Utility of Simple and Non-Invasive Strategies Alternative to Inferior Petrosal Sinus Sampling and Peripheral CRH Stimulation in Differential Diagnosis of ACTH-Dependent Cushing Syndrome.

We aimed to evaluate the utility of simple, cost-effective, and non-invasive strategies alternative to BIPSS and peripheral CRH stimulation in differential diagnosis of ACTH-dependent CS. First, we performed ROC analysis to evaluate the performance of various tests for differential diagnosis of ACTH-dependent CS in our cohort (CD, n=76 and EAS, n=23) and derived their optimal cut-offs. Subsequently, combining various demographic (gender), clinical (hypokalemia), biochemical (plasma ACTH, HDDST, peripheral CRH stimulation) and imaging (MRI pituitary) parameters, we derived non-invasive models with 100% PPV for CD. Patients with pituitary macroadenoma (n=14) were excluded from the analysis involving non-invasive models. Relative percent ACTH (AUC: 0.933) and cortisol (AUC: 0.975) increase on peripheral CRH stimulation demonstrated excellent accuracy in discriminating CD from EAS. Best cut-offs for CD were plasma ACTH<97.3 pg/ml, HDDST≥57% cortisol suppression, CRH stimulation≥77% ACTH increase and≥11% cortisol increase. We derived six models that provided 100% PPV for CD and precluded the need for BIPPS in 35/85 (41.2%) patients with ACTH-dependent CS and no macroadenoma (in whom BIPSS would have otherwise been recommended). The first three models included basic parameters and avoided both peripheral CRH stimulation and BIPSS in 19 (22.4%) patients, while the next three models included peripheral CRH stimulation and avoided BIPSS in another 16 (18.8%) patients. Using simple and non-invasive alternative strategies, BIPSS can be avoided in 41% and peripheral CRH stimulation in 22% of patients with ACTH-dependent CS and no macroadenoma; such patients can be directly referred for a pituitary surgery.

Late-night salivary cortisol cut-offs for diagnosis of Cushing syndrome using second-generation electrochemiluminescence immunoassay kits.

CONTEXT: Late-night salivary cortisol (LNSC) is a simple and reliable screening test for Cushing syndrome (CS). With improved analytical performance of the current second-generation electrochemiluminescence immunoassay (ECLIA; Elecsys Cortisol-II; Roche Diagnostics), there is a need to revisit the LNSC cut-offs, especially in a South-Asian population. OBJECTIVE: To derive LNSC cut-offs for diagnosis of CS using second-generation ECLIA kits. DESIGN: Diagnostic accuracy study. METHODS: We prospectively recruited 155 controls aged 18-60 years, including, normal-weight (body mass index [BMI] < 25 kg/m2 and no hypertension or diabetes [n = 53]) and overweight/obese (BMI 25-30 kg/m2 and hypertension and/or diabetes [n = 52] or BMI ≥ 30 kg/m2 with/without comorbidities [n = 50]) participants. All participants submitted LNSC samples collected at home; overweight/obese controls additionally underwent dexamethasone suppression test to exclude CS. We also reviewed records of adults with endogenous CS (cases, n = 92) and a valid LNSC result using the same method. RESULTS: The 95th percentile for LNSC in controls was 6.76 nmol/L. The mean ± SD LNSC levels were 40.47 ± 49.63 nmol/L in cases and 3.37 ± 1.18 nmol/L in controls (p < 0.001). Receiver operating characteristic (ROC) analysis showed excellent diagnostic performance of LNSC for CS, with area under curves (AUCs) of 0.994 (cases vs. all controls) and 0.993 (cases vs. overweight/obese controls), respectively. The best diagnostic performance was achieved at cut-offs ≥6.73 nmol/L (sensitivity: 97.8%, specificity: 94.8%) and ≥7.26 nmol/L (sensitivity: 97.8%, specificity: 95.1%), respectively. CONCLUSIONS: LNSC measured using second-generation ECLIA demonstrated high diagnostic accuracy for CS. Based on this study, we propose a LNSC cutoff ≥6.73 nmol/L to diagnose CS.

Clinical profile and treatment outcomes among patients with sporadic and multiple endocrine neoplasia syndrome-related primary hyperparathyroidism.

