A1c is used to detect serum glucose exposure over months, segmental hair cortisol can help identify patients with milder forms of and/or periodic or cyclical Cushing syndrome, which may reduce time and costs associated with collection of urine, salivary, and serum cortisol.

Areas Covered: Success of hair cortisol in detection of Cushing syndrome will be discussed in context of current literature, including differences between total or segmental hair cortisol in accurately determining timeline of cortisol exposure. Optimal methods of hair collection, storage, processing, and analysis and efforts toward standardization will be a major focus.

Expert Commentary: Recent evidence suggests increased sensitivity and specificity of hair cortisol in detecting Cushing syndrome. Future guidelines should consider this test as a routine part of the repertoire of screening tests for Cushing syndrome. Possible confounders to explain discrepant results in the literature will be discussed.
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http://dx.doi.org/10.1080/17446651.2018.1517043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6378952PMC
September 2018

Obesity and the diagnostic accuracy for primary aldosteronism.

J Clin Hypertens (Greenwich) 2017 Aug 13;19(8):790-797. Epub 2017 Jun 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

The effects of body mass index on the diagnostic accuracy of primary aldosteronism (PA) are inconsistent and yet important considering the high prevalence and frequent co-occurrence of obesity and hypertension. The current study included 59 adult patients who underwent a stepwise evaluation for PA, using aldosterone to renin ratio for case detection and plasma aldosterone concentration after saline suppression test and/or 24-hour urinary aldosterone after oral sodium loading for case confirmation. Body mass index had a quadratic (U-shaped) correlation with plasma aldosterone concentration, plasma renin activity, aldosterone to renin ratio, and plasma aldosterone concentration after saline suppression test. Among patients with a body mass index ≥30 kg/m , the aldosterone to renin ratio yielded lower case detection accuracy of PA. We conclude that obesity results in a nonlinear correlation with plasma aldosterone concentration, plasma renin activity, and aldosterone to renin ratio, which affects the accuracy of case detection for PA. Patients with a body mass index ≥30 kg/m are less accurately identified as having PA when saline suppression and/or oral salt loading tests are used for case confirmation.
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http://dx.doi.org/10.1111/jch.13041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602533PMC
August 2017

The Case for Diabetes Population Health Improvement: Evidence-Based Programming for Population Outcomes in Diabetes.

Curr Diab Rep 2017 07;17(7):51

Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument Street, Suite no. 333, Baltimore, MD, 21287, USA.

Purpose Of Review: The goal of this review is to describe diabetes within a population health improvement framework and to review the evidence for a diabetes population health continuum of intervention approaches, including diabetes prevention and chronic and acute diabetes management, to improve clinical and economic outcomes.

Recent Findings: Recent studies have shown that compared to usual care, lifestyle interventions in prediabetes lower diabetes risk at the population-level and that group-based programs have low incremental medial cost effectiveness ratio for health systems. Effective outpatient interventions that improve diabetes control and process outcomes are multi-level, targeting the patient, provider, and healthcare system simultaneously and integrate community health workers as a liaison between the patient and community-based healthcare resources. A multi-faceted approach to diabetes management is also effective in the inpatient setting. Interventions shown to promote safe and effective glycemic control and use of evidence-based glucose management practices include provider reminder and clinical decision support systems, automated computer order entry, provider education, and organizational change. Future studies should examine the cost-effectiveness of multi-faceted outpatient and inpatient diabetes management programs to determine the best financial models for incorporating them into diabetes population health strategies.
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http://dx.doi.org/10.1007/s11892-017-0875-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5553206PMC
July 2017

Pediatric Cushing disease: disparities in disease severity and outcomes in the Hispanic and African-American populations.

Pediatr Res 2017 Aug 17;82(2):272-277. Epub 2017 May 17.

Section on Endocrinology and Genetics, Developmental Endocrinology Branch, and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.

