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- Claahsen-van der Grinten, HL, et al.
(författare)
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Congenital Adrenal Hyperplasia-Current Insights in Pathophysiology, Diagnostics, and Management
- 2022
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Ingår i: Endocrine reviews. - : The Endocrine Society. - 1945-7189 .- 0163-769X. ; 43:1, s. 91-159
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Tidskriftsartikel (refereegranskat)abstract
- Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders affecting cortisol biosynthesis. Reduced activity of an enzyme required for cortisol production leads to chronic overstimulation of the adrenal cortex and accumulation of precursors proximal to the blocked enzymatic step. The most common form of CAH is caused by steroid 21-hydroxylase deficiency due to mutations in CYP21A2. Since the last publication summarizing CAH in Endocrine Reviews in 2000, there have been numerous new developments. These include more detailed understanding of steroidogenic pathways, refinements in neonatal screening, improved diagnostic measurements utilizing chromatography and mass spectrometry coupled with steroid profiling, and improved genotyping methods. Clinical trials of alternative medications and modes of delivery have been recently completed or are under way. Genetic and cell-based treatments are being explored. A large body of data concerning long-term outcomes in patients affected by CAH, including psychosexual well-being, has been enhanced by the establishment of disease registries. This review provides the reader with current insights in CAH with special attention to these new developments.
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- Hodson, L., et al.
(författare)
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Menopausal Status and Abdominal Obesity Are Significant Determinants of Hepatic Lipid Metabolism in Women
- 2015
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Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980. ; 4:10
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Tidskriftsartikel (refereegranskat)abstract
- Background-Android fat distribution (abdominal obesity) is associated with insulin resistance, hepatic steatosis, and greater secretion of large very low-density lipoprotein (VLDL) particles in men. Since abdominal obesity is becoming increasingly prevalent in women, we aimed to investigate the relationship between android fat and hepatic lipid metabolism in pre-and postmenopausal women. Methods and Results-We used a combination of stable isotope tracer techniques to investigate intrahepatic fatty acid synthesis and partitioning in 29 lean and 29 abdominally obese women (android fat/total fat 0.065 [0.02 to 0.08] and 0.095 [0.08 to 0.11], respectively). Thirty women were premenopausal aged 35 to 45 and they were matched for abdominal obesity with 28 postmenopausal women aged 55 to 65. As anticipated, abdominal obese women were more insulin resistant with enhanced hepatic secretion of large (404 +/- 30 versus 268 +/- 26 mg/kg lean mass, P<0.001) but not small VLDL (160 +/- 11 versus 142 +/- 13). However, postmenopausal status had a pronounced effect on the characteristics of small VLDL particles, which were considerably triglyceride-enriched (production ratio of VLDL2-triglyceride: apolipoprotein B 30 +/- 5.3 versus 19 +/- 1.6, P<0.05). In contrast to postmenopausal women, there was a tight control of hepatic fatty acid metabolism and triglyceride production in premenopausal women, whereby oxidation (r(s)=-0.49, P=0.006), de novo lipogenesis (r(s)=0.55, P=0.003), and desaturation (r(s)=0.48, P=0.012) were closely correlated with abdominal obesity-driven large VLDL-triglyceride secretion rate. Conclusions-In women, abdominal obesity is a major driver of hepatic large VLDL particle secretion, whereas postmenopausal status was characterized by increased small VLDL particle size. These data provide a mechanistic basis for the hyperlipidemia observed in postmenopausal obesity.
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- Husebye, E. S., et al.
(författare)
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Consensus statement on the diagnosis, treatment and follow-up of patients with primary adrenal insufficiency
- 2014
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 275:2, s. 104-115
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Forskningsöversikt (refereegranskat)abstract
- Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.
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- Nikolaou, Nikolaos, et al.
(författare)
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AKR1D1 is a novel regulator of metabolic phenotype in human hepatocytes and is dysregulated in non-alcoholic fatty liver disease.
