Addison's disease is a rare autoimmune disorder. In the developed world, autoimmune adrenalitis is the commonest cause of primary adrenal insufficiency, where the majority of patients have circulating antibodies against the key steroidogenic enzyme 21-hydroxylase. A complex interplay of genetic, immunological and environmental factors culminates in symptomatic adrenocortical insufficiency, with symptoms typically developing over months to years. Biochemical evaluation and further targeted investigations must confirm primary adrenal failure and establish the underlying aetiology. The diagnosis of adrenocortical insufficiency will necessitate lifelong glucocorticoid and mineralocorticoid replacement therapy, aiming to emulate physiological patterns of hormone secretion to achieve well-being and good quality of life. Education of patients and healthcare professionals is essential to minimise the risk of a life-threatening adrenal crisis, which must be promptly recognised and aggressively managed when it does occur. This article provides an overview of our current understanding of the natural history and underlying genetic and immunological basis of this condition. Future research may reveal novel therapeutic strategies for patient management. Until then, optimisation of pharmacological intervention and continued emphasis on education and empowerment of patients should underpin the management of individuals with autoimmune Addison's disease.
"body weight). Glucocorticoid excess (Cushing’s disease) increases central fat deposition, whereas decreased body weight is associated with glucocorticoid insufficiency (Addison’s disease) [19-21]. In addition to these effects on metabolism, alterations in the HPA axis can also influence anxiety and stress, which increase Neuropeptide Y (Npy) secretion. "
[Show abstract][Hide abstract] ABSTRACT: Estrogen-related receptors (ERRs) are orphan nuclear hormone receptors expressed in metabolically active tissues and modulate numerous homeostatic processes. ERRs do not bind the ligand estrogen, but they are able to bind the estrogen response element (ERE) embedded within the ERR response elements (ERREs) to regulate transcription of genes. Previous work has demonstrated that adult mice lacking Errbeta have altered metabolism and meal patterns. To further understand the biological role of Errbeta, we characterized the stress response of mice deficient for one or both alleles of Errbeta.
Sox2-Cre:Errbeta mice lack Errbeta expression in all tissues of the developing embryo. Sox2-Cre:Errbeta+/lox heterozygotes were obese, had increased Npy and Agrp gene expression in the arcuate nucleus of the hypothalamus, and secreted more corticosterone in response to stress. In contrast, Sox2-Cre:Errbetalox/lox homozygotes were lean and, despite increased Npy and Agrp gene expression, did not secrete more corticosterone in response to stress. Sox2-Cre:Errbeta+/lox and Sox2-Cre:Errbetalox/lox mice treated with the Errbeta and Errgamma agonist DY131 demonstrated increased corticotropin-releasing hormone (Crh) expression in the paraventricular nucleus of the hypothalamus, although corticosterone levels were not affected. Nes-Cre:Errbetalox/lox mice, which selectively lack Errbeta expression in the nervous system, also demonstrated elevated stress response during an acoustic startle response test and decreased expression of both Crh and corticotropin-releasing hormone receptor 2 (Crhr2).
Loss of Errbeta affects body composition, neuropeptide levels, stress hormones, and centrally-modulated startle responses of mice. These results indicate that Errbeta alters the function of the hypothalamic-pituitary-adrenocortical axis and indicates a role for Errbeta in regulating stress response.
[Show abstract][Hide abstract] ABSTRACT: Canine hypoadrenocorticism is believed to be an immune-related condition. It is rare in the overall dog population but shows a breed-related predisposition with Standard poodles and Portuguese water dogs having a greater prevalence of the condition. It shares many similarities with human primary adrenal insufficiency and is believed to be a naturally occurring, spontaneous model for the human condition. Short haplotype blocks and low levels of linkage disequilibrium in the human genome mean that the identification of genetic contributors to the condition requires large sample numbers. Pedigree dogs have high linkage disequilibrium and long haplotypes within a breed, increasing the potential of identifying novel genes that contribute to canine genetic disease. We investigated 222 SNPs from 42 genes that have been associated or may be implicated in human Addison's disease. We conducted case-control analyses in 3 pedigree dog breeds (Labrador retriever: affected n = 30, unaffected = 76; Cocker Spaniel: affected n = 19, unaffected = 53; Springer spaniel: affected n = 26, unaffected = 46) and identified 8 associated alleles in genes COL4A4, OSBPL9, CTLA4, PTPN22, and STXBP5 in 3 pedigree breeds. Association with immune response genes PTPN22 and CTLA4 in certain breeds suggests an underlying immunopathogenesis of the disease. These results suggest that canine hypoadrenocorticism could be a useful model for studying comparative genetics relevant to human Addison's disease.
The Journal of heredity 08/2013; 104(6). DOI:10.1093/jhered/est051 · 2.09 Impact Factor
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