Sleep, Cognition and Cortisol in Addison's Disease: A Mechanistic Relationship.

Sleep is a critical biological process, essential for cognitive well-being. Neuroscientific literature suggests there are mechanistic relations between sleep disruption and memory deficits, and that varying concentrations of cortisol may play an important role in mediating those relations. Patients with Addison's disease (AD) experience consistent and predictable periods of sub- and supra-physiological cortisol concentrations due to lifelong glucocorticoid replacement therapy, and they frequently report disrupted sleep and impaired memory. These disruptions and impairments may be related to the failure of replacement regimens to restore a normal circadian rhythm of cortisol secretion. Available data provides support for existing theoretical frameworks which postulate that in AD and other neuroendocrine, neurological, or psychiatric disorders, disrupted sleep is an important biological mechanism that underlies, at least partially, the memory impairments that patients frequently report experiencing. Given the literature linking sleep disruption and cognitive impairment in AD, future initiatives should aim to improve patients' cognitive performance (and, indeed, their overall quality of life) by prioritizing and optimizing sleep. This review summarizes the literature on sleep and cognition in AD, and the role that cortisol concentrations play in the relationship between the two.

Autoimmune Polyendocrine Syndrome Complicated by Pulmonary Hypertension.

A 24-years old female was admitted for acute renal failure, melanoderma, hyponatremia, and hyperkalemia. The clinical suspicion of Addison's disease was confirmed by laboratory test and the appropriate replacement therapy with corticosteroids and fludrocortisone was started. In the meantime primary hypothyroidism and diabetes mellitus type 1 were disclosed and treated, thus fulfilling a diagnosis of autoimmune polyendocrine syndrome type 2. Eighteen months later she was admitted for right-sided heart failure. The work-up allowed to diagnose pulmonary arterial hypertension. Here, we report the clinical course and discuss the putative link between these two rare diseases.

Micro- and macrovascular function in patients suffering from primary adrenal insufficiency: a cross-sectional case-control study.

BACKGROUND: Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function. METHODS: 26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)]. RESULTS: PWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p < .01], whereas no differences in microvascular function could be found. In Reninlow time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p < .05], whereas no differences in IMT and PWV were observed between Reninhigh and Reninlow. No impact of GC dose was observed. CONCLUSIONS: Microvascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Beyond the adrenals: Organ manifestations in inherited primary adrenal insufficiency in children.

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.

Renal involvement in adrenal insufficiency (Addison disease): can we always recognize it?

Addison disease is due to the destruction or dysfunction of the entire adrenal cortex. Nowadays, the causes of adrenal insufficiency are autoimmune disease for 70-90% and tuberculosis for 7-20%. Many typical signs and symptoms, such as hyponatremia, hyperkalaemia, or renal insufficiency can represent the reasons for a nephrology consultation, especially in conditions of urgency, and they can easily be confused with other causes. Moreover, the fact that in a short time range we have diagnosed the three cases described as a guide in this review, has aroused our attention as nephrologists on a disease in which we have probably already encountered but without recognizing it. The blood tests showed in all three patients severe electrolyte disorders and acute renal failure which will be discussed in their physiopathogenetic mechanisms. In a peculiar way, these alterations were not controlled with repolarizing solutions, fluid replacement and increased volemia, but only after steroid administration. In conclusion, in this review all the known pathogenic mechanisms causing disorders of nephrological interest in adrenal insufficiency are discussed.

Addison's disease in pregnancy: Case report, management, and review of the literature.

