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Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Department of Clinical Science, Department of Medicine, Department of Medicine, Pediatric Department, University of Bergen, Bergen, Norway
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Primary hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disorder characterized by neuromuscular symptoms in infancy due to extremely low levels of serum magnesium and moderate to severe hypocalcemia. Homozygous mutations in the magnesium transporter gene transient receptor potential cation channel member 6 (TRPM6) cause the disease. HSH can be misdiagnosed as primary hypoparathyroidism. The aim of this study was to describe the genetic, clinical and biochemical features of patients clinically diagnosed with HSH in a Norwegian cohort. Five patients in four families with clinical features of HSH were identified, including one during a national survey of hypoparathyroidism. The clinical history of the patients and their families were reviewed and gene analyses of TRPM6 performed. Four of five patients presented with generalized seizures in infancy and extremely low levels of serum magnesium accompanied by moderate hypocalcemia. Two of the patients had an older sibling who died in infancy. Four novel mutations and one large deletion in TRPM6 were identified. In one patient two linked homozygous mutations were located in exon 22 (p.F978L) and exon 23 (p.G1042V). Two families had an identical mutation in exon 25 (p.E1155X). The fourth patient had a missense mutation in exon 4 (p.H61N) combined with a large deletion in the C-terminal end of the gene. HSH is a potentially lethal condition that can be misdiagnosed as primary hypoparathyroidism. The diagnosis is easily made if serum magnesium is measured. When treated appropriately with high doses of oral magnesium supplementation, severe hypomagnesemia is uncommon and the long-term prognosis seems to be good.
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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, Division of Medicine, University of Bergen, 5021 Bergen, Norway
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In about 95% of cases, congenital adrenal hyperplasia (CAH) is caused by mutations in CYP21A2 gene encoding steroid 21-hydroxylase (21OH). Recently, we have reported four novel CYP21A2 variants in the Norwegian population of patients with CAH, of which p.L388R and p.E140K were associated with salt wasting (SW), p.P45L with simple virilising (SV) and p.V211M+p.V281L with SV to non-classical (NC) phenotypes. We aimed to characterise the novel variants functionally utilising a newly designed in vitro assay of 21OH enzyme activity and structural simulations and compare the results with clinical phenotypes. CYP21A2 mutations and variants were expressed in vitro. Enzyme activity was assayed by assessing the conversion of 17-hydroxyprogesterone to 11-deoxycortisol by liquid chromatography tandem mass spectroscopy. PyMOL 1.3 was used for structural simulations, and PolyPhen2 and PROVEAN for predicting the severity of the mutants. The CYP21A2 mutants, p.L388R and p.E140K, exhibited 1.1 and 11.3% of wt 21OH enzyme activity, respectively, in vitro. We could not detect any functional deficiency of the p.P45L variant in vitro; although prediction tools suggest p.P45L to be pathogenic. p.V211M displayed enzyme activity equivalent to the wt in vitro, which was supported by in silico analyses. We found good correlations between phenotype and the in vitro enzyme activities of the SW mutants, but not for the SV p.P45L variant. p.V211M might have a synergistic effect together with p.V281L, explaining a phenotype between SV and NC CAH.
Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Department of Biomedicine, University of Bergen, Bergen, Norway
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Background
Primary aldosteronism (PA) is associated with increased cardiovascular morbidity, presumably due to left ventricular (LV) hypertrophy and fibrosis. However, the degree of fibrosis has not been extensively studied. Cardiac magnetic resonance imaging (CMR) contrast enhancement and novel sensitive T1 mapping to estimate increased extracellular volume (ECV) are available to measure the extent of fibrosis.
Objectives
To assess LV mass and fibrosis before and after treatment of PA using CMR with contrast enhancement and T1 mapping.
Methods
Fifteen patients with newly diagnosed PA (PA1) and 24 age- and sex-matched healthy subjects (HS) were studied by CMR with contrast enhancement. Repeated imaging with a new scanner with T1 mapping was performed in 14 of the PA1 and 20 of the HS median 18 months after specific PA treatment and in additional 16 newly diagnosed PA patients (PA2).
