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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EAdrenal insufficiency is a rare disease that is difficult for patients to live with due to the lifelong requirement of steroid therapy and the ever-present risk of adrenal crisis. This article discusses the diagnosis of adrenal insufficiency, prevalence and prevention for adrenal crisis, and recent advances in the treatment of Addison\u0027s disease.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAdrenal Disorders\u003C\/li\u003E\u003C\/ul\u003E\u003Cul class=\u0022kwd-group clinical-trial\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003ERenal Disease\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EAdrenal Disorders\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EEndocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003EDiabetes \u0026amp; Metabolic Syndrome\u003C\/li\u003E\u003C\/ul\u003E\u003Cp id=\u0022p-2\u0022\u003EAdrenal insufficiency is a rare disease that is difficult for patients to live with due to the lifelong requirement of steroid therapy and the ever-present risk of adrenal crisis. Kristian L\u00f8v\u00e5s, MD, PhD, Haukeland University Hospital, Bergen, Norway, presented on the diagnosis of adrenal insufficiency, and emphasized the importance of being aware that adrenal insufficiency is possible and that it requires immediate treatment.\u003C\/p\u003E\u003Cp id=\u0022p-3\u0022\u003EMost patients with adrenal insufficiency present with fatigue and weight loss, and may also have hypotension. In addition, hyperpigmentation and salt cravings are highly specific symptoms of primary adrenal insufficiency. If serum cortisol and adrenocorticotropic hormone (ACTH) levels are low, secondary adrenal insufficiency is likely, but additional testing is usually required for a definitive diagnosis. The insulin tolerance test is the gold standard. If ACTH is high, then primary adrenal insufficiency is likely. Prof. L\u00f8v\u00e5s pointed out that an early diagnosis of primary adrenal insufficiency, particularly that caused by an autoimmune disorder, is important but difficult to achieve. Positive 21-hydroxylase (21OH) autoantibodies are associated with a greater risk of autoimmune adrenal insufficiency, particularly in children [Coco G et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2006]. In 21OH-positive individuals, testing the levels of ACTH in the morning is a better predictor than ACTH stimulation testing [Baker P et al. \u003Cem\u003EClin Endocrinol\u003C\/em\u003E 2012].\u003C\/p\u003E\u003Cp id=\u0022p-4\u0022\u003EProf. L\u00f8v\u00e5s recommended that one should be aware of unusual phenotypes of autoimmune Addison\u0027s disease, such as those which may occur in autoimmune polyendocrine syndrome type 1, which is caused by a mutation in the AIRE gene. Symptoms include hypoparathyroidism, chronic fungal infection, enamel dysplasia, and a young age of onset. A definitive diagnosis can be made by testing for autoantibodies against interferon (IFN)-\u03c9. If the patient is negative for 21OH-antibodies, then computed tomography of the adrenal glands should be performed, which can identify hemorrhage of the adrenals due to Waterhouse-Friderichsen syndrome, anticoagulant therapy, or antiphospholipid syndrome, as well as tuberculosis, or tumors. Another uncommon phenotype is that of adrenoleukodystrophy (ALD), which is caused by a mutation in the ABCD1 gene. Patients with ALD will test negative for IFN-\u03c9 and 21OH autoantibodies, but have elevated levels of very long chain fatty acids in serum.\u003C\/p\u003E\u003Cp id=\u0022p-5\u0022\u003EStephanie Hahner, MD, University Hospital Wuerzburg, Wuerzburg, Germany, discussed the prevalence and prevention for adrenal crisis. In an analysis of 1675 patients with primary adrenal insufficiency, the risk ratio for all-cause mortality in men was 2.19 (95% CI, 1.91 to 2.51) and 2.86 (95% CI, 2.54 to 3.20) in women [Bergthorsdottir R et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2006]. In addition, Addison\u0027s disease itself is the second most common cause of death in patients with Addison\u0027s disease, with cardiovascular disease first [Erichsen MM et al. \u003Cem\u003EEur J Endocrinol\u003C\/em\u003E 2009]. Interestingly, patients with Addison\u0027s disease are at a greater risk of dying from an infection than the general population, with a risk ratio of 1.74 (95% CI, 0.97 to 2.87) and 3.74 (95% CI, 2.52 to 5.34) in men and women, respectively, for respiratory disease, and 6.57 (95% CI, 2.56 to 15.17) and 5.57 (95% CI, 2.04 to 12.13) in men and women, respectively, for other infectious diseases [Bergthorsdottir R et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2006]. This may relate to inadequate treatment of adrenal crises.\u003C\/p\u003E\u003Cp id=\u0022p-6\u0022\u003EAdrenal crisis is estimated to occur 6.3 times per 100 patient years, with 23% and 17% of German patients with primary and secondary adrenal insufficiency, respectively, having required emergency treatment at least once since their diagnosis (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E) [Hahner S et al. \u003Cem\u003EEur J Endocrinol\u003C\/em\u003E 2010]. In a study of 275 Canadian and UK patients with Addison\u0027s disease, 16% of patients required emergency care once since their diagnosis [White K, Arlt W. \u003Cem\u003EEur J Endocrinol\u003C\/em\u003E 2010]. A retrospective analysis of 444 patients with adrenal insufficiency only identified limited risk factors for adrenal crisis [Hahner S et al. \u003Cem\u003EEur J Endocrinol\u003C\/em\u003E 2010].