OBJECTIVE: Accurate demarcation between multiple endocrine neoplasia, type 1 (MEN1)- related primary hyperparathyroidism (MPHPT) and sporadic PHPT (SPHPT) is important to plan the management of primary parathyroid disease and surveillance for other endocrine and nonendocrine tumours. The objective of this study is to compare the clinical, biochemical and radiological features and surgical outcomes in patients with MPHPT versus SPHPT and to identify the predictors of MEN1 syndrome in PHPT. DESIGN, PATIENTS AND MEASUREMENTS: This was an ambispective observationalstudy involving 251 patients with SPHPT and 23 patients with MPHPT evaluated at the endocrine clinic of All India Institute of Medical Sciences, New Delhi, India between January 2015 and December 2021. RESULTS: The prevalence of MEN1 syndrome among patients with PHPT was 8.2% and a genetic mutation was identified by Sanger sequencing in 26.1% of patients with MPHPT. Patients with MPHPT were younger (p < .001), had lower mean serum calcium (p = .01) and alkaline phosphatase (ALP; p = .03) levels and lower bone mineral density (BMD) Z score at lumbar spine (p < .001) and femoral neck (p = .007). The prevalence of renal stones (p = .03) and their complications (p = .006) was significantly higher in MPHPT group. On multivariable analysis, factors predictive of MPHPT were hyperplasia on histopathology [OR 40.1, p < .001], ALP levels within reference range [OR 5.6, p = .02] and lumbar spine BMD [OR 0.39 per unit increase in Z score, p < .001]. CONCLUSIONS: Patients with MPHPT have more severe, frequent and early onset of bone and renal involvement despite milder biochemical features. A normal serum ALP, low BMD for age and gender at lumbar spine and histopathology evidence of hyperplasia are predictive factors for MEN1 syndrome in PHPT.

Imaging characteristics of phosphaturic mesenchymal tumors.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome associated with phosphaturic mesenchymal tumors (PMTs). Localization of the causative tumor in these cases is an arduous task since the culprit lesions are usually small, slow-growing, and can be located almost anywhere from head to toe. PURPOSE: To describe the morphological characteristics of histologically proven PMTs on various radiological modalities. MATERIAL AND METHODS: After institutional ethical approval, this retrospective study analyzed 20 cases with a histopathological evidence of PMT. Various imaging characteristics of the tumors on available computed tomography (CT) and magnetic resonance imaging (MRI) scans were evaluated. Descriptive statistical analyses were conducted. RESULTS: The tumors were located in diverse locations: lower extremities (n = 10); head and neck (n = 5); vertebral column (n = 3); pelvis (n = 1); and upper extremities (n = 1). Bone lesions seen on CT had variable morphology: sclerotic (n = 3/8, 37.5%); lytic (n = 3/8, 37.5%), and both lytic and sclerotic (n = 2/8, 25%) with presence of narrow zone of transition in all cases (n = 8/8) and amorphous internal matrix calcifications in 25% of cases (n = 2/8). Of the tumors, 68.4% (n = 13/19) were hypointense on T1 and all of them showed hyperintense signal on T2-weighted and STIR images (n = 19/19) and contrast enhancement (n = 16/16). Of the tumors, 66.7% (n = 6/9) showed restricted diffusion. DOTANOC PET/CT showed tumor uptake in all cases (n = 8/8). CONCLUSION: PMTs may have variable and non-specific tumor appearances on various imaging modalities. However, in an appropriate clinical scenario and a background of suggestive biochemical work-up, the radiologist should keep a high index of suspicion.

Bone microarchitecture, bone mineral density and bone turnover in association with glycemia and insulin action in women with prior gestational diabetes.

OBJECTIVE: The aim of this cross-sectional study was to comprehensively assess bone health in women with prior gestational diabetes mellitus, including bone microarchitecture (TBS), bone mineral density (BMD, DXA) and bone turnover (osteocalcin). DESIGN, PATIENTS AND MEASUREMENTS: Study participants underwent a detailed anthropometric, biochemical and hormone assessment, including insulin and osteocalcin measurement. BMD was measured at lumbar spine, femur neck and total hip using DXA and TBS derived from lumbar spine DXA images using TBS iNsight software. RESULTS: A total of 240 women (mean age: 33.3 ± 5.0 years; median postpartum duration: 34 [interquartile range 13.0-54.5] months were evaluated. At the current visit, 115 (47.9%) and 36 (15%) women had prediabetes and diabetes, respectively. Women with dysglycemia (diabetes/prediabetes) had a higher BMD at all three sites, compared to those with normoglycemia; however, the difference was not statistically significant. Women with dysglycemia had a significantly lower TBS (1.32 ± 0.09 vs. 1.35 ± 0.09; p = .038). In the fully adjusted model, the odds ratio for association between diabetes and low TBS was 2.92 (95% confidence interval: 1.20, 7.08; p = .018). Women with dysglycemia had significantly lower serum osteocalcin levels (18.6 ± 8.5 ng/ml vs. 21.5 ± 9.7 ng/ml; p = .018). HOMA-IR (r = -.285, p < .001) was negatively correlated, while Matsuda index (r = .274, p < .001) and disposition index (r = .159, p = .016) were positively correlated with serum osteocalcin levels. CONCLUSIONS: Bone health is affected early in the natural history of diabetes and is associated with an overall low bone turnover state.

