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Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults

• Published: 18 July 2019
• Volume 42 , pages 1407–1433, ( 2019 )

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• C. Betterle 1 ,
• F. Presotto 1 , 2 &
• J. Furmaniak 3  

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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.

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.

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C.B. participated to Euradrenal Project: Pathophysiology and Natural Course of Autoimmune Adrenal Failure in Europe, Grant Agreement No. 2008-201167 of the European Union 7th Framework Program.

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Betterle, C., Presotto, F. & Furmaniak, J. Epidemiology, pathogenesis, and diagnosis of Addison’s disease in adults. J Endocrinol Invest 42 , 1407–1433 (2019). https://doi.org/10.1007/s40618-019-01079-6

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Received : 29 January 2019

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DOI : https://doi.org/10.1007/s40618-019-01079-6

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Addison’s Disease: Diagnosis and Management Strategies

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Authors Carsote M   , Nistor C  

Received 4 March 2023

Accepted for publication 29 May 2023

Published 2 June 2023 Volume 2023:16 Pages 2187—2210

DOI https://doi.org/10.2147/IJGM.S390793

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 2

Editor who approved publication: Dr Scott Fraser

Mara Carsote, 1, 2 Claudiu Nistor 3, 4 1 Department of Endocrinology, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 2 Department of Gonads and Infertility, “C.I. Parhon” National Institute of Endocrinology, Bucharest, Romania; 3 Department 4 – Cardio -Thoracic Pathology, Thoracic Surgery II Discipline, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania; 4 Thoracic Surgery Department, “Dr. Carol Davila” Central Emergency University Military Hospital, Bucharest, Romania Correspondence: Mara Carsote, Aviatorilor Ave, 34-38, Sector 1, Bucharest, 011683, Romania, Tel +40744 851 934, Email [email protected] Abstract: We aim to overview Addison’s disease (AD) with regard to current diagnosis and management. This is a narrative review of full-length articles published in English between January 2022 and December 2022 (including online ahead of print versions) in PubMed-indexed journals. We included original studies in living humans regardless of the level of statistical significance starting from the key search terms “Addison’s disease” or “primary adrenal insufficiency” in title or abstract. We excluded articles with secondary adrenal insufficiency. Briefly, 199 and 355 papers, respectively were identified; we manually checked each of them, excluded the duplicates, and then selected 129 based on their clinical relevance in order to address our 1-year analysis. We organized the data in different subsections covering all published aspects on the subject of AD. To our knowledge, this is the largest AD retrospective from 2022 on published data. A massive role of genetic diagnosis especially in pediatric cases is highlighted; the importance of both pediatric and adult awareness remains since unusual presentations continue to be described. COVID-19 infection is a strong player amid this third year of pandemic although we still not do have large cohorts in this particular matter as seen, for instance, in thyroid anomalies. In our opinion, the most important topic for research is immune checkpoint inhibitors, which cause a large panel of endocrine side effects, AD being one of them. Keywords: Addison disease, cortisol, primary adrenal insufficiency, synacthen, congenital adrenal hyperplasia, immune checkpoint inhibitor, COVID-19

Introduction

Affecting one in 5000–7000 (varying from 1000–14,000) individuals, Addison’s disease (AD) is mainly caused by destruction of the adrenocortical tissue caused by mononuclear infiltration of the inflammatory cells in 90% of adult cases (concerning geographic areas where tuberculosis is not highly prevalent) or by congenital adrenal hyperplasia (CAH) in the pediatric population. 1–3 The adult incidence of 4–6 cases per million per year has a less known correspondence in children. 2 , 3 Historically, AD was first described by Thomas Addison in 1855; the introduction of cortisone therapy in 1950 massively improved the prognosis; 21-hydroxylase deficiency was first recognized in 1957 followed by identification of other genetic defects in CAH after 1960; the genetics behind AD/CAH registered a great progress between 1984 and 2004; new data suggest other genes are involved such as CTLA4. 4 , 5

The main etiological type is autoimmune AD which is due to an aberrant T cell profile. 6 A progressive adrenalitis is registered years before the actual clinical consequences. 7

Due to life-threatening fulminant evolution unless adequately treated, AD represents a major point of interest for any clinician. While options such as allogeneic adrenocortical cell transplantation, stem cells derivate adrenal-like steroidogenic cells or gene therapy for CAH are still under development, in the meantime, glucocorticoid replacement remains the only lifesaving option, despite being associated with numerous limits such as decreased quality of life, repetitive acute crisis, lack of precise tools in order to assess adequate hormonal substitution and long-term consequences, with controversies around the use of different replacement regimes and formulas. 1

The paper is aiming to provide a 2022 retrospective on AD from a clinical perspective with regard to various data concerning its diagnosis and management.

Materials and Methods

This is a narrative review on full-length articles published in English between January 2022 and December 2022 (including online ahead of print versions) in PubMed-indexed journals. We included original studies in living humans regardless of the level of statistical significance starting from the key search terms “Addison’s disease” or “primary adrenal insufficiency (AI)” on title or abstract. We excluded articles with secondary AI. Briefly, 199 and 355 papers, respectively were identified; we manually checked each of them, excluded the duplicates, and then selected 129 based on their clinical relevance in order to address our 1-year analysis. We organized the data in different subsections covering all published aspects on the subject of AD.

