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An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health

Lahoti, Amit; Yu, Christine; Brar, Preneet Cheema; Dalgo, Austin; Gourgari, Evgenia; Harris, Rebecca; Kamboj, Manmohan K; Marks, Seth; Nandagopal, Radha; Page, Laura; Raman, Vandana; Reynolds, Danielle G; Sarafoglou, Kyriakie; Terrell, Carrie; Stanley, Takara L
Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.
PMID: 34388330
ISSN: 2191-0251
CID: 5011502

Hyperosmolar diabetic ketoacidosis-- review of literature and the shifting paradigm in evaluation and management

Brar, Preneet Cheema; Tell, Shoshana; Mehta, Shilpa; Franklin, Bonita
BACKGROUND:Hyperosmolar diabetic ketoacidosis (H-DKA), a distinct clinical entity, is the overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS). AIM/OBJECTIVE:We describe the clinical presentation, metabolic aberrations, and associated morbidity/mortality of these cases with H-DKA. We highlight the problem areas of medical care which require particular attention when caring for pediatric diabetes patients presenting with H-DKA. METHODS:In our study we reviewed the literature back to 1963 and retrieved twenty-four cases meeting the criteria of H-DKA: glucose >600 mg/dL, pH < 7.3, bicarbonate <15 mEq/L, and serum osmolality >320 mOsm/kg, while adding three cases from our institution. RESULTS:Average age of presentation of H-DKA was 10.2 years ± 4.5 years in females and 13.3 years ± 4 years in males, HbA1c was 13%. Biochemical parameters were consistent with severe dehydration: serum osmolality = 394.8±55 mOsm/kg, BUN = 48±22 mg/dL, creatinine = 2.81±1.03 mg/dL. Acute kidney injury, present in 12 cases, was the most frequent end-organ complication. CONCLUSION/CONCLUSIONS:Multi-organ involvement with AKI, rhabdomyolysis, pancreatitis, neurological and cardiac issues such as arrhythmias, are common in H-DKA. Aggressive fluid management, insulin therapy and supportive care can prevent acute and long term adverse outcomes in children and adolescents.
PMID: 34731818
ISSN: 1878-0334
CID: 5038192

Genotype - phenotype correlation in an adolescent girl with pathogenic variant in PPARÆ´ gene causing severe hypertriglyceridemia and early onset type 2 diabetes

Gutierrez Alvarez, Ana; Yachelevich, Naomi; Kohn, Brenda; Brar, Preneet Cheema
Severe hypertriglyceridemia (HTG) (>885 mg/dl) can be caused by familial partial lipodystrophy Type 3 (FPLD 3), an autosomal dominant disorder caused by a loss of function of the peroxisome proliferator activated receptor gamma (PPARG), characterized by abnormal distribution of fat and metabolic derangements. A 16-year-old female (body mass index, BMI 23.5 kg/m2) was hospitalized twice for pancreatitis (TG level >2200 mg/dl). She was managed with bowel rest, insulin infusion, and plasmapheresis. On a low fat 10 g daily diet and fenofibrate 160 mg daily her fasting TG had decreased to 411 mg/dL (range 0-149). She had a normal leptin level. Panel testing of genes involved in triglyceride metabolism revealed a known pathogenic variant in PPARG gene (c.452A>G p.Tyr151Cys). A second variant detected in this gene, c.1003G>C (p.Val335Leu), is considered benign. HbA1C of 6.6% and two-hours oral glucose tolerance test confirmed Type 2 diabetes (T2DM). We outline the earliest description of T2DM in an adolescent with a pathogenic variant of PPARG. PPARG related FLPD 3 should be considered in lean children presenting with severe HTG and insulin resistance and treatment with PPARy agonists Thiazolidinediones should be considered.
PMID: 34670072
ISSN: 2287-1012
CID: 5043332