SARS-CoV-2 Seroprevalence in Individuals With Type 1 and Type 2 Diabetes Compared With Controls.

OBJECTIVE: Data for the association between diabetes and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility are conflicting. We aimed to evaluate this association using an analytical cross-sectional study design. METHODS: Study participants were recruited from endocrine clinics of our hospital and belonged to 3 groups: group 1 (type 1 diabetes mellitus [T1DM]), group 2 (type 2 diabetes mellitus [T2DM]), and group 3 (controls). All participants submitted blood samples for SARS-CoV-2 S1/S2 immunoglobulin G antibody test (LIAISON; DiaSorin) and were interviewed for a history of documented infection. RESULTS: We evaluated a total of 643 participants (T1DM, 149; T2DM, 160; control, 334; mean age, 37.9 ± 11.5 years). A total of 324 (50.4%) participants were seropositive for SARS-CoV-2. The seropositivity rate was significantly higher in the T1DM (55.7% vs 44.9%, P = .028) and T2DM (56.9% vs 44.9%, P = .013) groups than in the control group. The antibody levels in seropositive participants with T1DM and T2DM were not significantly different from those in seropositive controls. On multivariable analysis, low education status (odds ratio [OR], 1.41 [95% CI, 1.03-1.94]; P = .035), diabetes (OR, 1.68 [95% CI, 1.20-2.34]; P = .002), and overweight/obesity (OR, 1.52 [95% CI, 1.10-2.10]; P = .012) showed a significant association with SARS-CoV-2 seropositivity. The association between diabetes and SARS-CoV-2 seropositivity was found to further increase in participants with coexisting overweight/obesity (adjusted OR, 2.63 [95% CI, 1.54-4.47]; P < .001). CONCLUSION: SARS-CoV-2 seropositivity, assessed before the onset of the national vaccination program, was significantly higher in participants with T1DM and T2DM than in controls. The antibody response did not differ between seropositive participants with and without diabetes. These findings point toward an increased SARS-CoV-2 susceptibility for patients with diabetes, in general, without any differential effect of the diabetes type.

High prevalence and a long delay in the diagnosis of primary aldosteronism among patients with young-onset hypertension.

BACKGROUND: Despite being the most common cause of secondary hypertension, prevalence of primary aldosteronism (PA) among patients with young-onset hypertension (YH - age of hypertension onset <40 years) remains poorly studied. OBJECTIVE: We assessed the prevalence of PA in patients with YH referred for evaluation of secondary hypertension. DESIGN AND PATIENTS: In this prospective, cross-sectional study, 202 patients with YH, visiting endocrine and cardiology clinics of All India Institute of Medical Sciences, India, were evaluated. MEASUREMENTS: Primary aldosteronism was screened by measuring plasma aldosterone concentration (PAC) and direct renin concentration (DRC) and calculating aldosterone-to-renin ratio (ARR), followed by confirmatory saline infusion test (SIT) according to Endocrine Society Guideline. Those confirmed with post-SIT PAC >5 ng/dl underwent adrenal computed tomography (CT), followed by adrenal venous sampling (AVS). RESULTS: Of 202 YH patients, 38 (18.8%) screened positive, and PA was confirmed in 36 (17.8%). The mean age was 43.9 ± 10.9 years, and median duration of hypertension was 10.5 (3.5-18) years. The prevalence of PA increased with grade of hypertension (8.1% in grade 1 to 37.1% in grade 3), number of antihypertensive medications (2.5% in those taking ≤1 to 50% in those taking ≥4 medications) and severity of hypokalaemia (0% in potassium >5 to 85.7% in potassium <3.5 mmol/L). The prevalence of PA by age of hypertension onset was highest in age group 30-39 years (31.3%). CONCLUSIONS: There is a high prevalence and a long delay in diagnosis of PA among patients with YH, and YH should be considered as a separate high-risk category in PA screening algorithm.

Is surgery effective for treating hypothalamic hamartoma causing isolated central precocious puberty? A systematic review.