Diagnosis of Addison’s Disease: Clinical, Biochemical and Hormonal Findings

Clinical presentation of addison’s disease.

Clinical manifestations of AD may be challenging due to its severity and heterogeneous aspects. 8 Interesting presentations have been reported such as: AD with mineralocorticoid–only deficiency; AD with spontaneous resolution; AD with symptomatic mineralocorticoid deficiency (not glucocorticoid); AD in the course of anti-phospholipid syndrome; AD with presentation as intractable nausea/vomiting. 9–11

Psychiatric overlap was reflected by one case of a 28-year-old female with a psychotic syndrome at AD onset with complete resolution after starting glucocorticoid replacement. 12 Another 56-year-old male was admitted for organic delusional disorder at onset of tuberculosis-associated AD. 13

Cardiologic anomalies were reported as a first step in identifying AD. A 63-year-old male was admitted for junctional rhythm requiring vasopressor support; another 26-year-old male was admitted for Brugada syndrome-like electrocardiogram elements. 14 , 15 A 40-year-old male had broad complex tachycardia, a cardiologic emergency that might not be related to ventricular tachycardia, but also to severe AD-associated hyperkalemia which, in this particular case, induced, as well, rapidly progressive muscle weakness to quadriparesis. 16 A woman in her 50s was admitted for cardiac tamponade as a consequence of AD. 17 So was a 39-year-old previously healthy male confirmed with APS (autoimmune poly-glandular syndrome)−2. 18

We identified several articles on adrenal location of a lymphoma. One case of a 66-year-old female with primary adrenal lymphoma (bilateral adrenal masses) was reported with AD and very aggressive evolution. 19 Another women in her 70s, and a 73-year-old patient were reported with an adrenal B-cell lymphoma, a challenging differential diagnosis among AD-associated etiological types. 20 , 21 Another 67-year-old male was reported with the same condition (primary site of lymphoma generally accounts for less than 1% of all lymphoma cases) which developed into an adrenal crisis. 22 A retrospective study of 26 patients with primary adrenal lymphoma (which is the largest on this disease we identified in 2022) showed that 81% of subjects had suffered bilateral spreading and 63% of them developed AD. 23

A first case of a 58-year-old female with primary gastric leiomyosarcoma with bilateral adrenal metastasis causing AD was reported with aggressive evolution. 24 A case of a 62-year-old female with prior history of colorectal cancer was found to have bilateral adrenal metastasis-associated AD; bilateral adrenalectomy was performed (in the absence of other metastasis) and confirmed the previous cancer adrenal spreading with a good post-operatory outcome, thus showing the importance of specifically addressing the cause of bilateral adrenal tumors. 25 AD following bilateral adrenalectomy or even unilateral procedure for adrenal tumors-associated hormonal excess still represents an area with many controversies and its clinical recognition might be done later after surgery. 26 Another forgotten presentation of AD amid an adrenal crisis is hypercalcemia. 27

Assessment of Electrolytes Anomalies Due to Addison’s Disease

According to our method, we found 6 studies on sodium and potassium levels in AD. AD may be identified starting from very severe hyponatremia among other causes; for instance, this is the case of a young adult male admitted with a low serum sodium level of 88 mmol/L. 28 Inadequate sodium correction might lead to osmotic demyelination. 28

One single-center retrospective pediatric study on 47 individuals admitted for hyperpotassemia identified 38 subjects with primary hypoaldosteronism (32 of them with CAH due to 21-hydroxylase deficiency) and 9 persons with aldosterone resistance; an additional 4 new cases of AD were identified starting from a clinical suspicion. 29 The data in the pediatric population are less abundant; mostly, genetic forms are detected; hyperkalemia might be a clue, but, generally, the associated aldosterone anomalies require further molecular testing. 29 A single center, retrospective study on 86 patients with hypoaldosteronism (55.4% males; median age of 77 y) showed that 94.6% of them experienced hyperpotassemia, while the diagnosis of AD was established only in 5% of all cases. 30

Endocrine Tests for Addison’s Disease Diagnosis

Particular attention is still needed for the pediatric population with subclinical AI requiring dynamic tests since a random cortisol assay might not be relevant. 38 New methods of plasma renin activity are being developed, this being an essential assessment in primary aldosteronism, but also in AD, CAH, Bartter syndrome, etc. One study introduced a semi-automated method of assay based on liquid chromatography and tandem mass spectrometry. 34 The method described by van der Gugten et al is applicable for other hormone measurements (for instance, aldosterone). 39

We identified two surveys with respect to clinician’s habits in treatment of AD. One survey from Riyadh included the endocrine practice of 162 physicians with respect to the use of a short synacthen test (SST); the indications of SST were: low blood pressure (78%), hyponatremia (65%), hypoglycemia (59%), and hyperkalemia (54%). The assays of baseline cortisol were the most frequent measurements (90%), followed by adrenocorticotropic hormone (ACTH) measurements (78%) whereas only 75% of clinicians assessed the hormones at 30 or 60 minutes, respectively; 93% of them considered the level of plasma cortisol of 550 nmol/L as the normal cutoff. 35 The other survey (among 221 practitioners in pediatric endocrinology) showed that 85% of them used high-dose SST for the diagnosis of AD, but with heterogeneous interpretations of the assays. 36

One of the most interesting and controversial topics remains the use of STT. Since 50% of the patients diagnosed with autoimmune AD have a body mass index (BMI) above 25 kg/m 2 , there is a question whether SST should be BMI-adjusted. We mention a study on 20 obese individuals (versus 20 controls) comparing a weight-adapted dose (0.2 µg/kg) versus low dose (1 µg) versus high dose (10 µg). At 30 minutes, cortisol levels were lower in the studied group after 1 µg versus controls (p = 0.04); at 60 minutes, cortisol peak was lower in obese group versus controls regardless of the dose of synacthen, thus the test with 1 µg might not be enough, and a 0.2 µg/kg body dose might be useful 37 ( Table 2 ).

