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Experimental and Clinical Endocrinology... Feb 2019Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or... (Review)
Review
Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or mineralocorticoid deficiency due to failure of the adrenal cortex which may result in an adrenal crisis with potentially life-threatening consequences. Even though efficient and safe pharmaceutical preparations for the substitution of endogenous gluco- and mineralocorticoids are established in therapy, the mortality in patients with PAI is still increased and the health-related quality of life (HRQoL) is often reduced.PAI is a rare disease but recent data report an increasing prevalence. In addition to the common "classical" causes of PAI like autoimmune, infectious, neoplastic and genetic disorders, other iatrogenic conditions - mostly pharmacological side effects (e. g., adrenal haemorrhage associated with anticoagulants, drugs affecting glucocorticoid synthesis, action or metabolism and some of the novel anti-cancer checkpoint inhibitors) are contributing factors to this phenomenon.Due to the rarity of the disease and often non-specific symptoms at least in the early stages, PAI is frequently not considered resulting in a delayed diagnosis. Successful therapy is mainly based on adequate patient education as a cornerstone in the prevention and management of adrenal crisis. A focus of current research is in the development of pharmacokinetically optimized glucocorticoid preparations as well as regenerative therapies.
Topics: Addison Disease; Humans
PubMed: 30562824
DOI: 10.1055/a-0804-2715 -
Journal of Endocrinological... Dec 2019Addison's disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. In contrast, in children genetic... (Review)
Review
BACKGROUND
Addison's disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. In contrast, in children genetic causes are responsible for AD in the majority of patients.
PURPOSE
This review describes epidemiology, pathogenesis, genetics, natural history, clinical manifestations, immunological markers and diagnostic strategies in patients with AD. Standard care treatments including the management of patients during pregnancy and adrenal crises consistent with the recent consensus statement of the European Consortium and the Endocrine Society Clinical Practice Guideline are described. In addition, emerging therapies designed to improve the quality of life and new strategies to modify the natural history of autoimmune AD are discussed.
CONCLUSIONS
Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD.
Topics: Addison Disease; Adrenal Cortex Hormones; Adult; Age Factors; Female; Hormone Replacement Therapy; Humans; Incidence; Male; Prevalence; Quality of Life; Sex Factors
PubMed: 31321757
DOI: 10.1007/s40618-019-01079-6 -
Best Practice & Research. Clinical... Jan 2020Primary adrenal insufficiency (PAI) occurs in 1/5000-1/7000 individuals in the general population. Autoimmune Addison's disease (AAD) is the major cause of PAI and is a... (Review)
Review
Primary adrenal insufficiency (PAI) occurs in 1/5000-1/7000 individuals in the general population. Autoimmune Addison's disease (AAD) is the major cause of PAI and is a major component of autoimmune polyendocrine syndrome type 1 (APS1) and type 2 (APS2). Presence of 21-hydroxylase autoantibodies (21OHAb) identifies subjects with ongoing clinical or pre-clinical adrenal autoimmunity. AAD requires life-long substitutive therapy with two-three daily doses of hydrocortisone (HC) (15-25 mg/day) or one daily dose of dual-release HC and with fludrocortisone (0.5-2.0 mg/day). The lowest possible HC dose must be identified according to clinical and biochemical parameters to minimize long-term complications that include osteoporosis and cardiovascular and metabolic alterations. Women with AAD have lower fertility and parity as compared to age-matched healthy controls. Patients must be educated to double-triple HC dose in the case of fever or infections and to switch to parenteral HC in the case of vomiting, diarrhoea or acute hypotension.
Topics: Addison Disease; Adrenal Insufficiency; Adult; Autoantibodies; Autoimmune Diseases; Autoimmunity; Female; Fludrocortisone; Humans; Hydrocortisone; Male; Pregnancy; Risk Factors; Steroid 21-Hydroxylase
PubMed: 32063488
DOI: 10.1016/j.beem.2020.101379 -
Annales D'endocrinologie Jun 2018Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries, with prevalence estimates ranging from 93-220 per million... (Review)
Review
Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries, with prevalence estimates ranging from 93-220 per million in Europe. The immune-mediated attack on adrenocortical cells cripples their ability to synthesize vital steroid hormones and necessitates life-long hormone replacement therapy. The autoimmune disease etiology is multifactorial involving variants in immune genes and environmental factors. Recently, we have come to appreciate that the adrenocortical cell itself is an active player in the autoimmune process. Here we summarize the complex interplay between the immune system and the adrenal cortex and highlight unanswered questions and gaps in our current understanding of the disease.