BackgroundLittle is known about the contribution of racial and socioeconomic disparities to severity and outcomes in children with Cushing disease (CD).MethodsA total of 129 children with CD, 45 Hispanic/Latino or African-American (HI/AA) and 84 non-Hispanic White (non-HW), were included in this study. A 10-point index for rating severity (CD severity) incorporated the degree of hypercortisolemia, glucose tolerance, hypertension, anthropomorphic measurements, disease duration, and tumor characteristics. Race, ethnicity, age, gender, local obesity prevalence, estimated median income, and access to care were assessed in regression analyses of CD severity.ResultsThe mean CD severity in the HI/AA group was worse than that in the non-HW group (4.9±2.0 vs. 4.1±1.9, P=0.023); driving factors included higher cortisol levels and larger tumor size. Multiple regression models confirmed that race (P=0.027) and older age (P=0.014) were the most important predictors of worse CD severity. When followed up a median of 2.3 years after surgery, the relative risk for persistent CD combined with recurrence was 2.8 times higher in the HI/AA group compared with that in the non-HW group (95% confidence interval: 1.2-6.5).ConclusionOur data show that the driving forces for the discrepancy in severity of CD are older age and race/ethnicity. Importantly, the risk for persistent and recurrent CD was higher in minority children.
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http://dx.doi.org/10.1038/pr.2017.58DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5552413PMC
August 2017

Hair cortisol in the evaluation of Cushing syndrome.

Endocrine 2017 Apr 13;56(1):164-174. Epub 2017 Feb 13.

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.

Purpose: Hair cortisol evaluation has been used to help detect patients with suspected Cushing syndrome. Our goal was to correlate segmental hair cortisol with biochemical testing in patients with Cushing syndrome and controls. This study was a prospective analysis of hair cortisol in confirmed Cushing syndrome cases over 16 months.

Methods: Thirty-six subjects (26.5 ± 18.9 years, 75% female, and 75% Caucasian) were analyzed by diurnal serum cortisol, 24 h urinary free cortisol corrected for body surface area (UFC/BSA), and 24 h urinary 17-hydroxysteroids corrected for creatinine (17OHS/Cr). Thirty patients were diagnosed with Cushing syndrome, and six were defined as controls. 3-cm hair samples nearest to the scalp, cut into 1-cm segments (proximal, medial, and distal), were analyzed for cortisol by enzyme immunoassay and measured as pmol cortisol/g dry hair. Hair cortisol levels were compared with laboratory testing done within previous 2 months of the evaluation.

Results: Proximal hair cortisol was higher in Cushing syndrome patients (266.6 ± 738.4 pmol/g) than control patients (38.9 ± 25.3 pmol/g) (p = 0.003). Proximal hair cortisol was highest of all segments in 25/36 (69%) patients. Among all subjects, proximal hair cortisol was strongly correlated with UFC/BSA (r = 0.5, p = 0.005), midnight serum cortisol (r = 0.4, p = 0.03), and 17OHS/Cr, which trended towards significance (r = 0.3, p = 0.06).

Conclusions: Among the three examined hair segments, proximal hair contained the highest cortisol levels and correlated the most with the initial biochemical tests for Cushing syndrome in our study. Further studies are needed to validate proximal hair cortisol in the diagnostic workup for Cushing syndrome.
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http://dx.doi.org/10.1007/s12020-017-1231-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437744PMC
April 2017

Diagnosis and Management of Hereditary Adrenal Cancer.

Recent Results Cancer Res 2016 ;205:125-47

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.

Benign adrenocortical tumours (ACT) are relatively frequent lesions; on the contrary, adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with unfavourable prognosis. Recent advances in the molecular understanding of adrenal cancer offer promise for better therapies in the future. Many of these advances stem from the molecular elucidation of genetic conditions predisposing to the development of ACC. Six main clinical syndromes have been described to be associated with hereditary adrenal cancer. In these conditions, genetic counselling plays an important role for the early detection and follow-up of the patients and the affected family members.
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http://dx.doi.org/10.1007/978-3-319-29998-3_8DOI Listing
July 2016

Pseudohypoaldosteronism type 1 due to novel variants of SCNN1B gene.

Endocrinol Diabetes Metab Case Rep 2016 7;2016:150104. Epub 2016 Jan 7.

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, BG 10-CRC, Room 1-3216, 10 Center Drive, Bethesda, Maryland, 20814, USA; Johns Hopkins University School of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Baltimore, Maryland, 21287, USA; Suburban Hospital, Bethesda, Maryland, 20814, USA.