Gene Testing

Congenital adrenal hyperplasia data.

CAH recognition (while being distinctive from AD) remains a major challenge in pediatric cases due to its severity and epidemiologic impact among primary adrenal types. A pediatric retrospective study (over a 30-year period) included 28 patients with AI and 25% had CAH while most causes were due to secondary (pituitary) causes. 40

Data on Non-Congenital Adrenal Hyperplasia

X-linked adrenoleukodystrophy was the subject of a consensus-based approach. 66 Assessment of very-long-chain fatty acids and ABCD1 testing are confirmatory. AD in boys represents an index of suspicion since AD may be identified prior to cerebral involvement. 46 , 47 Awareness of ABCD1 mutations in young males with AD might help the neurologic outcome. 48 Two novel mutations were reported in a 27-year-old male harboring ABCD1 mutation c.874_876delGAG (p.Glu292del), and a 31-year-old man with c.96_97delCT (p.Tyr33Profs*161) pathogenic variant. 49 X-linked adrenoleukodystrophy (the most common peroxisomal disorder in the majority carrying ABCD1 mutations) has been addressed in a longitudinal study involving, among others, ABCD1 sequencing (including whole exome sequencing): 16.7% (N = 2 males) of the 22 patients (male to female ratio of 12:10) carrying ABCD1 variants developed AD after a median of 2.28 years. This study is part of the screening protocol at birth that has been added to a larger protocol concerning other peroxisomal diseases in Taiwan. 50 Similarly, a pilot Italian study was launched in 2021, also concerning NBS (newborn screening) of the same condition. The dramatic disease associates AD, adrenomyeloneuropathy and cerebral leukodystrophy (white matter progressive disease) requiring hematopoietic stem cell transplant for survival, thus the importance of early detection. 51

Another single-center, retrospective study included data regarding peroxisomal diseases of patients who were followed for 12 years and identified peroxisomal biogenesis disorders in 6 individuals and one person with peroxisomal enzyme deficiency HSD17B4 (overall average age at diagnosis of 0.61 years); AD was identified in 4/7 individuals, requiring either daily glucocorticoids replacement in 3 subjects or hydrocortisone in stress circumstances in one case; the authors concluded that heterozygous PEX1 variants of exon 13 (c.2097dupT and c.2528G>A) are at higher risk for clinical manifestations as AD. 52 A retrospective, single-center study (Northern China, between 2015 and 2021) on 16 pediatric patients with non-CAH AD showed through a next-generation sequencing analysis that 87.5% of them had a gene mutation, ABCD1 being the most frequent (37.5%) followed by NR0B1 (25.0%), NR5A1 (12.5%), and 6.25% for each AAAS , and NNT . 53

An interesting analysis on reported cases included 55 patients with sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) harboring SGPL1 mutations; 71.2% of patients had AD and 32.7% had hypothyroidism with kidney disorders affecting 80% of them; among 30 SGPL1 mutations, the most frequent was c.665G > A (p.Arg222Gln) in one-fifth of cases. 67 According to Ron et al, since 2017 when SGPL1 mutations were first identified, 36 cases were reported until 2022; the authors added a new case with prenatal adrenal calcifications and congenital nephrotic syndrome in addition to severe combined immunodeficiency. 54 However, Maharaj et al found 50 cases and identified a 64% prevalence of AD. 68 Novel SGPL1 mutation has been reported in relationship with pediatric presentation without hyperpigmentation. 69

More than 200 NR0B1 mutations have been recorded so far. A novel frameshift mutation of NR0B1 gene (c.1005delC, p.V336Cfs*36) was described in a young male admitted for AD and hypogonadotropic hypogonadism underlying congenital adrenal hypoplasia. 55 Another novel mutation of NR0B1 ( DAX-1 ) gene (p.*471K) was reported in two siblings with different clinical manifestations who inherited the mutation from their mother. 56 A novel frameshift mutation was described in adult X-linked onset congenital adrenal hypoplasia with delayed puberty in a male harboring NR0B1 gene : c.1034delC (exon 1). 57 Of note, a carrier of NROB1 variant experienced transitory central precocious puberty by the age of 11 months that remitted after hydrocortisone replacement for AD. 58

A dramatic male case with Xp21 contiguous gene deletion syndrome underlying complex glycerol kinase deficiency was reported with rapid fatal outcome due to acute respiratory failure following an infection. 59 Another 3-year-old boy was confirmed with the chromosome Xp21 deletion syndrome while being recognized with AD amid a tuberculosis infection. 60 A neonatal case of AD was reported in a male patient with congenital hypothyroidism carrying a novel GNAS mutation (heterozygous c.432 + 1G > A). 61 The case of an 8-year-old boy with AD and multiple somatic complications represents the longest survival with QRSL1 mutation underlying mitochondrial combined oxidative phosphorylation deficiency-40; Dursun et al reported a novel biallelic mutation - c.300T>A;Y100* and c.610G>A;G204R. 62