The aim of this review was to determine the role of surgery in treating hypothalamic hamartoma (HH) causing isolated central precocious puberty (CPP). Literature review was done according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Patients with isolated CPP due to HH, managed with surgical resection, were included. We found 33 studies, reporting 103 patients (76 pedunculated, 27 sessile). Patients were considered "cured" if the symptoms of PP had regressed and the hormone profile had normalized after surgery. Indications for surgery included hamartoma deemed surgically resectable (n-12), for the purpose of tissue diagnosis (n-3), partial response/failure of preoperative therapy (n-9), and unable to afford/to avoid long-term medical therapy (n-7). The extent of resection was total (TR) (n-39), near total/subtotal (NTR/STR) (n-20), partial (PR) (n-35), or unspecified (n-9). On follow-up (range: 3 months-16 years), 73.6% (56/76) of patients with pedunculated HH were cured, while 17.1% (13/76) had partial relief. Only 3/27 (11.1%) of patients with sessile HH were cured. All patients with a pedunculated hamartoma who underwent TR (n=36) improved, with 88.88% cured of the symptoms. Surgery had no effect in 17/23 (73.9%) patients with sessile HH who underwent PR. Psychological symptoms improved in 10/11 patients. There was no mortality. Permanent complications, in the form of 3rd nerve palsy, occurred in 3.7% (2/54) of the patients. To conclude, in the current era of availability of GnRH analogs, surgical resection in a subset of patients may be acceptable especially for small pedunculated hamartomas.

Concordance of glycaemic and cardiometabolic traits between Indian women with history of gestational diabetes mellitus and their spouses: an opportunity to target the household.

AIMS/HYPOTHESIS: The aim of this study was to investigate the concordance of dysglycaemia (prediabetes or diabetes) and cardiometabolic traits between women with a history of gestational diabetes mellitus (GDM) and their spouses. METHODS: Using hospital medical records, women with GDM (diagnosed between 2012 and 2016) and their spouses were invited to participate in the study and to attend a scheduled hospital visit in a fasting state. Sociodemographic, anthropometric and medical data were collected, and a 75 g OGTT with serum insulin estimation, HbA1c measurement and fasting lipid profile were performed at the visit. Prediabetes and diabetes were defined using ADA criteria and the metabolic syndrome was defined using IDF criteria. RESULTS: A total of 214 couples participated in the study. Women were tested at a mean ± SD age of 32.4 ± 4.6 years and median (quartile [q]25-q75) of 19.5 (11-44) months following the index delivery, while men were tested at a mean ± SD age of 36.4 ± 5.4 years. A total of 72 (33.6%) couples showed concordance for dysglycaemia, while 99 (46.3%) and 51 (23.8%) couples were concordant for overweight/obesity and the metabolic syndrome, respectively. A total of 146 (68.2%) couples showed concordance for any of the above three factors. The presence of dysglycaemia in one partner was associated with an increased risk of dysglycaemia in the other partner (OR 1.80 [95% CI 1.04, 3.11]). Similarly, being overweight/obese (OR 2.19 [95% CI 1.22, 3.93]) and presence of the metabolic syndrome (OR 2.01 [95% CI 1.16, 3.50]) in one partner was associated with an increased risk of these conditions in the other partner. Both women and men were more likely to have dysglycaemia if they had a partner with dysglycaemia. Women with a partner with dysglycaemia had a significantly higher BMI, waist circumference and diastolic BP, and a significantly higher probability of low HDL-cholesterol (<1.29 mmol/l) and the metabolic syndrome compared with women with a normoglycaemic partner. No such differences were observed for men with or without a partner with dysglycaemia. CONCLUSIONS/INTERPRETATION: The high degree of spousal concordance found in this study suggests social clustering of glycaemic and cardiometabolic traits among biologically unrelated individuals. This provides us with an opportunity to target the behavioural interventions at the level of the 'married couple', which may be a novel and cost-effective method of combating the current diabetes epidemic.

A Curious Case of Afebrile Dengue.

A 50-year-old male presented to us with features of diabetic ketoacidosis which was managed with adequate hydration and insulin therapy. His routine laboratory investigation revealed transaminitis, acute kidney injury and pancytopenia. Further evaluation for hematological and biochemical derangements uncovered positive dengue test (NS1 antigen and polymerase chain reaction assay). Patient distinctively reported no history of fever and remained afebrile during the course of illness. We report this case to highlight the possibility of afebrile dengue in endemic areas.

Burosumab: Current status and future prospects.

Hypophosphatemic rickets/osteomalacia caused by FGF23 excess is conventionally treated with multiple doses of inorganic phosphate salts and active vitamin D analogs. However, conventional therapy targets the consequences of elevated FGF23 and not the elevated FGF23 itself and is associated with poor adherence and long-term complications such as nephrocalcinosis and secondary/tertiary hyperparathyroidism. Burosumab is a fully human IgG1 monoclonal antibody that binds to and neutralises FGF-23, thereby leading to improvement in phosphate homeostasis and healing of rickets and osteomalacia. Data from phase 2 and 3 trials report overall safety and efficacy and Burosumab is now FDA approved for treatment of XLH and TIO in children and adults. Cost and absence of long-term data are major issues with Burosumab which should be addressed in near future. At present, experts recommend Burosumab use in patients with severe disease or those with mild-moderate disease and a failed response to a trial of conventional therapy.

