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Open access

Ramjan Sanas Mohamed, Biyaser Abuelgasim, Sally Barker, Hemanth Prabhudev, Niamh M Martin, Karim Meeran, Emma L Williams, Sarah Darch, Whitlock Matthew, Tricia Tan, and Florian Wernig

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.

Open access

Keiko Ohkuwa, Kiminori Sugino, Ryohei Katoh, Mitsuji Nagahama, Wataru Kitagawa, Kenichi Matsuzu, Akifumi Suzuki, Chisato Tomoda, Kiyomi Hames, Junko Akaishi, Chie Masaki, Kana Yoshioka, and Koichi Ito

Objective

Parathyroid carcinoma is a rare tumor among parathyroid tumors. Aspiration cytology and needle biopsy are generally not recommended for diagnostic purposes because they cause dissemination. Therefore, it is commonly diagnosed by postoperative histopathological examination. In this study, we investigated whether preoperative inflammatory markers can be used as predictors of cancer in patients with primary hyperparathyroidism.

Design

This was a retrospective study.

Methods

Thirty-six cases of parathyroid carcinoma and 50 cases of parathyroid adenoma (PA) operated with the diagnosis of primary hyperparathyroidism and confirmed histopathologically at Ito Hospital were included in this study. Preoperative clinical characteristics and inflammatory markers (neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio (LMR)) were compared and their values in preoperative prediction were evaluated and analyzed.

Results

Preoperative intact-parathyroid hormone (P  = 0.0003), serum calcium (P  = 0.0048), and tumor diameter (P  = 0.0002) were significantly higher in parathyroid carcinoma than in PA. LMR showed a significant decrease in parathyroid carcinoma (P  = 0.0062). In multivariate analysis, LMR and tumor length diameter were independent predictors. In the receiver operating characteristics analysis, the cut-off values for LMR and tumor length diameter were 4.85 and 28.0 mm, respectively, for parathyroid cancer prediction. When the two extracted factors were stratified by the number of factors held, the predictive ability improved as the number of factors increased.

Conclusion

In the preoperative evaluation, a combination of tumor length diameter of more than 28 mm and LMR of less than 4.85 was considered to have a high probability of cancer.

Open access

Martijn J J Finken, Aleid J G Wirix, Ines A von Rosenstiel-Jadoul, Bibian van der Voorn, Mai J M Chinapaw, Michaela F Hartmann, Joana E Kist-van Holthe, Stefan A Wudy, and Joost Rotteveel

Objective

Childhood obesity is associated with alterations in hypothalamus–pituitary–adrenal axis activity. We tested the hypothesis that multiple alterations in the metabolism of glucocorticoids are required for the development of hypertension in children who become overweight.

Methods

Spot urine for targeted gas chromatography-mass spectrometry steroid metabolome analysis was collected from (1) overweight/hypertensive children (n  = 38), (2) overweight/non-hypertensive children (n  = 83), and (3) non-overweight/non-hypertensive children (n  = 56).

Results

The mean (± s.d.) age of participants was 10.4 ± 3.4 years, and 53% of them were male. Group 1 and group 2 had higher excretion rates of cortisol and corticosterone metabolites than group 3 (869 (interquartile range: 631–1352) vs 839 (609–1123) vs 608 (439–834) μg/mmol creatinine × m2 body surface area, P < 0.01, for the sum of cortisol metabolites), and group 1 had a higher excretion rate of naive cortisol than group 3. Furthermore, groups differed in cortisol metabolism, in particular in the activities of 11β-hydroxysteroid dehydrogenases, as assessed from the ratio of cortisol:cortisone metabolites (group 2 < group 3), 5α-reductase (group 1 > group 2 or 3), and CYP3A4 activity (group 1 < group 2 or 3).

Discussion

The sequence of events leading to obesity-associated hypertension in children may involve an increase in the production of glucocorticoids, downregulation of 11β-hydroxysteroid dehydrogenase type 1 activity, and upregulation of 5α-reductase activity, along with a decrease in CYP3A4 activity and an increase in bioavailable cortisol.