BACKGROUND: Addison's disease is an uncommon condition encountered during pregnancy; however, pregnant patients with Addison's disease are at higher risk for multiple pregnancy related complications. Treatment during pregnancy involves steroid replacement therapy. CASE REPORT: A 34-year-old previously healthy G2P1001 presented with lethargy, skin hyperpigmentation, polyuria, and salt craving. Laboratory evaluation showed hyperkalemia, hyponatremia, elevated ACTH, and low cortisol. The patient terminated the pregnancy due to her symptoms. She was then placed on a regimen of hydrocortisone and fludrocortisone, leading to symptom resolution. On second presentation as a G5P1031, her Addison's disease was managed with hydrocortisone and fludrocortisone. When Addison's symptoms recurred, ACTH levels were checked to determine if her current medications could be optimized. She ultimately delivered a healthy male infant vaginally. For her third presentation as a G6P2032, her pregnancy was managed in a similar manner to the previous pregnancy. CONCLUSION: There is currently minimal cohesive literature on the management of Addison's disease during pregnancy. Patients can be managed successfully by monitoring for recurrence of Addison's symptoms and adjusting medication dosing as needed.

Association of adrenal insufficiency with patient-oriented health-care outcomes in adult medical inpatients.

OBJECTIVE: Adrenal insufficiency in the outpatient setting is associated with excess morbidity, mortality, and impaired quality of life. Evidence on its health-care burden in medical inpatients is scarce. The aim of this study was to assess the health-care burden of primary adrenal insufficiency (PAI) and secondary adrenal insufficiency (SAI) among hospitalized inpatients. DESIGN AND METHODS: In this nationwide cohort study, adult medical patients with either PAI or SAI hospitalized between 2011 and 2015 were compared with propensity-matched (1:1) medical controls, respectively. The primary outcome was 30-day all-cause in-hospital mortality. Main secondary outcomes included ICU admission rate, length-of-hospital stay, 30-day and 1-year all-cause readmission rates. RESULTS: In total, 594 hospitalized cases with PAI and 4880 cases with SAI were included. Compared with matched controls, in-hospital mortality was not increased among PAI or SAI patients, respectively. Patients with adrenal insufficiency were more likely to be admitted to ICU (PAI: OR 1.9 (95% CI, 1.27 to 2.72) and SAI: OR 1.5 (95% CI, 1.35 to 1.75)). Length of hospital stay was prolonged by 1.0 days in PAI patients (8.9 vs 7.9 days (95% CI, 0.06 to 1.93)), and by 3.3 days in SAI patients (12.1 vs 8.8 days (95% CI, 2.82 to 3.71)), when compared with matched controls. Patients with SAI were found to have higher 30-day and 1-year readmission rates (14.1 vs 12.1% and 50.0 vs 40.7%; P < 0.001) than matched controls. CONCLUSIONS: While no difference in in-hospital mortality was found, adrenal insufficiency was associated with prolonged length of hospital stay, and substantially higher rates of ICU admission and hospital readmission.

Plasma renin levels are associated with cardiac function in primary adrenal insufficiency.

BACKGROUND: Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, primary adrenal insufficiency (AI) is associated with an increased mortality, mainly due to cardiovascular disease. The role of MC replacement is not known. Therefore, we assessed whether renin concentrations during routine GC and MC substitution therapy are associated with heart function and morphology. METHODS: Thirty two patients with primary AI were included in a cross-sectional case-control study. In total, 17 patients and 34 healthy controls (age: 48 ± 12 vs. 46 ± 18 years; BMI: 23 ± 3 vs. 24 ± 3 kg/m2) underwent magnetic resonance spectroscopy and imaging measurements to assess cardiac function, morphology, ectopic lipids, and visceral/subcutaneous fat mass. Patients were divided according to their actual plasma renin concentration at the study visit (Actual-Reninlow vs. Actual-Reninhigh) and their median plasma renin concentration of previous visits (Median-Reninlow vs. Median-Reninhigh). RESULTS: Ejection fraction was higher (67 ± 5 vs. 55 ± 3%; p = 0.001) and left ventricular mass was lower (60 ± 9 vs. 73 ± 10 g/m2; p = 0.025) in Actual-Reninhigh. Median-Reninhigh was associated with lower cardiac mass (64 ± 9 vs. 76 ± 11 g/m2; p = 0.029). Blood pressure, glucose, and lipid metabolism, as well as ectopic lipid content, pericardial fat mass, and visceral/subcutaneous fat were not different between the groups. Compared with controls, ejection fraction was significantly lower in patients with AI (56 ± 4 vs. 63 ± 8%; p = 0.019). No differences were found in patients with ≤20 mg compared with >20 mg of hydrocortisone per day. CONCLUSIONS: Higher renin concentrations are associated with more favorable cardiac function and morphology in patients with primary AI.