One family with 3 brothers carrying a novel NNT (nicotinamide nucleotide transhydrogenase) mutation (biallelic pathogenic variant, homozygous for c.1575dup) was reported with AD in the oldest brothers. 63 Also, we mention here a large study on patients with Down syndrome (N = 6078 versus 30,326 controls) over a 28-year period of time that evaluated 21 endocrine conditions, including AD which was found with a higher prevalence based on OR of 1.68 (95% CI: 1.18–2.4). 64 Another study on pediatric non-CAH AD showed a genetic diagnosis via targeted-gene panel sequencing in 70% of cases (N = 29) 65 ( Table 3 ).

Management and Outcome in Addison’s Disease

Etiology-based strategy.

Disseminated tuberculosis remains an important cause of AD that requires additional anti-infectious drugs in addition with adrenal hormones replacement. 70 , 71 Other infectious causes might trigger AD requiring a collateral infectious management, as well. 72 Of note, one study from 2023 on North Indian patients enrolled 89 individuals with AD (age: 15–83 years; median of 5.9) between 2006 and 2019. Interestingly, due to infectious aspects of this geographic area, the most frequent cause of AD was histoplasmosis (45%) followed by tuberculosis (15%) and then autoimmune AD (25%), and lymphoma (6%). 42% of subjects were admitted due to an acute crisis. The prevalence of 21-hydroxylase antibodies, respective of thyroid antibodies was higher in autoimmune AD than infectious AD (41% versus 3%, respective 46% versus 5%). The highest mortality was registered in histoplasmosis-associated AD (45%) followed by tuberculosis-related AD (8%) and autoimmune AD (5%). Among the most frequent mortality causes, there were acute adrenal crisis and progression of histoplasmosis. 73

Considerations of Hormonal Replacement Regimes

One of the causes regarding a suboptimal outcome and poor quality of life (HRQoL) in AD involves suboptimal standard glucocorticoid replacement. Dual-release hydrocortisone (DH) formulation might overcome these negative aspects. A longitudinal study on 21 patients (male to female ratio of 17:4) included 16 patients treated with cortisone acetate (25 mg/day twice a day) switched to DH and 5 subjects treated with hydrocortisone (20 mg/day 3 times a day) that was switched to DH; the results showed a statistically significant reduction of waist circumference and BMI after 3 and 6 months with DH, as well as an improvement of HRQoL, but with a significance decrease of HDL cholesterol, thus the potential benefits of this new regime should be carefully followed. 77

Fludrocortisone (mineralocorticoid replacement) was studied in a single-center, cohort study on 193 patients with AD (130/193 with autoimmune AD). Doses of 50–75 µg/day were stable in 50% of cases; mineralocorticoid activity of the drug was dose-dependent being correlated with serum Na (r = 0.132, p <0.001), potassium (r = −0.162, p<0.001) and renin (r=−0.131, p <0.001); this indicated the usefulness of renin and plasma electrolytes to adjust the doses of mineralocorticoid replacement in AD as lifespan indication 78 ( Table 4 ).

Quality of Life in Patients with Addison’s Disease

As a general note, HRQoL in AD remains lower than in the general non-AD population. One team proposed the launch of a self-management telecare promoter namely “Addison Care”, as a new alternative to survey-based assessments in patients older than 65 years. The results of this one-arm, non-randomized pilot study are yet to be published. 79

A few studies specifically addressed HRQoL evaluation based on interviews. A Swedish study of 67 persons with autoimmune AD (and 80 controls) showed that females (N = 39) experienced more problems with emotional and cognitive regulation versus controls, while both sexes were affected at the level of executive functions in association with mental fatigue and lower doses of glucocorticoids. 80 One study on 40 persons with AI (versus 20 controls) showed that questionnaire-based quality of life was significantly affected in terms of general health and daytime sleepiness regardless of primary or secondary type while increased hydrocortisone replacement is negatively correlated with mental health. 81 One tri-center study from the USA assessed quality of life in 529 subjects with AI (42.2% had AD). Abnormal physical scores were associated with female sex (OR = 3.3, 95% CI: 1.8–6), a replacement dose of hydrocortisone higher than 25 mg/day (OR = 2.3, 95% CI: 1.2–4.6), while worse mental scores were associated with female sex (OR = 2.1, 95% CI: 1.08–4) and poor family support (OR = 9.1, 95% CI: 2.3–33.3). 82

Moreover, quality of life in terms of preventing adrenal crisis is also reflected by the adjustment of the hormonal replacement when dental procedures and treatment is provided. A survey-based study in 18 dental teaching hospitals (UK) showed that only 29% of them have written guidance for these patients with various doses of glucocorticoids. 83 Interestingly, one study (N = 75 patients with AD) evaluated via ISAQ (immune system assessment questionnaire) the accuracy of predicting an adrenal crisis: ISAQ score was similar pre-pandemic versus pandemic, while the rate of adrenal crisis decreased from 8.8 to 2.4/100 patient-years due to new (pandemic) regulations. 84 A significant disease burden is due to frequent hospitalizations and presentations at hospital. A population-based study from Alberta included patients with AI; the study pointed out that the average number of medical visits compared with regular controls for their endocrine condition was 17.8 per year (as outpatients), and 2.3 per year for presentation as an emergency (this being 3–4 times higher than the average resident population) 85 ( Table 4 ).