Open access

Mohamed Asrih, Flore Sinturel, Richard Dubos, Idris Guessous, Zoltan Pataky, Charna Dibner, François R Jornayvaz, and Karim Gariani

Objective

Growth differentiation factor-15 (GDF15), a key metabolic regulator, is associated with obesity and diabetes in which sex-specific differences have been reported. Thus, we assessed whether GDF15 could be dependent on sex in diabetes and/or obesity groups.

Methods

We measured serum GDF15 levels by ELISA in eight lean women and men (n = 16), eight women and eight men having obesity (n = 16), eight women and eight men with type 2 diabetes (T2D, n = 16), and seven women and nine men with both diabetes and obesity (n = 16). Estimation of the difference in the means of each group was performed by two-way ANOVA. The interdependence of the different variates was addressed by multivariate analysis. Correlations between GDF15 levels and HOMA-IR, HbA1c, triglycerides, HDL, and LDL were explored by linear regression.

Results

Being a woman and having obesity alone or in combination with diabetes decreased GDF15 serum levels (β = −0.47, CI = −0.95, 0.00, P = 0.052; β = −0.45, CI = −0.94, 0.05, P= 0.075). Diabetes independently of metformin treatment and obesity were not predictive of low GDF15 levels (β = 0.10, CI = −0.36, 0.57, P = 0.7). Correlation analysis showed that HOMA-IR (r = 0.45, P = 0.008) and triglycerides (r = 0.41, P = 0.017) were positively correlated and HDL (r = −0.48, P = 0.005) was negatively correlated with GDF15 levels in men.

Conclusions/interpretation

GDF15 level was significantly different between men and women, as well as between the groups. Sex and group interaction revealed that being a woman and having obesity alone or in combination with diabetes decreased GDF15 levels.

Open access

Elena Valassi, Iacopo Chiodini, Richard A Feelders, Cornelie D Andela, Margueritta Abou-Hanna, Sarah Idres, and Antoine Tabarin

Background

Cushing’s syndrome (CS) is a rare condition of chronically elevated cortisol levels resulting in diverse comorbidities, many of which endure beyond successful treatment affecting the quality of life. Few data are available concerning patients’ experiences of diagnosis, care and persistent comorbidities.

Objective

To assess CS patients’ perspectives on the diagnostic and care journey to identify unmet therapeutic needs.

Methods

A 12-item questionnaire was circulated in 2019 by the World Association for Pituitary Organisations. A parallel, 13-item questionnaire assessing physician perceptions on CS patient experiences was performed.

Results

Three hundred twenty CS patients from 30 countries completed the questionnaire; 54% were aged 35–54 and 88% were female; 41% were in disease remission. The most burdensome symptom was obesity/weight gain (75%). For 49% of patients, time to diagnosis was over 2 years. Following treatment, 88.4% of patients reported ongoing symptoms including, fatigue (66.3%), muscle weakness (48.8%) and obesity/weight gain (41.9%). Comparisons with delay in diagnosis were significant for weight gain (P = 0.008) and decreased libido (P = 0.03). Forty physicians completed the parallel questionnaire which showed that generally, physicians poorly estimated the prevalence of comorbidities, particularly initial and persistent cognitive impairment. Only a minority of persistent comorbidities (occurrence in 1.3–66.3%; specialist treatment in 1.3–29.4%) were managed by specialists other than endocrinologists. 63% of patients were satisfied with treatment.

Conclusion

This study confirms the delay in diagnosing CS. The high prevalence of persistent comorbidities following remission and differences in perceptions of health between patients and physicians highlight a probable deficiency in effective multidisciplinary management for CS comorbidities.

Open access

Rongpeng Gong, Yuanyuan Liu, Gang Luo, Jiahui Yin, Zuomiao Xiao, and Tianyang Hu

Background

In recent decades, with the development of the global economy and the improvement of living standards, insulin resistance (IR) has become a common phenomenon. Current studies have shown that IR varies between races. Therefore, it is necessary to develop individual prediction models for each country. The purpose of this study was to develop a predictive model of IR applicable to the US population.