Identifying a disease-specific renin-angiotensin-aldosterone system fingerprint in patients with primary adrenal insufficiency.

BACKGROUND: In patients suffering from primary adrenal insufficiency (AI) mortality is increased despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, mainly due to an increased cardiovascular risk. Since activation of the renin-angiotensin-aldosterone system (RAAS) plays an important role in the modulation of cardiovascular risk factors, we performed in-depth characterization of the RAAS activity. METHODS: Eight patients with primary AI (female = 5; age: 56 ± 21 years; BMI: 22.8 ± 2 kg/m2; mean blood pressure: 140/83 mmHg; hydrocortisone dose: 21.9 ± 5 mg/day; fludrocortisone dose: 0.061 ± 0.03 mg/day) and eight matched healthy volunteers (female = 5; age: 52 ± 21 years; BMI: 25.2 ± 4 kg/m2; mean blood pressure:135/84 mmHg) were included in a cross-sectional case-control study. Angiotensin metabolite profiles (RAS-fingerprints) were performed by liquid chromatography mass spectrometry. RESULTS: In patients suffering from primary AI, RAAS activity was highly increased with elevated concentrations of renin concentration (P = 0.027), angiotensin (Ang) I (P = 0.022), Ang II (P = 0.032), Ang 1-7 and Ang 1-5. As expected, aldosterone was not detectable in the majority of AI patients, resulting in a profoundly suppressed aldosterone-to-AngII ratio (AA2 ratio, P = 0.003) compared to controls. PRA-S, the angiotensin-based marker for plasma renin activity, correlated with plasma renin activity (r = 0.983; P < 0.01) and plasma renin concentration (r = 0.985; P < 0.001) and was significantly increased in AI patients. CONCLUSIONS: AI is associated with a unique RAAS profile characterized by the absence of aldosterone despite strongly elevated levels of angiotensin metabolites, including the potent vasoconstrictor AngII. Despite state-of-the-art hormone replacement therapy, the RAAS remains hyperactivated. The contribution of Ang II in cardiovascular diseases in AI patients as well as a potential role for providing useful complementary information at diagnosis and follow up of AI should be investigated in future trials.

Latent Adrenal Insufficiency: Concept, Clues to Detection, and Diagnosis.

In 1855, Thomas Addison described an illness now known as Addison disease (AD) caused by damage to the adrenal cortex and manifesting in weakness, weight loss, hypotension, gastrointestinal disturbances, and brownish pigmentation of the skin and mucous membranes. Corticosteroid supplementation, corticotropin (adrenocorticotropic hormone [ACTH] of medicinal use) test, and anti-adrenal auto-antibodies (AA) have come into use in the 100 years since Addison's death. Following the methodological innovations, 4 disorders which share impaired response to corticotropin in common have been discovered (i.e., partial AD, apigmented adrenal insufficiency [AI], subclinical AI, and the AA-positive state exclusively in subjects proven to have an impaired response to corticotropin). As they are hidden, potentially serious conditions, these disorders are bound together as latent AI (LAI). Diagnosis of AD is often delayed, which may lead to adrenal crisis. If LAI were widely recognized, such delays would not exist and crises would be averted. The 3 existing guidelines do not refer much to LAI patients outside those in acute situations. To address this, information relevant to clinical manifestations and diagnostic tests of LAI was sought in the literature. Signs and symptoms that are useful clues to begin a diagnostic workup are presented for endocrinologists to identify patients with suspected LAI. The utility of 2 corticotropin test protocols is reviewed. To endorse LAI shown by the corticotropin test, monitoring items following corticosteroid supplementation are cited from the guidelines and supplemented with the author's observations. ABBREVIATIONS: AA = anti-adrenal auto-antibodies; Ab = antibodies; ACA = AA detected by immunofluorescence; ACTH = adrenocorticotropic hormone; AD = Addison disease; AI = adrenal insufficiency; DHEA = dehydroepiandrosterone; GC = glucocorticoid; IFA = immunofluorescence assay; LAI = latent AI; LDT = low-dose test; MC = mineralocorticoid; 21OHAb = anti-21-hydroxylase Ab; ST = standard test; URI = upper respiratory infection.

