Two Adults with Adrenal Myelolipoma and 21-Hydroxylase Deficiency

We present incidentally discovered adrenal myelolipomas in two adult males with untreated congenital adrenal hyperplasia (CAH). The patients had simple virilizing form of CAH due to mutations in the CYP21 gene coding for 21-hydroxylase; one was heterozygous for the I172N mutation and the other compound heterozygous for the I172N and I2splice mutations. The masses were not removed since myelolipomas are considered benign tumors, and the tumor size did not increase during four- and nine-year observation periods. An adrenal myelolipoma is an important exception to the rule that large tumours should be removed. Untreated CAH with prolonged excessive ACTH stimulation might contribute to the growth of adrenal masses. CAH should be considered as a differential diagnosis of patients with adrenal masses or adrenal myelolipomas

Beta cell function, hepatic insulin clearance, and insulin sensitivity in South Asian and Nordic women after gestational diabetes mellitus

South Asians have higher risk of type 2 diabetes after gestational diabetes mellitus (GDM) than Nordic women; however the mechanisms behind this difference remain unclear. We investigated insulin sensitivity, beta cell function, and hepatic insulin clearance, in 179 South Asian and 108 Nordic women ∼17 months after GDM (mean age 35.3 years and BMI 29.1 kg/m2), via an oral glucose tolerance test using deconvolution of C-peptide kinetics. 31% of South Asian and 53% of Nordic participants were normoglycemic at the time of measurement. South Asian women had higher area under the curve (AUC) for glucose, pre-hepatic insulin, peripheral insulin, and lower levels of insulin sensitivity, disposition index, and fasting hepatic insulin clearance compared with Nordic women. In the group with prediabetes or diabetes, South Asian women displayed similar AUC for glucose and pre-hepatic insulin, but higher AUC for peripheral insulin, and lower levels of disposition index, and fasting hepatic insulin clearance compared with Nordic women. The waist-to-height ratio mediated ∼25-40% of the ethnic differences in insulin sensitivity in normoglycemic women. Overall, our novel data showed that normoglycemic South Asian women after GDM displayed lower insulin secretion for a given insulin resistance, and lower hepatic insulin clearance compared with Nordic women. South Asian women are at high risk of developing type 2 diabetes after GDM, and preventive efforts should be prioritized

High prevalence and significant ethnic differences in actionable HbA 1C after gestational diabetes mellitus in women living in Norway

Background: The type 2 diabetes risk after gestational diabetes mellitus (GDM) is twice as high in South Asian compared to European women. Current guidelines differ regarding which test to use as a screening-tool post-GDM. We aimed to identify ethnic differences in the prevalence rates and early predictors for actionable HbA1c (defined as prediabetes and diabetes) short time after GDM. Methods: This cross-sectional study, enrolling South Asian and Nordic women 1–3 years after a diagnosis of GDM, was undertaken at three hospitals in Norway. We performed a clinical and laboratory evaluation including an oral glucose tolerance test (OGTT). Medical records were used to retrieve data during pregnancy. Prediabetes was classified with HbA1c alone or combined with OGTT glucose measurements according to the WHO, WHO-IEC, and ADA criteria (fasting plasma glucose (FPG) 6.1–6.9 mmol/L, FPG 6.1–6.9 mmol/L and/or HbA1c 42-47 mmol/mol (6.0-6.4%), and FPG 5.6–6.9 mmol/L and/or HbA1c 39-47 mmol/mol (5.7-6.4%)). Ethnic differences in prevalence and predictors of glucose deterioration were assed by χ2 (Pearson) tests and logistic regression models. Results: We included 163 South Asian and 108 Nordic women. Actionable HbA1c levels were highly prevalent and more so among South Asian than Nordic women (WHO-IEC-HbA1c: 25.8% vs. 6.5% (p ≤ 0.001), ADA-HbA1c: 58.3% vs. 22.2% (p ≤ 0.001)). Although adding OGTT-data gave higher combined prevalence rates of prediabetes and diabetes (WHO: 65.6% vs. 47.2% (p ≤ 0.05), WHO-IEC: 70.6% vs. 47.2% (p ≤ 0.001), ADA: 87.8% vs. 65.7% (p ≤ 0.001)), the excess risk in the South Asian women was best captured by the HbA1c. Important predictors for glucose deterioration after GDM were: South Asian ethnicity, GDM before the index pregnancy, use of glucose-lowering drugs in pregnancy, higher age, and higher in-pregnancy fasting glucose levels. Conclusions: In women with GDM 1–3 year previously, we found high prevalence and significant ethnic differences in actionable ADA-HbA1c levels, with South Asian ethnicity, GDM before the index pregnancy, and the use of glucose-lowering drugs in pregnancy as the most important risk factors. This study reinforces the importance of annual screening—preferably with HbA1c measurements—to facilitate early intervention after GDM

Plasma-Metanephrines in Patients with Autoimmune Addison’s Disease with and without Residual Adrenocortical Function

Purpose: Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison’s disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. Methods: We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Results: Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Conclusion: Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study

Objective - Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. Methods - We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Results - Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = −0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (−0.15 normalized protein expression [NPX], P = .0001, and −0.25 NPX, P = .0003, respectively). Conclusions - We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small