\u003C\/p\u003E\u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/10\/18\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022Incidence of Adrenal Crisis in Patients With Adrenal Insufficiency\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1099800955\u0022 data-figure-caption=\u0022Incidence of Adrenal Crisis in Patients With Adrenal Insufficiency\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/10\/18\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/10\/18\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/13\/10\/18\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/13315\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption attrib\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n            \u003Cp id=\u0022p-7\u0022 class=\u0022first-child\u0022\u003EIncidence of Adrenal Crisis in Patients With Adrenal Insufficiency\u003C\/p\u003E\n         \u003Cq class=\u0022attrib\u0022 id=\u0022attrib-1\u0022\u003EReproduced with persmission from S Hahner, MD.\u003C\/q\u003E\u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cp id=\u0022p-8\u0022\u003EIn a 2-year prospective trial of 455 patients with adrenal insufficiency, adrenal crisis occurred at a rate of 7.8 per 100 patient years. In addition, 2 patients died following hospitalization for adrenal crisis and 2 additional patients died due to adrenal crisis after the study had been completed. Factors preceding adrenal crisis included gastroenteritis, fever or infection, psychological stress, and surgery. Importantly, 30% of patients that entered adrenal crisis experienced no relief of symptoms following oral hydrocortisone; however, intravenous hydrocortisone did result in improvement.\u003C\/p\u003E\u003Cp id=\u0022p-9\u0022\u003EProf. Hahner highlighted that for the prevention and treatment of adrenal crisis: it is important that patients are able to self-inject glucocorticoids. Patients with adrenal insufficiency should have an emergency card on their person, as well as an emergency set containing hydrocortisone. A study of 12 patients with autoimmune Addison\u0027s disease demonstrated that 100 mg of subcutaneous or intramuscular hydrocortisone resulted in a rapid and substantial increase in serum cortisol levels (p=0.004) [Hahner S et al. \u003Cem\u003EEur J Endocrinol\u003C\/em\u003E 2013]. Prof. Hahner suggested that perhaps a hydrocortisone pen should be produced for patients with adrenal insufficiency to carry in case of adrenal crisis.\u003C\/p\u003E\u003Cp id=\u0022p-10\u0022\u003ESimon H.S. Pearce, MBBS, MD, Newcastle University, Newcastle Upon Tyne, United Kingdom, presented recent advances in the treatment of Addison\u0027s disease. Patients with adrenal insufficiency require lifelong treatment with glucocorticoids, but clearly, a cure would be better.\u003C\/p\u003E\u003Cp id=\u0022p-11\u0022\u003EIn a small study, 6 patients with primary adrenal failure diagnosed within 28 days were treated with rituximab 1 g on Days 1 and 15 and followed for 1 year [Pearce SH et al. \u003Cem\u003EJ Clin Endocrinol Metab\u003C\/em\u003E 2012]. Following rituximab therapy, B lymphocyte levels dropped to undetectable levels for 5 months and the 21OH autoantibodies decreased in the 5 patients who were 21OH autoantibody positive. Cortisol levels decreased rapidly in 5 patients. However, 1 patient experienced an initial decrease in cortisol, but by 6 months her cortisol levels increased to baseline, by 12 months her cortisol levels were back to those at diagnosis, and by 15 months her peak cortisol was over 400 nmol. The patient was able to wean off of hydrocortisone and remained in remission from Addison\u0027s disease for 17 months.\u003C\/p\u003E\u003Cp id=\u0022p-12\u0022\u003EProf. Pearce suggested that administering hydrocortisone to patients with adrenal insufficiency at diagnosis may actually be detrimental to the residual function of their adrenal glands. He noted that in the study of six patients, all experienced a decrease of about two thirds in their cortisol at the study baseline, which was only 2 to 3 weeks after their initial diagnosis and cortisol level measurements. Because the adrenal progenitor cells do not normally express 21OH, they may be intact despite the presence of Addison\u0027s [Wood MA, Hammer GD. \u003Cem\u003EMol Cell Endocrinol\u003C\/em\u003E 2011].\u003C\/p\u003E\u003Cp id=\u0022p-13\u0022\u003EIn the Revival of Stem Cells in Addison\u0027s Study [RoSA; \u003Ca class=\u0022external-ref external-ref-type-clintrialgov\u0022 href=\u0022\/lookup\/external-ref?link_type=CLINTRIALGOV\u0026amp;access_num=NCT01371526\u0026amp;atom=%2Fspmdc%2F13%2F10%2F18.atom\u0022\u003ENCT01371526\u003C\/a\u003E] study, 13 patients with Addison\u0027s disease for at least 1 year and up to 19 years received 1 mg of tetracosactrin subcutaneous injections on alternate days for up to 20 weeks. Two patients experienced a dramatic increase in cortisol levels and eventually experienced remission from Addison\u0027s disease, with 1 still in remission and the other requiring steroid therapy after about 6 months of remission. All patients treated with tetracosactrin therapy experienced hyperpigmentation and 4 out 9 premenopausal women had menstrual disturbances. Prof. Pearce concluded by suggesting that some patients with Addison\u0027s disease have residual adrenal function, which may be remediable.\u003C\/p\u003E\u003Cp id=\u0022p-14\u0022\u003ETraditionally, adrenal insufficiency has been treated with glucocorticoid therapy. Although more research is needed, recent studies demonstrate that new therapies with the potential for eliciting remission may be on the horizon.\u003C\/p\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2013 MD Conference Express\u00ae\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/13\/10\/18.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nznogp\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nznogp\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}