Bone Status in Patients Diagnosed with Addison’s Disease

We found 3 studies dedicated to an issue that is still a matter of discussion, namely bone status and fracture risk in AD. A study on 29 patients with autoimmune AD (62% females; mean age of 49.7 ± 11.7 years) versus 33 healthy, age-, sex- and BMI-matched controls showed similar results at central DXA (Dual-Energy X-Ray Absorptiometry) in terms of bone mineral density and T-score and TBS (Trabecular Bone Score), but higher sclerostin (p = 0.006) with a negative correlation between TBS and AD duration and age that might explain a certain influence of AD on bone status. 86

A longitudinal study comparing DH (N = 35) to standard glucocorticoid replacement (N = 35) in AD showed after 60 months a higher BMI in standard group (p = 0.004) in addition to a lower osteocalcin (p = 0.002) and bone alkaline phosphatase (p = 0.029) and decreased lumbar T-score (p <0.001) and increased vertebral fractures prevalence (p = 0.021) versus baseline. DH groups showed increased bone formation marker alkaline phosphatase (p = 0.019), lumbar and femoral neck T-score (p = 0.032 and p = 0.023, respectively) versus baseline, thus suggesting to be a better option for bone status consideration. 87 A small sized, uncontrolled study on 37 patients with AD under hydrocortisone replacement showed a prevalence of osteoporosis of 14.3%, and osteopenia of 34.3%; lumbar and femoral neck BMD associated with daily hydrocortisone dose (r = −0.36, p = 0.03, and r = −0.34, p = 0.02, respectively), and cumulative dose (r = −0.43, p <0.01); osteocalcin levels associated with cumulative dose (r = −0.43, p <0.01), and disease duration (r = −0.38, p = 0.02); multivariate regression showed that daily hydrocortisone dose of ≥12 mg/m 2 was an independent risk factor for osteoporosis/osteopenia (OR = 9, 95% CI: 1.1–74.6, p = 0.04) 88 ( Table 4 ).

Cardiovascular Risk in Addison’s Disease

One of the most complex studies published in 2022 is represented by a population-based analysis in UK (22 million persons); newly identified subjects with any of 19 types of autoimmune diseases (N = 446,449), including AD, were analyzed considering the cardiovascular risk. The autoimmune cohort (mean age of 46.2 years) displayed a higher risk than controls expressed as HR of 1.56 (95% CI: 1.52–1.59), especially younger individuals and those with multiple autoimmune conditions, AD being among the diseases with highest HR of 2.83 (95% CI: 1.96–4.09) 89 ( Table 4 ).

New Insights of Distinct Entities in Addison’s Disease

Autoimmune poly-endocrine syndrome type 1 and 2.

Awareness for APS, including for AD, is required at any time in life if the patient is already identified with an autoimmune endocrine disease. 90–94 Recognition of AD is essential, including in children and teenagers that associate a general rate of an adrenal crisis of 6–8 crisis per 100 patient-years. 95–97 One Australian study analyzed the admission rates in children and teenagers with AI: from 3386 admissions, 24% were caused by an adrenal crisis. 98 Pregnancy also represents a hallmark of clinical approach in females with APS. 99 One multi-center, register-based study on 321 females with APS-1 evaluated 43 of them while being pregnant, a total of 83 pregnancies with a delivery rate of 72%; 36% of them had AD. 100

APS-2, having a prevalence of one case in 1000–20,000 individuals may mimic other conditions, for instance, a young male was misdiagnosed with Crohn’s disease, being in fact AD with a good response to hormonal replacement and a normalization of colonoscopic aspects. 101 New conditions might be identified despite a long-term history of different autoimmune disorders, for instance, a case of ocular sarcoidosis was reported in an 86-year-old female with APS-2. 102 APS-2 was detected starting from Takotsubo cardiomyopathy when AD was confirmed. 103 Subacute degeneration of spinal cord due to pernicious anemia in combination with APS-2 led to the AD identification in another presentation. 104 An unusual evolution to end-stage renal disease was reported in a 45-year-old male with APS-2. 105 A first case with APS (specifically APS-2), multiple endocrine neoplasia syndrome (MEN) type 2A and Kabuki syndrome was reported in a 16-year-old male (which is also the first report of a teenager carrying RET and KMT2D pathogenic variant). 106

In 2022, an exceptional case of a 4-year-old girl was identified with both autoimmune APS-1 ( AIRE mutation) and lacrimo-auriculo-dento-digital syndrome ( FGFR mutation). 107 A novel AIRE mutation namely c.1024C>T (exon 9) was identified in a 36-year-old male with APS-1. 108 A small study on 7 patients with APS-1 (Southern Croatia) evaluated AIRE R257X mutations; the patients, who were followed for 17.8 years, had an average age at APS onset of 6.5 years. 109 One study on APS-1 (11 patients from unrelated families of Iranian non-Jewish origin) identified 2 novel mutations: homozygous (c.308–1G>C), and a combination of 2 heterozygotes (c.1496delC + c.232T>C). 110 A post-mortem study on a potential eye donor with APS-1 harboring a mutation at R257X (C to T substitution) at exon 6 showed pigmentary deposits at the level of inner retinal vessels causing retinal atrophy, thus confirming retinitis pigmentosa as part of an APS-AD picture. 111 A novel AIRE mutation was identified in a 7-year-old girl with APS-1 complicated with AD-associated left ventricular systolic dysfunction. 112