Method

In total, 11 cycles of data from the NHANES database were selected for this study. Of these, participants from 1999 to 2010 (n  =  14931) were used to establish the model, and participants from 2011 to 2020 (n  =  13,646) were used to validate the model. Univariate and multivariable logistic regression was used to analyze the factors associated with IR. Optimal subset regression was used to filter the best modeling variables. ROC curves, calibration curves, and decision curve analysis were used to determine the strengths and weaknesses of the model.

Results

After screening the variables by optimal subset regression, variables with covariance were excluded, and a total of seven factors (including HDL, LDL, ALB, GLB, GLU, BMI, and waist) were finally included to establish the prediction model. The AUCs were 0.851 and 0.857 in the training and validation sets, respectively, and the Brier value of the calibration curve was 0.153.

Conclusion

The optimal subset predictive model proposed in this study has a great performance in predicting IR, and the decision curve analysis shows that it has a high net clinical benefit, which can help clinicians and epidemiologists easily detect IR and take appropriate interventions as early as possible.

Open access

Ditte Sofie Dahl Sørensen, Jesper Krogh, Åse Krogh Rasmussen, and Mikkel Andreassen

Background

There is no consensus regarding markers of optimal treatment or timing between glucocorticoid intake and assessment of hormone levels in the follow-up of female 21-hydroxylase deficient patients.

Objective

To examine visit-to-visit repeatability in levels of adrenal hormones in adult female patients, to identify predictors of repeatability in hormone levels and to examine concordance between levels of different adrenal hormones.

Method

All patients with confirmed 21-hydroxylase deficiency treated with glucocorticoids, were included. The two most recent blood samples collected on a stable dose of glucocorticoid replacement were compared. Complete concordance was defined as all measured adrenal hormones either within, below or above normal range evaluated in a single-day measurement.

Results

Sixty-two patients, median age of 35 (range 18–74) years were included. All hormone levels showed moderate to excellent repeatability with an intraclass correlation coefficient between 0.80 and 0.99. Repeatability of hormone levels was not affected by the use of long-acting glucocorticoids or time of day for blood sample collection. The median difference in time between the two sample collections was 1.5 (range 0–7.5) h. Complete concordance between 17-hydroxyprogesterone, androstenedione, and testosterone was found in 21% of cases.

Conclusion

During everyday, clinical practice hormone levels in adult female patients with 21-hydroxylase deficiency showed a moderate to excellent repeatability, despite considerable variation in time of day for blood sample collection. We found no major predictors of hormone level variation. Future studies are needed to address the relationship between the timing of glucocorticoid intake vs adrenal hormone levels and clinical outcome in both adults and children.

Open access

Muriel Houang, Thao Nguyen-Khoa, Thibaut Eguether, Bettina Ribault, Séverine Brabant, Michel Polak, Irène Netchine, and Antonin Lamazière

Neonatal screening for congenital adrenal hyperplasia (CAH) faces many specific challenges. It must be done using a performant analytical approach that combines sensitivity and specificity to capture the potential causes of mortality during the first week of life, such as salt wasting and glucocorticoid deficiency. Here, we confirm that maternal inhaled corticosteroid intake during pregnancy is a possible cause of missed CAH diagnosis. Thanks to liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) analysis, we were able to quantify endogenous steroid metabolites and also detect the presence of exogenous steroids in the dried blood spot of a newborn. Adding LC-MS/MS analysis as second-tier test, especially one that includes both 17-hydroxyprogesterone and 21-deoxycortisol measurements, would probably improve CAH diagnosis. In familial neonatal screening one could also look for maternal corticosteroid therapies that are hidden to prevent false-negative tests.