Unlabelled: Autosomal recessive pseudohypoaldosteronism type 1 (PHA1) is a rare disorder characterized by sodium wasting, failure to thrive, hyperkalemia, hypovolemia and metabolic acidosis. It is due to mutations in the amiloride-sensitive epithelial sodium channel (ENaC) and is characterized by diminished response to aldosterone. Patients may present with life-threatening hyperkalemia, which must be recognized and appropriately treated. A 32-year-old female was referred to the National Institutes of Health (NIH) for evaluation of hyperkalemia and muscle pain. Her condition started in the second week of life, when she was brought to an outside hospital lethargic and unresponsive. At that time, she was hypovolemic, hyperkalemic and acidotic, and was eventually treated with sodium bicarbonate and potassium chelation. At the time of the presentation to the NIH, her laboratory evaluation revealed serum potassium 5.1 mmol/l (reference range: 3.4-5.1 mmol/l), aldosterone 2800 ng/dl (reference range: ≤21 ng/dl) and plasma renin activity 90 ng/ml/h (reference range: 0.6-4.3 ng/ml per h). Diagnosis of PHA1 was suspected. Sequencing of the SCNN1B gene, which codes for ENaC, revealed that the patient is a compound heterozygote for two novel variants (c.1288delC and c.1466+1 G>A), confirming the suspected diagnosis of PHA1. In conclusion, we report a patient with novel variants of the SCNN1B gene causing PHA1 with persistent, symptomatic hyperkalemia.

Learning Points: PHA1 is a rare genetic condition, causing functional abnormalities of the amiloride-sensitive ENaC.PHA1 was caused by previously unreported SCNN1B gene mutations (c.1288delC and c.1466+1 G>A).Early recognition of this condition and adherence to symptomatic therapy is important, as the electrolyte abnormalities found may lead to severe dehydration, cardiac arrhythmias and even death.High doses of sodium polystyrene sulfonate, sodium chloride and sodium bicarbonate are required for symptomatic treatment.
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http://dx.doi.org/10.1530/EDM-15-0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722246PMC
January 2016

The ARMC5 gene shows extensive genetic variance in primary macronodular adrenocortical hyperplasia.

Eur J Endocrinol 2015 Oct 10;173(4):435-40. Epub 2015 Jul 10.

Section on Endocrinology and GeneticsProgram on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, Maryland 20892, USADepartment of Radiology and Imaging SciencesNational Institutes of Health (NIH), Clinical Center, Bethesda, Maryland 20892, USADepartment of EndocrinologyMetabolism, and Diabetes, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 1016, Institut Cochin, Centre National de la Recherche Scientifique (CNRS) UMR 8104, 75014 Paris, FranceGroup for Advanced Molecular InvestigationGraduate Program in Health Science, Medical School, Pontificia Universidade Catolica do Paraná, Curitiba, Paraná, Brazil.

Objective: Primary macronodular adrenal hyperplasia (PMAH) is a rare type of Cushing's syndrome (CS) that results in increased cortisol production and bilateral enlargement of the adrenal glands. Recent work showed that the disease may be caused by germline and somatic mutations in the ARMC5 gene, a likely tumor suppressor gene (TSG). We investigated 20 different adrenal nodules from one patient with PMAH for ARMC5 somatic sequence changes.

Design: All of the nodules were obtained from a single patient who underwent bilateral adrenalectomy. DNA was extracted by standard protocol and the ARMC5 sequence was determined by the Sanger method.

Results: Sixteen of 20 adrenocortical nodules harbored, in addition to what appeared to be the germline mutation, a second somatic variant. The p.Trp476* sequence change was present in all 20 nodules, as well as in normal tissue from the adrenal capsule, identifying it as the germline defect; each of the 16 other variants were found in different nodules: six were frame shift, four were missense, three were nonsense, and one was a splice site variation. Allelic losses were confirmed in two of the nodules.

Conclusion: This is the most genetic variance of the ARMC5 gene ever described in a single patient with PMAH: each of 16 adrenocortical nodules had a second new, 'private,' and--in most cases--completely inactivating ARMC5 defect, in addition to the germline mutation. The data support the notion that ARMC5 is a TSG that needs a second, somatic hit, to mediate tumorigenesis leading to polyclonal nodularity; however, the driver of this extensive genetic variance of the second ARMC5 allele in adrenocortical tissue in the context of a germline defect and PMAH remains a mystery.
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http://dx.doi.org/10.1530/EJE-15-0205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4572515PMC
October 2015

Protein kinase A defects and cortisol-producing adrenal tumors.