Reduced Slow-Wave Sleep and Altered Diurnal Cortisol Rhythms in Patients with Addison's Disease.

OBJECTIVES: Cortisol plays a key role in initiating and maintaining different sleep stages. Patients with Addison's disease (AD) frequently report disrupted sleep, and their hydrocortisone medication regimes do not restore the natural diurnal rhythm of cortisol. However, few studies have investigated relations between sleep quality, especially as measured by polysomnographic equipment, and night-time cortisol concentrations in patients with AD. METHODS: We used sleep-adapted EEG to monitor a full night of sleep in 7 patients with AD and 7 healthy controls. We sampled salivary cortisol before bedtime, at midnight, upon awakening, and at 30-minutes post-waking. RESULTS: Controls had lower cortisol concentrations than patients before bedtime and at midnight. During the second half of the night, patient cortisol concentrations declined steeply, while control concentrations increased steadily. Whereas most controls experienced a positive cortisol awakening response, all patients experienced a decrease in cortisol concentrations from waking to 30-minutes post-waking (P = .003). Patients experienced significantly lower proportions of slow-wave sleep (SWS; P = .001), which was associated with elevated night-time cortisol concentrations. CONCLUSION: Overall, these results suggest that patients with AD demonstrate different patterns of night-time cortisol concentrations to healthy controls, and that relatively elevated concentrations are associated with a reduction of SWS. These hormonal and sleep architectural aberrations may disrupt the routine sleep-dependent processes of memory consolidation, and hence may explain, at least partially, the memory impairments often experienced by patients with AD.

The natural history of autoimmune Addison's disease with a non-classical presentation: a case report and review of literature.

Autoimmune Addison's disease (AAD) is the most frequent cause of adrenocortical insufficiency. The natural history of AAD usually comprises five consecutive stages with the first stage characterized by the increase of plasma renin consistent with the impairment of pars glomerulosa, which is usually the first affected layer of the adrenal cortex. We describe a 19-year-old female with Hashimoto's thyroiditis (HT) who underwent an autoantibody screening due to having the personal and family history of other autoimmune diseases in the absence of relevant clinical manifestations. She was positive for adrenal cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies (21-OH Ab) at high titers. She had increased basal levels of ACTH with normal basal cortisol not responding to ACTH stimulation, reduced levels of dehydroepiandrosterone-sulfate but normal levels of orthostatic renin and aldosterone. This scenario was consistent with a subclinical AAD presenting with first impairments in pars fasciculata and reticularis and conserved pars glomerulosa function. Only subsequently, progressive deficiency in pars glomerulosa function has become evident. Review of the literature showed that there was only one case, reported to date, with a similar atypical natural history of AAD. The strategies for screening for ACA/21-OH Ab in patients with HT are discussed.

[Adrenal crisis]. / Nebennierenkrise.