Lymph node metastases in pediatric medullary thyroid carcinoma

Oliver, Jamie R; Patel, Kepal N; Chang, Clifford M; Baldwin, Chelsey K; Brar, Preneet C; Morris, Luc G T; Givi, Babak
BACKGROUND:Unlike medullary thyroid carcinoma in adults, the vast majority of pediatric medullary thyroid carcinoma is hereditary. Pediatric medullary thyroid carcinoma is known to have different genetic alterations driving tumorigenesis, but it is not known if pediatric medullary thyroid carcinoma has different clinicopathologic features. This study aims to identify which pediatric medullary thyroid carcinoma patients might warrant elective neck dissection. METHODS:We selected all patients ages 0 to 19 diagnosed with clinically evident medullary thyroid carcinoma in the National Cancer Database between 2004 to 2016. Clinicopathologic factors, treatments, and outcomes were analyzed and compared between this cohort and adults (ages ≥20) with medullary thyroid carcinoma. RESULTS:One hundred twenty-five pediatric medullary thyroid carcinoma (median age: 13) and 5,086 adult medullary thyroid carcinoma (median age: 57) patients were identified. Pediatric patients had smaller tumors (median diameter: 1.2 cm vs 2.0 cm; P < .001), lower rates of nodal metastases (n = 31, 36.9% vs 1,689, 50.4%; P = .02) but double the incidence of multifocal tumors (n = 70, 59.3%, vs 1,412, 29.9%; P < .001) compared with adults. Multifocal tumors conferred a significantly increased risk of nodal metastases in adult medullary thyroid carcinoma (64.4% vs 43.2%; P < .001) but not pediatric medullary thyroid carcinoma (37.7% vs 35.7%; P = .85). Nodal metastases were more frequent among older children (0-5 years: 0.0%, 6-12: 40.7%, 13-19: 41.7%; P = .04). However, rates of occult nodal metastases were similar between older children (6-19 years: n = 12, 21.4%) and adults (557, 25.8% P = .56). CONCLUSION/CONCLUSIONS:Pediatric medullary thyroid carcinoma has lower rates of lymph node metastases compared with adults. The risk of nodal disease was low among the youngest children, but older children ages 6 to 19 were at considerable risk for occult metastases. These findings could guide clinicians in selecting pediatric patients considered for elective lymph node dissection.
PMID: 33838880
ISSN: 1532-7361
CID: 4842142

Management and Appropriate Use of Diazoxide in Infants and Children with Hyperinsulinism

Brar, Preneet Cheema; Heksch, Ryan; Cossen, Kristina; De Leon, Diva D; Kamboj, Manmohan K; Marks, Seth D; Marshall, Bess A; Miller, Ryan; Page, Laura; Stanley, Takara; Mitchell, Deborah; Thornton, Paul
BACKGROUND:The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only Food and Drug Agency-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. METHODS:We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. CONCLUSIONS:Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized the information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.
PMID: 32810255
ISSN: 1945-7197
CID: 4650092

Impaired myocardial deformation and ventricular vascular coupling in obese adolescents with dysglycemia

Brar, Preneet Cheema; Chun, Anne; Fan, Xiazhou; Jani, Vivek; Craft, Mary; Bhatla, Puneet; Kutty, Shelby
BACKGROUND:It is unknown that dysglycemia in obese adolescents has effects on myocardial deformation that are more pronounced when compared to obesity alone. We hypothesized that obesity associated abnormal glucose tolerance (dysglycemia) would have adverse effects on two-dimensional speckle tracking echocardiography derived longitudinal, radial and circumferential strain (LS, RS, CS) compared to age and gender lean controls. We also examined if changes in deformation would be reflected in abnormal ventricular vascular coupling indices (VVI). METHODS:In a prospective cross-sectional design 39 obese adolescents (15.9 ± 1.7 years; 101.5 ± 39 kg; female - 58%) were compared to age and gender matched lean controls (15.7 ± 1.8 yrs, 60 ± 12.8 kg). Based on results from an oral glucose tolerance test (OGTT), obese adolescents were categorized as obese normoglycemic (ONG, n = 25) or obese dysglycemic (ODG, n = 14). Left ventricular (LV) global and average LS, CS, RS and strain rate were measured. LV ejection fraction and mass index were measured and VVI approximated as ratio of arterial elasticity (Ea) and end-systolic elastance (Ees). RESULTS:Adolescents with ODG had significantly (P = 0.005) impaired global LS (- 20.98% ± 2.8%) compared to controls (- 23.01% ± 2.3%). A similar (P = 0.0027) reduction was observed in average LS for adolescents with ODG (18.87% ± 2.5%) compared to controls (20.49% ± 2%). Global CS was also decreased (P = 0.03) in ODG (- 23.95%) compared to ONG (- 25.80). A similar trend was observed in average CS after multivariate regression for BMI and blood pressure. CS correlated with HbA1c in both groups (P = 0.05). VVI had a negative correlation with both LS (r = - 0.4, P = 0.025) and CS rate (r = - 0.36, P = 0.04). CONCLUSIONS:Myocardial strain and strain rate were significantly altered in obese adolescents. Unfavorable subclinical reductions in global and average CS were more pronounced in adolescents with dysglycemia compared to obese adolescents with normoglycemia and controls. These data indicate progressive worsening of subendocardial function across the spectrum of glucose tolerance. Strain rate was predictive of VVI in obese adolescents, suggesting strain rate may be a sensitive marker for cardiac remodeling in abnormal glucose homeostasis states.
PMCID:6921397
PMID: 31856856
ISSN: 1475-2840
CID: 4334662