Topics: Addison Disease; Autoimmune Diseases; Autoimmunity; Europe; Hormone Replacement Therapy; Humans
PubMed: 29631795
DOI: 10.1016/j.ando.2018.03.008 -
Clinical Endocrinology Jan 2020Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are... (Review)
Review
Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1). Reaching a specific diagnosis can have life-long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, "Addison's disease."
Topics: Addison Disease; Humans
PubMed: 31610036
DOI: 10.1111/cen.14109 -
Medicina Clinica Sep 2021Pluriglandular autoimmune syndrome (APS) can affect multiple endocrine glands and is associated with other autoimmune diseases. APS type 1 presents with... (Review)
Review
Pluriglandular autoimmune syndrome (APS) can affect multiple endocrine glands and is associated with other autoimmune diseases. APS type 1 presents with hypoparathyroidism, mucocutaneous candidiasis and Addison's disease. It is caused by AutoImmune Regulator (AIRE) gene mutation. The diagnosis includes clinical manifestations in addition to AIRE gene sequencing. SPA type 2 presents with Addison's disease, type 1 diabetes, or autoimmune thyroid disease. Multiple genes have been implicated, including those of the class II major histocompatibility complex. SPA type 3 is characterized by autoimmune thyroid disease and other autoimmune disease, excluding Addison's disease and hypoparathyroidism, 4 genes have been implicated and confer susceptibility. The diagnosis of APS type 2 and type 3 includes clinical manifestations, nevertheless, the determination of autoantibodies can be useful to predict the risk of disease manifestation and to confirm the autoimmune disease in some cases.
Topics: Addison Disease; Autoantibodies; Diabetes Mellitus, Type 1; Humans; Hypoparathyroidism; Polyendocrinopathies, Autoimmune
PubMed: 33958142
DOI: 10.1016/j.medcli.2021.02.004 -
Endocrine Reviews Feb 2019Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic... (Review)
Review
Immune checkpoints are small molecules expressed by immune cells that play critical roles in maintaining immune homeostasis. Targeting the immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed death 1 (PD-1) with inhibitory antibodies has demonstrated effective and durable antitumor activity in subgroups of patients with cancer. The US Food and Drug Administration has approved several immune checkpoint inhibitors (ICPis) for the treatment of a broad spectrum of malignancies. Endocrinopathies have emerged as one of the most common immune-related adverse events (irAEs) of ICPi therapy. Hypophysitis, thyroid dysfunction, insulin-deficient diabetes mellitus, and primary adrenal insufficiency have been reported as irAEs due to ICPi therapy. Hypophysitis is particularly associated with anti-CTLA-4 therapy, whereas thyroid dysfunction is particularly associated with anti-PD-1 therapy. Diabetes mellitus and primary adrenal insufficiency are rare endocrine toxicities associated with ICPi therapy but can be life-threatening if not promptly recognized and treated. Notably, combination anti-CTLA-4 and anti-PD-1 therapy is associated with the highest incidence of ICPi-related endocrinopathies. The precise mechanisms underlying these endocrine irAEs remain to be elucidated. Most ICPi-related endocrinopathies occur within 12 weeks after the initiation of ICPi therapy, but several have been reported to develop several months to years after ICPi initiation. Some ICPi-related endocrinopathies may resolve spontaneously, but others, such as central adrenal insufficiency and primary hypothyroidism, appear to be persistent in most cases. The mainstay of management of ICPi-related endocrinopathies is hormone replacement and symptom control. Further studies are needed to determine (i) whether high-dose corticosteroids in the treatment of ICPi-related endocrinopathies preserves endocrine function (especially in hypophysitis), and (ii) whether the development of ICPi-related endocrinopathies correlates with tumor response to ICPi therapy.