- 2019
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Ingår i: Metabolism: clinical and experimental. - : Elsevier BV. - 1532-8600. ; 99, s. 67-80
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Tidskriftsartikel (refereegranskat)abstract
- Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome. Steroid hormones and bile acids are potent regulators of hepatic carbohydrate and lipid metabolism. Steroid 5β-reductase (AKR1D1) is highly expressed in human liver where it inactivates steroid hormones and catalyzes a fundamental step in bile acid synthesis.Human liver biopsies were obtained from 34 obese patients and AKR1D1 mRNA expression levels were measured using qPCR. Genetic manipulation of AKR1D1 was performed in human HepG2 and Huh7 liver cell lines. Metabolic assessments were made using transcriptome analysis, western blotting, mass spectrometry, clinical biochemistry, and enzyme immunoassays.In human liver biopsies, AKR1D1 expression decreased with advancing steatosis, fibrosis and inflammation. Expression was decreased in patients with type 2 diabetes. In human liver cell lines, AKR1D1 knockdown decreased primary bile acid biosynthesis and steroid hormone clearance. RNA-sequencing identified disruption of key metabolic pathways, including insulin action and fatty acid metabolism. AKR1D1 knockdown increased hepatocyte triglyceride accumulation, insulin sensitivity, and glycogen synthesis, through increased de novo lipogenesis and decreased β-oxidation, fueling hepatocyte inflammation. Pharmacological manipulation of bile acid receptor activation prevented the induction of lipogenic and carbohydrate genes, suggesting that the observed metabolic phenotype is driven through bile acid rather than steroid hormone availability.Genetic manipulation of AKR1D1 regulates the metabolic phenotype of human hepatoma cell lines, driving steatosis and inflammation. Taken together, the observation that AKR1D1 mRNA is down-regulated with advancing NAFLD suggests that it may have a crucial role in the pathogenesis and progression of the disease.
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- van Oosten, H. Herman, et al.
(författare)
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Hatching failure and accumulation of organic pollutants through the terrestrial food web of a declining songbird in Western Europe
- 2019
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Ingår i: Science of the Total Environment. - : Elsevier BV. - 0048-9697 .- 1879-1026. ; 650:1, s. 1547-1553
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Tidskriftsartikel (refereegranskat)abstract
- Population growth in passerine birds is largely driven by fecundity. If fecundity is affected, for instance by hatching failure, populations may decline. We noted high hatching failure of up to 27% per year in relict populations of the Northern wheatear (Oenanthe oenanthe) in The Netherlands, a strongly declining, migratory passerine in Europe. This hatching failure itself can cause population decline, irrespective of other adverse factors. Additionally, we investigated the cause of hatching failure. Unhatched eggs showed egg yolk infections or embryonic malformations, part of which is associated with the actions of dioxin-like compounds (DLCs). Indeed, DLCs appear to bioaccumulate in the local foodweb, where the soil contained only background concentrations, similar to those found at many other locations. DLC concentrations in Dutch eggs were six-fold higher than those in a reference population in Sweden, where egg failure was only 6%. However, Northern wheatears appear to be only moderately sensitive to the actions of DLCs, because of their specific Ah-receptor type which may moderate the receptor mediated effects of DLCs. This indicates that the concentrations of DLCs, although elevated, may not have caused the embryo malformations or the low hatching rates. We discuss whether other toxins may be important or imbalances in the nutrition and if inbreeding may play a larger role than expected.
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- Verhees, MJM, et al.
(författare)
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Quality of Life in Men With Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency
- 2021
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Ingår i: Frontiers in endocrinology. - : Frontiers Media SA. - 1664-2392. ; 12, s. 626646-
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Tidskriftsartikel (refereegranskat)abstract
- Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21OHD) is a disorder of adrenal steroid biosynthesis, leading to hypocortisolism, hypoaldosteronism, and hyperandrogenism. Impaired quality of life (QoL) has been demonstrated in women with CAH, but data on men with CAH are scarce. We hypothesized that disease severity and poor treatment control are inversely associated with QoL. In this study, 109 men (16-68 years) with 21OHD were included. The WHOQOL-BREF questionnaire was used to measure self-reported QoL domain scores on a 0-100 scale, where higher scores reflect better QoL. QoL domain scores were compared to published data on healthy and chronically ill reference populations from France, Germany, the Netherlands, and the United Kingdom. Differences in QoL scores among groups of disease severity and treatment control were tested within the study population. Overall, the men with CAH in this study appeared to rate their QoL as good. Median domain scores were 78.6 (IQR: 67.9-85.7) for physical health, 79.2 (IQR: 66.7-87.5) for psychological health, 75.0 (IQR: 58.3-83.3) for social relationships, and 81.3 (IQR: 71.9-90.6) for environment. In general, these scores were similar to WHOQOL-BREF domain scores in healthy references and higher compared to chronically ill reference populations. The domain scores did not differ among genotype groups, but patients with undertreatment or increased 17-hydroxyprogestrone concentrations scored higher on several QoL domains (p<0.05). Patients treated with dexamethasone or prednisone scored higher on the physical health, psychological health, and social relationships domains, but not on the environmental domain. In conclusion, QoL domain scores appeared to be comparable to healthy reference populations and higher compared to patients with a chronic illness. QoL was not influenced by genotype, but undertreatment and use of dexamethasone or prednisone were associated with higher QoL.
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