Curr Opin Endocrinol Diabetes Obes 2015 Jun;22(3):157-62

Section on Endocrinology and Genetics, Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA.

Purpose Of Review: Cushing syndrome caused by cortisol-producing adrenal adenomas is a rare condition, associated with high morbidity due to weight gain, diabetes mellitus, osteoporosis, hypertension, muscle weakness, mood disturbance and others. The first gene to be identified as causative of Cushing syndrome was PRKAR1A. We present an update on protein kinase A (PKA) defects and Cushing syndrome.

Recent Findings: The cyclic AMP-dependent PKA catalytic subunit alpha (PRKACA) hotspot point mutation (c.617A > C [p.Leu206Arg]), leading to an increase of basal PKA activity, and formation of cortisol-producing adenoma has been frequently shown to cause the most common form of adrenocorticotropic hormone-independent Cushing syndrome.

Summary: Somatic PRKACA mutations have been found in up to 50% of patients with adrenal adenomas. Germline PRKACA amplification was also seen in bilateral adrenal hyperplasias. PRKACA activation was associated with higher cortisol levels, smaller tumor size and overt Cushing syndrome. This breakthrough is expected to improve our understanding of how PKA defects lead to Cushing syndrome and may spearhead the development of new, molecularly designed therapies.
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http://dx.doi.org/10.1097/MED.0000000000000149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4560837PMC
June 2015

Primary Aldosteronism and ARMC5 Variants.

J Clin Endocrinol Metab 2015 Jun 30;100(6):E900-9. Epub 2015 Mar 30.

Section on Endocrinology and Genetics (M.Z., P.X., F.R.F., A.B., A.G., M.H.S.-R., M.B., S.B.A., S.E., M.B.L., C.A.S.), Program on Developmental Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Biostatistics and Clinical Epidemiology Service (N.S.), Clinical Center, National Institutes of Health, Bethesda, Maryland 20892; Laboratory of Pathology (M.M.Q., M.M.), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Pediatrics (A.H.), University Hospitals Case Medical Center, Rainbow Babies and Children's Hospital, Cleveland, Ohio 44106; Cardiovascular Disease Section (R.L., G.A., L.D., B.R.), Genomics of Metabolic, Cardiovascular, and Inflammatory Disease Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; Department of Endocrinology, Metabolism, and Diabetes (A.D., S.Y.G., R.N., J.B.), Inserm Unit 1016, Centre National de la Recherche Scientifique UMR 8104, Institut Cochin, 75014 Paris, France; and Endocrine Oncology Branch (E.K.), National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892.

Context: Primary aldosteronism is one of the leading causes of secondary hypertension, causing significant morbidity and mortality. A number of genetic defects have recently been identified in primary aldosteronism, whereas we identified mutations in ARMC5, a tumor-suppressor gene, in cortisol-producing primary macronodular adrenal hyperplasia.

Objective: We investigated a cohort of 56 patients who were referred to the National Institutes of Health for evaluation of primary aldosteronism for ARMC5 defects.

Methods: Patients underwent step-wise diagnosis, with measurement of serum aldosterone and plasma renin activity followed by imaging, saline suppression and/or oral salt loading tests, plus adrenal venous sampling. Cortisol secretion was also evaluated; unilateral or bilateral adrenalectomy was performed, if indicated. DNA, protein, and transfection studies in H295R cells were conducted by standard methods.

Results: We identified 12 germline ARMC5 genetic alterations in 20 unrelated and two related individuals in our cohort (39.3%). ARMC5 sequence changes in 6 patients (10.7%) were predicted to be damaging by in silico analysis. All affected patients carrying a variant predicted to be damaging were African Americans (P = .0023).

Conclusions: Germline ARMC5 variants may be associated with primary aldosteronism. Additional cohorts of patients with primary aldosteronism and metabolic syndrome, particularly African Americans, should be screened for ARMC5 sequence variants because these may underlie part of the known increased predisposition of African Americans to low renin hypertension.
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http://dx.doi.org/10.1210/jc.2014-4167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4454793PMC
June 2015