Residual Corticosteroid Production in Autoimmune Addison Disease

Context - Contrary to current dogma, growing evidence suggests that some patients with autoimmune Addison disease (AAD) produce corticosteroids even years after diagnosis. Objective - To determine frequencies and clinical features of residual corticosteroid production in patients with AAD. Design - Two-staged, cross-sectional clinical study in 17 centers (Norway, Sweden, and Germany). Residual glucocorticoid (GC) production was defined as quantifiable serum cortisol and 11-deoxycortisol and residual mineralocorticoid (MC) production as quantifiable serum aldosterone and corticosterone after > 18 hours of medication fasting. Corticosteroids were analyzed by liquid chromatography–tandem mass spectrometry. Clinical variables included frequency of adrenal crises and quality of life. Peak cortisol response was evaluated by a standard 250 µg cosyntropin test. Results - Fifty-eight (30.2%) of 192 patients had residual GC production, more common in men (n = 33; P P P P P P P  Conclusion - In established AAD, one-third of the patients still produce GCs even decades after diagnosis. Residual production is more common in men and in patients with shorter disease duration but is not associated with adrenal crises or quality of life

Prevalence and characteristics of adrenal tumors and myelolipomas in congenital adrenal hyperplasia: A systematic review and meta-analysis

Objective: The prevalence of adrenal tumors in congenital adrenal hyperplasia (CAH) is uncertain. Our objective was to estimate the prevalence and characteristics of adrenal tumors and myelolipoma in CAH, and investigate clinical features of this population. Methods: We carried out systematic searches in Medline Ovid and Embase for articles published until January, 2020. Studies with confirmed CAH, biochemically and/or genetically, were included. The two authors independently extracted data from each study. Results: Six cohort studies were included in the prevalence calculation. In addition, 32 case reports on adrenal myelolipomas and CAH were included. The prevalence of adrenal tumors in CAH was 29.3%. When only studies with genetically verified cytochrome P450, Family 21, subfamily A, polypeptide 2 gene (CYP21A2) mutations were included the prevalence was 23.6%. The prevalence of myelolipoma in CAH was 7.4% (verified CYP21A2 mutations 8.6%). The proportion of myelolipoma in the adrenal tumors was 25.4% (genetically verified 36.6%). The median (range) age at tumor diagnosis was 36.0 (12 to 60) years and there were more tumors in males than in females (37.9% versus 22.1%; P<.05). In patients with myelolipomas, 93.5% had an undiagnosed or poorly managed CAH. Conclusion: Patients with CAH had a high prevalence of adrenal tumors, particularly myelolipomas. Those with myelolipomas had a high frequency of late-diagnosed or poorly controlled CAH. Adrenal imaging may be considered in patients with CAH, especially if abdominal pain is present

Psychological adjustment, quality of life, and self-perceptions of reproductive health in males with congenital adrenal hyperplasia: a systematic review

Purpose Congenital adrenal hyperplasia (CAH) has been shown to potentially affect psychological adjustment. However, most research has focused on females, and knowledge about psychological challenges in males remains sparse. The aim of this systematic review was therefore to assess these in males with CAH. Methods We systematically searched the OVID Medline, PsycINFO, CINAHL, and Web of Science databases, for articles published up to April 20, 2018, investigating psychological adjustment in males with CAH. Results Eleven studies were included in the review. Three main health domains were identified: psychological and psychiatric health, quality of life (QoL), and self-perceptions of reproductive health. Some studies covered more than one health domain. Seven studies explored psychological adjustment and/or the presence of psychiatric symptoms or disorders. Results indicated that males with CAH had more problems related to internalizing behaviors (negative behaviors directed toward the self) and more negative emotionality compared to reference groups. Six studies examined QoL, five of them reporting reduced QoL compared to reference groups. Three studies explored the impact of fertility and sexual health issues on psychological health with varying results from impaired to normal sexual well-being. Conclusions CAH seems to have an impact on males' psychological health. However, the number of identified studies was limited, included few participants, and revealed divergent findings, demonstrating the need for larger studies and highlighting a number of methodological challenges that should be addressed by future research

The usage of fasting glucose and glycated hemoglobin for the identification of unknown type 2 diabetes in high risk patients with morbid obesity

Background: In spite of increased vigilance of undiagnosed type 2 diabetes (DM2), the prevalence of unknown DM2 in subjects with morbid obesity is not known. Aim: To assess the prevalence of undiagnosed DM2 and compare the performance of glycated A1c (HbA1c) and fasting glucose (FG) for the diagnosis of DM2 and prediabetes (preDM) in patients with morbid obesity. Patients and methods: We measured fasting glucose and HbA1c in 537 consecutive patients with morbid obesity without previously known DM2. Results: A total of 49 (9%) patients with morbid obesity had unknown DM2 out of which 16 (33%) fulfilled both the criteria for HbA1c and FG. Out of 284 (53%) subjects with preDM, 133 (47%) fulfilled both the criteria for HbA1c and FG. Measurements of agreement for FG and HbA1c were moderate for DM2 (κ = 0.461, p < .001) and fair for preDM (κ = 0.317, p < .001). Areas under the curve for FG and HbA1c in predicting unknown DM2 were 0.970 (95% CI 0.942, 0.998) and 0.894 (95% CI 0.837, 0.951) respectively. The optimal thresholds to identify unknown DM2 were FG ≥6.6 mmol/L and HbA1c ≥ 6.1% (43 mmol/mol). Conclusions: The prevalence of DM2 remains high and both FG and HbA1c identify patients with unknown DM2. FG was slightly superior to HbA1c in predicting and separating patients with unknown DM2 from patients without DM2. We suggest that an FG ≥6.6 mmol/L or an HbA1c ≥6.1% (43 mmol/mol) may be used as primary cut points for the identification of unknown DM2 among patients with morbid obesity