Patients with chronic adrenal insufficiency suffer from reduced quality of life and increased mortality. An association between mortality and adrenal crisis is assumed. The frequency of adrenal crisis is about 8/100 patient years. The main causes are infectious disease. Pathophysiology is poorly understood to date. An association with an exaggerated inflammatory response due to a lack of glucocorticoid modulation as well as mineralocorticoid deficiency and diminished adrenomedullary function are discussed. The therapy of adrenal crisis includes prompt parenteral administration of hydrocortisone combined with isotonic saline. To prevent adrenal crisis, patients are equipped with an emergency card and set and educated in glucocorticoid dose adjustment.

Health-related quality of life of patients with hypothalamic-pituitary-adrenal axis dysregulations: a cohort study.

OBJECTIVE: Health-related quality of life (HrQoL) is increasingly considered to be an important outcome of care for hypothalamic-pituitary-adrenal (HPA) axis dysregulation. The objective of this study was to assess the influence of type of HPA axis dysregulation and cortisol status on HrQOL and its evolution with time and treatment. DESIGN: Prospective cohort study. METHODS: Between September 2007 and April 2014, HrQoL questionnaires were administered during routine management to all patients with HPA axis dysregulation hospitalized in a single department, and this was repeated after 6- 12-, 24- and 36-month during standard follow-up. The Medical Outcomes Study 36-item short-form health survey (SF-36) and the General Health Questionnaire 12 (GHQ-12) were used simultaneously, with a common time schedule to measure the impact of HPA axis dysregulation on HrQoL. Multivariate mixed linear regression models were constructed to adjust for potential confounders. RESULTS: 343 patients (206 with Cushing's syndrome of pituitary origin, 91 with Cushing's syndrome of adrenal origin and 46 with Addison's disease) responded to the questionnaires. Overall, HrQoL scores were well below population values. Cushing syndrome of pituitary origin was associated with worse HrQoL, especially in physical dimensions. More than half of the patients, of all diagnoses and cortisol status, had psychological distress requiring attention according to the GHQ-12. Hypercortisolism had the greatest negative influence on HrQoL. CONCLUSIONS: HRQoL appears significantly altered by all forms of HPA axis dysregulation, and most substantially and broadly by Cushing's syndrome, notably during periods of hypercortisolism. These effects on HRQoL deserve further consideration both in clinical practice and research.

Impaired quality and efficiency of sleep impairs cognitive functioning in Addison's disease.

BACKGROUND: Standard replacement therapy for Addison's disease (AD) does not restore a normal circadian rhythm. Periods of sub- and supra- physiological cortisol levels experienced by patients with AD likely induce disrupted sleep. Given that healthy sleep plays an important role in memory consolidation, the novelty of the current study was to characterise, using objective measures, the relationship between sleep and memory in patients with AD, and to examine the hypothesis that poor sleep is a biological mechanism underlying memory impairment in those patients. METHODS: We used a within-subjects design. Ten patients with AD and 10 matched healthy controls completed standardised neuropsychological tests assessing declarative memory (Rey Auditory Verbal Learning Test) and procedural memory (Finger Tapping Task) before and after a period of actigraphy-measured sleep, and before and after a period of waking. RESULTS: Relative to healthy controls, patients with AD experienced disrupted sleep characterised by poorer sleep efficiency and more time spent awake. Patients also showed impaired verbal learning and memory relative to healthy controls (p=0.007). Furthermore, whereas healthy controls' declarative memory performance benefited from a period of sleep compared to waking (p=0.032), patients with AD derived no such benefit from sleep (p=0.448). Regarding the procedural memory task, analyses detected no significant between-group differences (all p's<0.065), and neither group showed significant sleep-enhanced performance. CONCLUSIONS: We demonstrated, using actigraphy and standardized measures of memory performance, an association between sleep disturbances and cognitive deficits in patients with AD. These results suggest that, in patients with AD, the source of memory deficits is, at least to some extent, disrupted sleep patterns that interfere with optimal consolidation of previously-learned declarative information. Hence, treating the sleep disturbances that are frequently experienced by patients with AD may improve their cognitive functioning.