Results
PA1 had higher baseline LV mass index than HS (69 (53–91) vs 51 (40–72) g/m2; P < 0.001), which decreased significantly after treatment (58 (40–86) g/m2; P < 0.001 vs baseline), more with adrenalectomy (n = 8; −9 g/m2; P = 0.003) than with medical treatment (n = 6; −5 g/m2; P = 0.075). No baseline difference was found in contrast enhancement between PA1 and HS. T1 mapping showed no increase in ECV as a myocardial fibrosis marker in PA. Moreover, ECV was lower in the untreated PA2 than HS 10 min post-contrast, and in both PA groups compared with HS 20 min post-contrast.
Conclusion
Specific treatment rapidly reduced LV mass in PA. Increased myocardial fibrosis was not found and may not represent a common clinical problem.
Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
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Department of Clinical Science, Department of Medicine, University of Bergen, N-5021 Bergen, Norway
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Objective
Liquid chromatography–tandem mass spectrometry (LC–MS/MS) offers superior analytical specificity compared with immunoassays, but it is not available in many regions and hospitals due to expensive instrumentation and tedious sample preparation. Thus, we developed an automated, high-throughput LC–MS/MS assay for simultaneous quantification of ten endogenous and synthetic steroids targeting diseases of the hypothalamic–pituitary–adrenal axis and gonads.
Methods
Deuterated internal standards were added to 85 μl serum and processed by liquid–liquid extraction. Cortisol, cortisone, prednisolone, prednisone, 11-deoxycortisol, dexamethasone, testosterone, androstenedione and progesterone were resolved by ultra-high-pressure chromatography on a reversed-phase column in 6.1 min and detected by triple-quadrupole mass spectrometry. The method was used to assess steroid profiles in women with Addison's disease (AD, n=156) and blood donors (BDs, n=102).
Results
Precisions ranged from 4.5 to 10.1% relative standard deviations (RSD), accuracies from 95 to 108% and extraction recoveries from 60 to 84%. The method was practically free of matrix effects and robust to individual differences in serum composition. Most postmenopausal AD women had extremely low androstenedione concentrations, below 0.14 nmol/l, and median testosterone concentrations of 0.15 nmol/l (interquartile range 0.00–0.41), considerably lower than those of postmenopausal BDs (1.28 nmol/l (0.96–1.64) and 0.65 nmol/l (0.56–1.10) respectively). AD women in fertile years had androstenedione concentrations of 1.18 nmol/l (0.71–1.76) and testosterone concentrations of 0.44 nmol/l (0.22–0.63), approximately half of those found in BDs of corresponding age.
Conclusion
This LC–MS/MS assay provides highly sensitive and specific assessments of glucocorticoids and androgens with low sample volumes and is suitable for endocrine laboratories and research. Its utility has been demonstrated in a large cohort of women with AD, and the data suggest that women with AD are particularly androgen deficient after menopause.
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Division of Medicine, Akershus University Hospital, Lørenskog, Norway
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Department of Clinical Medicine, University of Bergen, Bergen, Norway
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K.G. Jebsen-Center for Autoimmune Diseases, University of Bergen, Bergen, Norway
Department of Medicine, Haukeland University Hospital, Bergen, Norway
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K.G. Jebsen-Center for Autoimmune Diseases, University of Bergen, Bergen, Norway
Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Immunoassays of steroid hormones are still used in the diagnosis and monitoring of patients with congenital adrenal hyperplasia. However, cross-reactivity between steroids can give rise to falsely elevated steroid levels. Here, we compare the use of immunoassays and liquid chromatography–tandem mass spectrometry (LC–MS/MS) in the monitoring of patients with classic 21-hydroxylase deficiency (21OHD). Steroid profiles in different mutation groups (genotypes) were also compared. Fifty-five patients with classic 21OHD (38 women) were studied. Blood samples were collected in the morning after an overnight medication fast. LC–MS/MS and immunoassays were employed to assay 17-hydroxyprogesterone (17OHP), testosterone and androstenedione. In addition, 21-deoxycortisol (21DF), 11-deoxycortisol (11DF), corticosterone, deoxycorticosterone, cortisone and cortisol were analyzed by LC–MS/MS. Testosterone, androstenedione and 17OHP levels were consistently lower (by about 30–50%) when measured by LC–MS/MS compared with immunoassays, with exception of testosterone in men. There was a significant correlation between 21DF and 17OHP (r = 0.87, P < 0.001), but three patients had undetectable 21DF. Subjects with no enzyme activity had significantly lower mean 11DF concentrations than subjects with residual activity. The use of LC–MS/MS gives a more specific view of adrenal steroid levels in 21OHD compared with immunoassays, which seem to considerably overestimate the levels of 17OHP and androstenedione. Falsely elevated levels of 17OHP and androstenedione could lead to overtreatment with glucocorticoids.
Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
K. G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
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K. G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
K. G. Jebsen Center for Autoimmune Disorders, University of Bergen, Bergen, Norway
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Objective:
Autonomous cortisol secretion (ACS) is a condition with ACTH-independent cortisol overproduction from adrenal incidentalomas (AI) or adrenal hyperplasia. The hypercortisolism is often mild, and most patients lack typical clinical features of overt Cushing’s syndrome (CS). ACS is not well defined and diagnostic tests lack validation.
Methods:
Retrospective study of 165 patients with AI evaluated clinically and by assay of morning plasma ACTH, late-night saliva cortisol, serum DHEA sulphate (DHEAS), 24-h urine-free cortisol, and cortisol after dexamethasone suppression.
Results:
Patients with AI (n = 165) were diagnosed as non-functioning incidentalomas (NFI) (n = 82) or ACS (n = 83) according to current European guidelines. Late-night saliva cortisol discriminated poorly between NFI and ACS, showing a high rate of false-positive (23/63) and false-negative (38/69) results. The conventional low-dose dexamethasone suppression test (LDDST) did not improve the diagnostic specificity, compared with the 1 mg overnight DST. Receiver operating characteristic curve analysis of DHEAS in the two cohorts demonstrated an area under the curve of 0.76 (P < 0.01) with a sensitivity for ACS of 58% and a specificity of 80% using the recommended cutoff at 1.04 µmol/L (40 µg/dL).
Conclusion:
We here demonstrate in a large retrospective cohort of incidentaloma patients, that neither DHEAS, late-night saliva cortisol nor 24-h urine free cortisol are useful to discriminate between non-functioning adrenal incidentalomas and ACS. The conventional LDDST do not add further information compared with the 1 mg overnight DST. Alternative biomarkers are needed to improve the diagnostic workup of ACS.
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Department of Endocrinology, Diabetes and Metabolism, Karolinska University Hospital, Stockholm, Sweden
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
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Adrenal insufficiency is a life-threatening condition requiring chronic glucocorticoid replacement therapy, as well as stress adaptation to prevent adrenal crises. To increase patients’ self-sustainability, education on how to tackle an adrenal crisis is crucial. All patients should carry the European Emergency Card.
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Division of Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Turin, Italy
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Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
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Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan Italy
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Department of Medicine, Haukeland University Hospital, Bergen, Norway
Department of Medicine, Karolinska Institutet, Stockholm, Sweden
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Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, The Netherlands
Developmental Endocrinology Research Group, University of Glasgow, Glasgow, United Kingdom
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Background
Information on clinical outcomes of coronavirus disease 19 (COVID-19) infection in patients with adrenal disorders is scarce.
Methods
A collaboration between the European Society of Endocrinology (ESE) Rare Disease Committee and European Reference Network on Rare Endocrine Conditions via the European Registries for Rare Endocrine Conditions allowed the collection of data on 64 cases (57 adrenal insufficiency (AI), 7 Cushing’s syndrome) that had been reported by 12 centres in 8 European countries between January 2020 and December 2021.
Results
Of all 64 patients, 23 were males and 41 females (13 of those children) with a median age of 37 and 51 years. In 45/57 (95%) AI cases, COVID-19 infection was confirmed by testing. Primary insufficiency was present in 45/57 patients; 19 were affected by Addison’s disease, 19 by congenital adrenal hyperplasia and 7 by primary AI (PAI) due to other causes. The most relevant comorbidities were hypertension (12%), obesity (n = 14%) and diabetes mellitus (9%). An increase by a median of 2.0 (IQR 1.4) times the daily replacement dose was reported in 42 (74%) patients. Two patients were administered i.m. injection of 100 mg hydrocortisone, and 11/64 were admitted to the hospital. Two patients had to be transferred to the intensive care unit, one with a fatal outcome. Four patients reported persistent SARS-CoV-2 infection, all others complete remission.
Conclusion
This European multicentre questionnaire is the first to collect data on the outcome of COVID-19 infection in patients with adrenal gland disorders. It suggests good clinical outcomes in case of duly dose adjustments and emphasizes the importance of patient education on sick day rules.