Characterization of the duration of treatment with diazoxide in infants with prolonged hyperinsulinism (PHI)

Raisingani, Manish; Brar, Preneet Cheema
Background Prolonged neonatal hyperinsulinism (PHI) causes hypoglycemia in the neonatal period and is associated with perinatal stress. Even though diazoxide is an effective treatment option for PHI, it has serious adverse effects making an argument for safe yet expeditious wean off of diazoxide while ensuring normoglycemia. The objective of this study was to characterize clinical course, dose requirement and duration of treatment with diazoxide in our cohort of infants diagnosed with PHI. Methods A retrospective chart review of infants diagnosed with PHI during a 6-year period was done documenting the diagnostic workup and the duration of treatment with diazoxide. Results PHI was diagnosed (n = 20; mean ± standard deviation [SD]) at 14.3 ± 22.4 days. Elevated insulin (8.3 ± 8.4 mIU/L), normal cortisol (15.5 ± 6.6 μg/dL [6-21]), normal growth hormone (18.8 ± 15.7 ng/mL [0.1-6.2]) and inappropriate low serum free fatty acids (0.3 ± 0.2 mmol/L [>1.5]) levels were measured during hypoglycemia (plasma glucose <50 mg/dL). Detectable insulin at the time of hypoglycemia was measured in 17 of 20 infants while the same number (17/20) of infants had a positive glucagon stimulation test (GST). The dose of diazoxide was 10 ± 3.7 mg/kg/day and duration of treatment was 44.9 ± 27.9 days. Conclusions This study illustrates that the duration of treatment with diazoxide in infants with PHI can be shorter than previously reported in the literature. We speculate that active tapering of diazoxide started within a week after discharge from hospital as well an outpatient tapering of diazoxide based on glucose monitoring were possible reasons for this outcome.
PMID: 31465295
ISSN: 2191-0251
CID: 4054602

Use of the microbiome in the management of children with type 2 diabetes mellitus

Brar, Preneet Cheema; Kohn, Brenda
PURPOSE OF REVIEW/OBJECTIVE:The purpose of this review is to present recent data that defines our current understanding of the role of the gut microbiome in the development of T2DM. RECENT FINDINGS/RESULTS:Recent studies focus on the physiology and molecular pathways of the gut microbiome-host interaction. Short-chain fatty acids (SCFAs) derived from the fermentation of plant-based nonsoluble fiber bind to G-protein-coupled receptors (GPR) GPR 41 and GPR 43 to induce enteroendocrine molecules that control appetite, and to upregulate intestinal gluconeogenesis gene expression that controls glucose regulation. "Metabolic endotexemia" reflects a state of low-grade systemic inflammation that results from lipopolysaccharide (LPS) release from the gut into the systemic circulation in response to a high-fat diet. Inflammatory pathways induced by LPS, activation of toll-like receptor-4 (TLR-4), and other inflammatory signaling pathways are mediators of systemic inflammation, insulin resistance and type II diabetes mellitus. SUMMARY/CONCLUSIONS:Recent scientific data support that derangements in the composition of the microbiota, termed "microbiome dysbiosis" is a factor in the development of "metabolic endotoxemia" and T2DM. Therapeutic options that target the gut microbiome in the treatment of T2DM are explored.
PMID: 31299021
ISSN: 1531-698x
CID: 3976892