Postpartum diabetes and cardiometabolic outcomes among Indian (South Asian) women with early Gestational diabetes mellitus: Insights from the CHIP-F study.

Early GDM is associated with adverse pregnancy outcomes, however data on other outcomes are scarce. We evaluated women with early (n = 117) and classical (n = 412) GDM for long-term postpartum (median 32 months) glycemic and cardiometabolic outcomes and found a significantly higher prevalence of diabetes in the former [22.2 % vs. 12.6 %, p = 0.010].

Bone mass, microarchitecture and turnover among young Indian women with non-alcoholic fatty liver disease.

PURPOSE: To evaluate comprehensive bone health among young Indian women, including bone mass, microarchitecture, and turnover, in relation to their non-alcoholic fatty liver disease (NAFLD) status. METHODS: This cross-sectional study (May 2018-November 2019) recruited women with a history of gestational diabetes mellitus (GDM) and normoglycemia in their index pregnancy, who were at least 6 months postpartum. All participants underwent abdominal ultrasonography for determination of NAFLD status (grades 2 and 3: severe NAFLD) and transient elastography (FibroScan) for hepatic fibrosis (LSM >6 kPa). Bone mass was assessed by DXA, bone microarchitecture with trabecular bone score {TBS} (low TBS ≤ 1.310) and bone turnover with markers of bone formation (osteocalcin and P1NP), and resorption (CTX). RESULTS: Bone mineral density (BMD) at femoral neck (p = 0.026) and total hip (p = 0.007) was significantly higher among women with NAFLD (n = 170) compared to those without (n = 124). There was no significant difference in bone turnover markers between the two groups. The presence of NAFLD [adjusted OR: 1.82 (1.07, 3.11)] was associated with low TBS, with a greater strength of association among women with severe NAFLD [adjusted OR: 2.97 (1.12, 7.88)]. However, these associations were attenuated and no longer significant after additionally adjusting for BMI. Women with NAFLD and hepatic fibrosis manifested significantly higher BMD at lumbar spine, femoral neck, and total hip (p < 0.001 for all) and significantly lower bone turnover markers (osteocalcin, p = 0.009 and CTX, p = 0.029), however, the association with low TBS was not observed. CONCLUSION: Among young Indian women, NAFLD is associated with increased bone mass and impaired bone microarchitecture, and hepatic fibrosis with increased bone mass and reduced bone turnover.

Postpartum glycemic and cardiometabolic profile of women testing positive for gestational diabetes mellitus by International Association of Diabetes and Pregnancy Study Groups (IADPSG) but negative by alternate criteria: Insights from CHIP-F study.

OBJECTIVE: To evaluate burden of postpartum diabetes and other cardiometabolic risk factors among women who test positive for gestational diabetes mellitus (GDM) by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria, but negative by alternate criteria. METHODS: This prospective cross-sectional study was conducted from 2019 to 2022 and is a sub-study of the CHIP-F cohort (Cohort Study of Indian Women with Hyperglycemia in Pregnancy and their Families). RESULTS: Study participants (n = 826; 183 with normoglycemia and 643 with GDM using IADPSG criteria) were evaluated at a median (IQR) postpartum interval of 31 (21-45) months. Using the United Kingdom National Institute of Health and Care Excellence (UK NICE), Canadian Diabetes Association (CDA), and Diabetes in Pregnancy Study Group India (DIPSI) criteria, 251 (39.0 %), 148 (23.0 %) and 384 (59.7 %) women who tested positive for GDM by IADPSG criteria, would have tested negative. The incidence of postpartum diabetes among such women was 30.4, 34.3, and 48.2 per 1000 women-years, respectively, which was significantly higher than those testing negative by both IADPSG and UK NICE (5.0 per 1000 women-years), IADPSG and CDA (9.2/1000 women-years) and IADPSG and DIPSI criteria (5.0/1000 women-years). The burden of obesity and metabolic syndrome was also significantly higher in such women. CONCLUSIONS: We found a significant burden of postpartum diabetes and cardiometabolic risk factors among women who tested positive for GDM by IADPSG, but negative by alternate criteria. There are potential clinical implications of a "failed" diagnosis for future cardiometabolic diseases that need to be carefully examined.