Open access

Paola Parra Ramírez, Patricia Martín Rojas-Marcos, Miguel Paja Fano, Marga González Boillos, Eider Pascual-Corrales, Ana García-Cano, Jorge Gabriel Ruiz-Sanchez, Almudena Vicente, Emilia Gómez-Hoyos, Rui Ferreira, Iñigo García Sanz, Mònica Recasens, Begoña Pla Peris, Rebeca Barahona San Millan, María José Picón César, Patricia Díaz Guardiola, Juan Jesús García González, Carolina Perdomo, Laura Manjón, Rogelio García-Centeno, Juan Carlos Percovich, Ángel Rebollo Román, Paola Gracia Gimeno, Cristina Robles Lázaro, Manuel Morales, Felicia Hanzu, and Marta Araujo-Castro

Objective

To compare the presentation and evolution of primary aldosteronism (PA) in the elderly (≥65 years) and young patients (<65 years).

Methods

A retrospective multicenter study was performed in 20 Spanish hospitals of PA patients in follow-up between 2018 and 2021.

Results

Three hundred fifty-two patients with PA <65 years and 88 patients ≥65 years were included. Older PA patients had a two-fold higher prevalence of type 2 diabetes, dyslipidemia, and cerebrovascular disease, but these differences disappeared after adjusting for hypertension duration. At diagnosis, diastolic blood pressure was lower than in young patients (83.3 ± 11.54 vs 91.6 ± 14.46 mmHg, P < 0.0001). No differences in the rate of overall correct cannulation (56.5% vs 42.3%, P = 0.206) or the diagnosis of unilaterality (76.9% vs 62.5%, P = 0.325) in the adrenal venous sampling (AVS) was observed between the elderly and young groups. However, there was a lower proportion of PA patients who underwent adrenalectomy in the elderly group than in the younger group (22.7% (n  = 20) vs 37.5% (n  = 132), P = 0.009). Nevertheless, no differences in the rate of postsurgical biochemical (100% (n  = 14) vs 92.8% (n  = 90), P = 0.299) and hypertension cure (38.6% (n  = 51) vs 25.0% (n  = 5), P = 0.239) were observed between both groups.

Conclusion

Older patients with PA have a worse cardiometabolic profile than young patients with PA that it is related to a longer duration of hypertension. However, the results of the AVS, and adrenalectomy are similar in both groups. Therefore, the management of elderly patients with PA should be based not only on age, but rather on the overall medical, physical, social, and mental characteristics of the patients.

Open access

Melody Lok-Yi Chan, Sammy Wing-Ming Shiu, Ching-Lung Cheung, Anskar Yu-Hung Leung, and Kathryn Choon-Beng Tan

The inducible degrader of low-density lipoprotein receptor (IDOL) is an E3 ubiquitin ligase involved in the post-transcriptional regulation of LDL receptor (LDLR). Statins lower plasma LDL by activating transcription of hepatic LDLR expression, and we have determined whether statins modulate IDOL expression and influence LDLR protein abundance. IDOL expression in monocytes and serum IDOL level was determined in statin-treated familial hypercholesterolemia (FH) patients and compared with control subjects. Serum IDOL level was also evaluated in a group of untreated FH patients before and after the initiation of statin. The mechanism underlying the inhibitory effect of statin on IDOL expression was investigated in vitro. In statin-treated FH patients, serum IDOL level and its expression in monocytes was reduced compared with control (P < 0.05). In contrast, untreated FH patients had higher serum levels of IDOL and proprotein convertase subtilisin/kexintype 9 (PCSK9) than control (P < 0.05), and serum IDOL level decreased after statin therapy (P < 0.05) whereas an increase was observed in PCSK9 level (P < 0.01). In vitro, atorvastatin significantly decreased IDOL abundance in a dose-dependent manner in cultured macrophages and hepatocytes with a concomitant increase in LDLR expression. The transcription of IDOL was restored by adding either an LXR agonist T0901317 or oxysterol 22(R)-hydroxycholesterol, indicating that statin inhibited IDOL expression by reducing LXR activation. The LXR-IDOL-LDLR axis can be modulated by statins in vitro and in vivo. Statins inhibit IDOL expression by reducing LXR activation and upregulate LDLR, and statins exert the opposite effect on IDOL and PCSK9.