Severe, persistent neonatal hypoglycemia as a presenting feature in patients with congenital hypopituitarism: a review of our case series

Mehta, Shilpa; Brar, Preneet Cheema
Objective Persistent hypoglycemia (PH) beyond 3 days of life warrants investigation which includes a critical sample. We report our case series of five neonates who presented with PH as the first sign of congenital hypopituitarism. Design This is a case series. Methods/Results This is a case series of five neonates evaluated at our academic institution in a 3-year period (2013-2016), who presented with persistent severe hypoglycemia and were subsequently diagnosed with congenital hypopituitarism. All neonates were full term (mean gestational age 39.8 ± 1.4 weeks) born by caesarian section with a mean weight of 3.5 ± 0.16 kg and a mean length of 51.2 ± 1.2 cm at birth. All five neonates had PH beyond 3 days with an average blood glucose (BG) <35 mg/dL at presentation, requiring a mean glucose infusion rate (GIR) of 7.22 ± 1.98 mg/kg/min. The average BG during the critical sample was 42 ± 0.16 mg/dL (three patients). The mean duration of requirement of the glucose infusion was 6.2 ± 3 days during the immediate neonatal period. Diagnosis of the hypopituitarism took 2-52 days from the initial presentation of hypoglycemia. Besides growth hormone (GH) deficiency, cortisol deficiency was diagnosed in all the five neonates. Neuroimaging findings in all the neonates were consistent with pituitary stalk interruption syndrome (hypoplastic anterior pituitary, ectopic posterior pituitary [EPP] and interrupted pituitary stalk). Conclusions Hypoglycemia is a common metabolic complication affecting an infant in the immediate neonatal period. Delay in the diagnosis of hypopituitarism presenting as hypoglycemia is the result of the lack of awareness among neonatologists and/or pediatricians. We propose that providers be cognizant that PH can be the only presentation of hypopituitarism in the neonatal period. Therefore, having a high index of suspicion about this condition can avoid a delay in the evaluation, diagnosis and treatment of hypopituitarism.
PMID: 31211689
ISSN: 2191-0251
CID: 3939092

Update on the current modalities used to screen high risk youth for prediabetes and/or type 2 diabetes mellitus

Brar, Preneet Cheema
The modalities currently employed to screen for type 2 diabetes mellitus (T2DM)/prediabetes are HbA1c, fasting plasma glucose (FPG), and 2-hour plasma glucose (PG) during an oral glucose tolerance test (OGTT). The purpose of this review is to highlight the positive qualities and pitfalls of these diagnostic modalities and reflect on the most reasonable and effective approach to screen high risk youth. Given its inherent preanalytical advantages, glycated hemoglobin (HbA1c) continues to be the preferred diagnostic modality used by pediatricians to screen high risk youth. However, when the three aforementioned tests are performed in youths of different races/ethnicities, discrepant results for T2DM/prediabetes are observed. The prevalence rates for T2DM vary from 0.53% in Chinese youth (including youth of all body mass indexes) to 18.3% in high-risk, overweight, obese Korean youth. Moreover, the FPG is abnormal (>100 less than <126 mg/dL) in 15% of Korean youth versus 8.7% of Chinese youth. The prevalence rates for prediabetes are 1.49% in Chinese youth versus 21% in Emirati youth (HbA1c, 5.7%-6.4%). The coefficient of agreement, k, between these screening tests for T2DM are fair, 0.45-0.5 across all youth. However, using HbA1c as a comparator, the agreement is weak with FPG (k=0.18 in German youth versus k=0.396 in Korean youth). The American Diabetes Association (ADA) Standards of Medical Care Guidelines define "high risk youth" who need to be tested for T2DM and/or prediabetes. OGTT and HbA1c do not always detect T2DM in similar individuals. HbA1c may not be an ideal test for screening Hispanic and African American youth. FPG and OGTT are suitable screening tests for youth of ethnic minorities and those with cystic fibrosis or hemoglobinopathies. Performing all three tests either together or sequentially may be the only way to encompass all youth who have aberrations in different aspects of glucose homeostasis.
PMID: 31261470
ISSN: 2287-1012
CID: 3967952