A first study exploring the prevalence of APS in the pediatric population included 879 Danish subjects diagnosed with type 1 diabetes mellitus, autoimmune thyroid disease (ATD) or AD who were followed for a decade. Out of 35 individuals identified with APS, 65.7% had APS-3 and none had APS-1. Patients with APS-associated type 1 diabetes and ATD experienced the conditions earlier than non-APS (7.7 versus 9.3 years, p = 0.04; 7.7 versus 13.1 years, p <0.01). 113

The burden of AD in one family was analyzed in a study on 116 subjects with AD; 74% of them had at least one relative diagnosed with an autoimmune condition (most frequent were Hashimoto thyroiditis, followed by Graves’ disease and vitiligo). A correlation between the number of autoimmune comorbidities in one subject with AD and the number of affected relatives was confirmed (p = 0.031); also, female sex was more affected in first- and second-degree relatives. 114

An interesting study performing screening for autoantibodies against IL22 and IGN-ω, as signature elements of APS-1 detected 29 patients with positive antibodies (a cohort of 675 patients with AD and 1778 subjects with autoimmune endocrine diseases) and further gene testing for AIRE showed four new cases of APS-1. 115

Adrenal Hemorrhage

Immune Checkpoint Inhibitors – Induced Adrenal Failure

Also, tyrosine kinase inhibitors such as lenvatinib might induce AD. One study on 13 patients with thyroid cancer showed that 54% of these experienced AD, while 85% of them reported fatigue without requiring cessation of anti-cancer drugs. 135 Another type of drug-induced AD has been reported in relationship with fluconazole use as prophylaxis for hematopoietic cell transplantation (a first such case was reported in 2022). 136

COVID-19 Infection and Addison’s Disease

The COVID-19 pandemic involved at least two practical points when it comes to AD. Early recommendations during the COVID-19 pandemic included patients with AI of any type who were asked to double or triple the doses of daily glucocorticoids (or switch to injectable substitution) when suffering even mild forms of infection or at the moment of each vaccine dose. 137 , 138 Awareness was mandatory since going through COVID-19 infection required intensive glucocorticoid replacement in severe forms. 139 , 140 Another aspect concerns two types of virus-induced AI: either primary (for instance, due to adrenal hemorrhage or due to the infection itself acting as trigger for a previously undiagnosed AD) or secondary (as seen in hypophysitis). 141

The papers concerning COVID-19 infection and AD in 2022 include unusual clinical presentation of AD under these recent circumstances. One teenager with coronavirus-associated myocarditis was identified with AD due to this trigger infection. 142 One male in his 20s was confirmed with AD while being identified COVID-19 positive. This is the first case of AD in a patient with a history of autoimmune disseminated encephalomyelitis that experienced the coronavirus infection. 143 A first case of 4A syndrome (alacrima, achalasia, and AI and autonomic nervous system anomalies) was suspected of COVID-19 and reported. 144 Collaterally, we mention a matched case-control study on 6769 patients with achalasia (versus 27,076 controls) that was strongly associated with AD as reflected by an OR of 3.83 (95% CI: 1.83–8.04). 145 Moreover, an adult male with APS-2 developed an adrenal crisis while going through COVID-19 infection. 146 A 14-year-old girl previously known with vitiligo was confirmed with adrenal crisis due to COVID-19 infection; she developed multisystem inflammatory syndrome in children (MIS-C), this being the first pediatric case of autoimmune AI and hypothyroidism that were diagnosed due to the infection. 147

Of note, a study analyzing medical deprivation rate in patients with endocrine disease during pandemic showed that individuals with AD had the lowest rate (of 0%) as opposed, for instance, with high rates for differentiated thyroid carcinoma (of 89%). 148

Unexpected clinical presentations of AD might still surprise us; gathering the data on primary adrenal lymphoma might be one of the most useful trans-disciplinary initiatives to be explored in future. Cutting edge in electrolytes assaying seems to be Na-MRI in AD. Survey-based studies showed a large variation of SST protocols. Further trials on using BMI-adjusted SST are needed. 9 novel mutations on CAH were reported; additionally, 2 novel mutations of ABCD1 , 3 of NROB1 , and one of each – SGPL1, GNAS, QRSL1 , and NNT . Studies on infectious AD are mostly provided by India. The spectrum of quality of life assessment in AD goes from studies on using DH regimes (N = 21), and different fludrocortisone doses (N = 193) to questionnaire-based cohorts (N of 40, 67 and 529, respectively) including ISAQ with a poor prediction of an adrenal crisis. New data suggest a pandemic reduction of acute forms rates (8.8.↘2.4/100 patient-year); while the outcome is highlighted by 2.3–17.8 visits/year in one patient with AD.

The 3 clinical studies specifically addressing bone status and fracture risk in AD offered heterogeneous results (a total of 126 subjects with AD). Most impressive UK cohort on different autoimmune entities pointed out a statistically significant higher cardiovascular risk in AD of 2.83.