Topics: Addison Disease; Antineoplastic Agents, Immunological; CTLA-4 Antigen; Diabetes Mellitus, Type 1; Humans; Hypophysitis; Immunotherapy; Neoplasms; Programmed Cell Death 1 Receptor; Thyroid Diseases
PubMed: 30184160
DOI: 10.1210/er.2018-00006 -
Annals of Clinical Biochemistry May 2017Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or... (Review)
Review
Cortisol is a steroid hormone produced in response to stress. It is essential for maintaining health and wellbeing and leads to significant morbidity when deficient or present in excess. It is lipophilic and is transported bound to cortisol-binding globulin (CBG) and albumin; a small fraction (∼10%) of total serum cortisol is unbound and biologically active. Serum cortisol assays measure total cortisol and their results can be misleading in patients with altered serum protein concentrations. Automated immunoassays are used to measure cortisol but lack specificity and show significant inter-assay differences. Liquid chromatography - tandem mass spectrometry (LC-MS/MS) offers improved specificity and sensitivity; however, cortisol cut-offs used in the short Synacthen and Dexamethasone suppression tests are yet to be validated for these assays. Urine free cortisol is used to screen for Cushing's syndrome. Unbound cortisol is excreted unchanged in the urine and 24-h urine free cortisol correlates well with mean serum-free cortisol in conditions of cortisol excess. Urine free cortisol is measured predominantly by immunoassay or LC-MS/MS. Salivary cortisol also reflects changes in unbound serum cortisol and offers a reliable alternative to measuring free cortisol in serum. LC-MS/MS is the method of choice for measuring salivary cortisol; however, its use is limited by the lack of a single, validated reference range and poorly standardized assays. This review examines the methods available for measuring cortisol in serum, urine and saliva, explores cortisol in disease and considers the difficulties of measuring cortisol in acutely unwell patients and in neonates.
Topics: Addison Disease; Adrenocorticotropic Hormone; Adult; Chromatography, High Pressure Liquid; Circadian Rhythm; Corticotropin-Releasing Hormone; Cushing Syndrome; Energy Metabolism; Female; Gas Chromatography-Mass Spectrometry; Humans; Hydrocortisone; Immunoassay; Infant; Male; Observer Variation; Reproducibility of Results; Saliva; Sex Factors; Stress, Physiological
PubMed: 28068807
DOI: 10.1177/0004563216687335 -
Praxis Sep 2022Just Anorexia? We report the case of a 30-year-old woman presenting with fatigue, loss of weight, nausea, emesis and hyponatremia. The evaluation proved Addison's...
Just Anorexia? We report the case of a 30-year-old woman presenting with fatigue, loss of weight, nausea, emesis and hyponatremia. The evaluation proved Addison's disease due to an autoimmune polyendocrine syndrome type 2 with Hashimoto thyreoiditis. Under substitution with hydrocortisone and fludrocortisone all the symptoms subsided completely.
Topics: Addison Disease; Adult; Anorexia; Female; Humans; Hydrocortisone; Hyponatremia; Polyendocrinopathies, Autoimmune
PubMed: 36102024
DOI: 10.1024/1661-8157/a003899 -
Italian Journal of Pediatrics Sep 2021In healthy adolescents, delayed pubarche is generally a benign condition that is caused by a physiological discrepancy between gonadarche and adrenarche. In presence of... (Review)
Review
In healthy adolescents, delayed pubarche is generally a benign condition that is caused by a physiological discrepancy between gonadarche and adrenarche. In presence of other clinical signs and symptoms, delayed pubarche can be caused by single or multiple hormones deficiency (such as adrenal insufficiency, panhypopituitarism and hypothyroidism) and/or genetic conditions (Turner syndrome, androgen insensitivity syndrome). Exposition to endocrine disruptors has also been described as a possible cause of delay of pubic hair development. Basic blood tests, karyotype and first level imaging studies are helpful in the differential diagnosis.
Topics: Addison Disease; Adolescent; Adrenal Insufficiency; Androgen-Insensitivity Syndrome; Endocrine Disruptors; Environmental Exposure; Female; Humans; Hypothyroidism; Male; Puberty, Delayed; Turner Syndrome
PubMed: 34488834
DOI: 10.1186/s13052-021-01134-0