We separately acknowledged 4 distinct entities based on practical points. APS domain provided novel genetic combinations: RET+KMT2D, AIRE+FGFR and 4 more new AIRE mutations. Five studies (2 observational, 2 cross-sectional and one national cohort) also analyzed different autoimmune-associated risks in AD patients. An additional 9 new cases of adrenal hemorrhage were identified according to our methodology. The strongest new entry in AD field is, in our opinion, ICP. Cui et al gathered 206 published cases of AI and primary type represented only a small fraction of them (5%). 133 Awareness of tyrosine kinase inhibitors-associated fatigue regarding AD might expand the connection with oncologic drugs. 135 Nevertheless, an AD spectrum of a traditional side effect related to with anti-fungal medication might be re-shaped amid increased number of transplantations and a first such case was reported in 2022. 136

During the third year since the COVID-19 pandemic started, we identified on PubMed 8 new case reports with AD triggered by the infection. New data showed that patients with AI did not suffer from new restrictions for a certain period of time as opposed to other endocrine patients and that the first two doses of vaccines required a higher glucocorticoid dose in less than one out of 10 individuals. 148 , 149

Overall, this review covers a recent, wide area of topics related to AD. As limits of the current work, we acknowledge that we followed a limited timeframe and only using PubMed as literature search might bring a potential bias.

To our knowledge, this is the largest retrospective on published data with regard to a 2022 analysis on AD. We are aware than by searching only one database, some papers may be missed. However, consistent data are found. A massive role of genetic diagnosis especially in pediatric cases is highlighted; the importance of both pediatric and adult awareness remains since unusual presentations continue to be described. COVID-19 infection is a strong player amid this third year of pandemic, although we still do not have large cohorts in this particular matter as seen, for instance, in thyroid anomalies. In our opinion, the most important topic is ICPs causing a large panel of endocrine side effects, with AD being one of them, not particularly frequent, but mostly severe, and further studies are expected to provide the statistical impact of it.

Abbreviations

AI, Adrenal insufficiency/adrenal failure; ACTH, Adrenocorticotropic Hormone; AD, Addison disease; AACE, American Association of Clinical Endocrinology; APS, autoimmune poly-endocrine syndrome; ATD, autoimmune thyroid disease; BMI, body mass index; CAH, congenital adrenal hyperplasia; DH, dual-release hydrocortisone; DXA, Dual-Energy X-Ray Absorptiometry; HR, hazard ratios; HRQoL, Health-related quality of life; ICP, immune checkpoint inhibitors; ISAQ, immune system assessment questionnaire; MEN, multiple endocrine neoplasia; MIS-C, multisystem inflammatory syndrome in children; MRI, magnetic resonance imaging; N, number of patients; NBS, Newborn Screening; NNT, nicotinamide nucleotide transhydrogenase; SST, short synacthen test; SPLIS, sphingosine-1-phosphate lyase insufficiency syndrome; TBV, total brain volume; TBS, Trabecular Bone Score.

The authors report no conflicts of interest in this work.

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Premature Mortality in Patients with Addison’s Disease: A Population-Based Study

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Ragnhildur Bergthorsdottir, Maria Leonsson-Zachrisson, Anders Odén, Gudmundur Johannsson, Premature Mortality in Patients with Addison’s Disease: A Population-Based Study, The Journal of Clinical Endocrinology & Metabolism , Volume 91, Issue 12, 1 December 2006, Pages 4849–4853, https://doi.org/10.1210/jc.2006-0076

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Background: The survival rate of patients with primary adrenal insufficiency (Addison’s disease) undergoing currently accepted replacement therapy is not known, although well-informed patients are considered to have a normal survival rate. In this study, we evaluated the mortality of patients with Addison’s disease in Sweden.

Methods: A population-based, retrospective, observational study was performed, using the National Swedish Hospital and Cause of Death Registers, covering the period from 1987–2001. After a diagnosis of Addison’s disease, each patient was followed until the end of follow-up or death. Mortality was compared with that of the Swedish background population.

Findings: We identified 1675 patients (995 women and 680 men) diagnosed with primary adrenal insufficiency. The average follow-up from initial diagnosis was 6.5 yr. Five hundred seven patients died during the study period compared with an expected 199. The risk ratio for all-cause mortality was 2.19 (confidence interval 1.91–2.51) for men and 2.86 (confidence interval 2.54–3.20) for women. The excess mortality in both men and women was attributed to cardiovascular, malignant, and infectious diseases. Concomitant diabetes mellitus was observed in 12% of the patients, but only contributed to the increased mortality to a minor extent.

Interpretation: Compared with the background population, we observed that the risk ratio for death was more than 2-fold higher in patients with Addison’s disease. Cardiovascular, malignant, and infectious diseases were responsible for the higher mortality rate.

IN PRIMARY ADRENAL insufficiency, or Addison’s disease, as first described by Thomas Addison in 1855 ( 1 ), the adrenal cortex produces and secretes insufficient amounts of glucocorticoids, mineralocorticoids, and androgens. Addison’s disease is uncommon, having an estimated prevalence of 93–140 per million and an incidence of 4.7–6.2 per million in Caucasian populations ( 2 ). The disease has a female preponderance ( 3 , 4 ), and most patients are diagnosed in their third to fifth decade of life ( 5 – 7 ). Tuberculosis was an important cause of the disease during the last century ( 8 , 9 ). However, autoimmune disease accounts for most cases in developed countries today ( 6 , 10 ), causing 80–90% of the current cases in Scandinavia, for example ( 11 ).

In the 1950s, before the availability of glucocorticoids, the 1-yr survival rate in patients with Addison’s disease was 20% or less ( 12 ). However, Mason ( 8 ) studied survival after the introduction of glucocorticoid replacement therapy and estimated that mortality was similar to that of the background population, except in the case of those patients in whom the disease was undiagnosed at the time of death and in patients living under poor social conditions. Therefore, survival now is considered to be normal or comparable with that of the background population in patients receiving replacement therapy and adequate follow-up.

The dramatic improvement in survival observed after the availability of glucocorticoid replacement therapy, the low prevalence of the disease, and the reassuring data from Dunlop ( 12 ) and Mason ( 8 ) have not prompted additional survival studies in Addison’s patients. However, recent studies have demonstrated excess mortality in hypopituitary patients, a large proportion of whom are similarly dependent on life-long glucocorticoid replacement therapy ( 13 – 15 ). Whether these observations are the result of inadequate glucocorticoid replacement therapy ( 15 ), inadequate replacement with sex steroids ( 14 ), or untreated growth hormone deficiency ( 13 ) is not clear. To study the long-term outcome of patients with a life-long daily requirement for glucocorticoid replacement therapy, we investigated the standardized mortality rate of patients with Addison’s disease between 1987–2001 in Sweden. The existence of low population diversity within Sweden, a homogenous health care system, and the Swedish National Board of Health and Welfare (SNBW) Registers all offer unique conditions under which to study the long-term outcome of this rare disease.

National survey

The National Hospital and Cause of Death Registers at the SNBW were used to identify and track patients. We evaluated all patients hospitalized in Swedish hospitals for primary adrenal insufficiency between 1987–2001 using a technique similar to that described previously ( 16 , 17 ). Patients with primary adrenal insufficiency who were coded 255.4 according to the International Classification of Diseases, ninth revision (ICD 9) and E27.1 or E27.2 (adrenal crisis) according to the International Classification of Diseases, tenth revision (ICD 10), were identified. Patients who were, at any time, diagnosed with Cushing’s syndrome or any pituitary disease were excluded from the analysis. We also looked for the presence of diabetes mellitus (DM) at the time of the initial diagnosis of primary adrenal insufficiency. By making use of unique, personal identification codes, each individual was counted once only. The patient’s county of residence and date of hospitalization were recorded. After the registered hospitalization during which the diagnosis of primary adrenal failure first occurred, each patient was tracked until the end of follow-up or death. Cause of death was identified using the Swedish Cause of Death Register. The mortality rate after hospitalization for primary adrenal failure was compared with that of the general Swedish population.

More than 99% of deaths are reported in the Cause of Death Register and the frequency of miscoding is between 1.2–6.3%, as has been shown by repeated quality control tests ( 18 ). The National Hospital Register covers more than 99% of all hospital admissions, and the rate of miscoding reported during quality control checks is less than 8.3% ( 19 ).

Local study

To validate the selection criteria used in the national survey, a similar search was performed using a local hospital register. Patients with primary adrenal insufficiency, adrenal crises, drug-induced adrenal insufficiency and other unspecified adrenal insufficiencies (ICD 10 codes E27.1–4), and receiving inpatient or outpatient medical care between 1999 and 2003 were identified and their medical records reviewed. A broader search strategy was performed in the local register to estimate the proportion of patients with Addison’s disease who were not identified in the National Survey, as well as the proportion classified with adrenal crises or primary adrenal insufficiency who did not have Addison’s disease.

Statistical analysis

The expected numbers of deaths, if the risk coincided with that of the general population, were calculated for men and women separately, taking age and calendar time into account. Comparisons between observed and expected numbers were performed using Poisson distributions, which were also applied to the calculation of 95% confidence intervals (CI) of risk ratios (RR). A Poisson model ( 16 , 20 ) was used to estimate the risk of Addison’s disease with respect to latitude. Poisson regression was also used to estimate the hazard function of death as a continuous function of time from the initial Addison’s diagnosis and depending on the presence of DM at the time of diagnosis. We have used the term “hazard ratio” for the quotient between two hazard functions and RR for the quotient between observed and expected number of deaths. The two terms essentially reflect the same function. The χ 2 test was used to assess the difference between regions with respect to the risk of Addison’s. All tests were two-tailed.

The search in the National Hospital Register identified 1675 patients with Addison’s disease between 1987–2001 ( Table 1 ). The mean age at initial identification was 52.8 yr ( sd 22.0), and the average follow-up period was 6.5 yr; 3.4 yr for those patients who died and were found in the National Cause of Death Register and 7.9 yr for those who survived the period of observation.

The number of men and women with Addison’s disease obtained from The National Hospital and Cause of Death Registers at the SNBW during the period 1987–2001

The number and percentage of patients with concomitant DM at the time of detection is also shown.

There was an equal distribution of Addison’s disease within Sweden with no significant difference in the number of cases reported between regions or with respect to latitude ( i.e . a North-to-South gradient).

Within the time period of 1987–2001, 507 deaths were noted compared with the expected 199 deaths ( Fig. 1 ). The overall RR was 2.19 (CI 1.91–2.51) for men and 2.86 (CI 2.54–3.20) for women. The greatest number of deaths occurred from cardiovascular (n = 239), malignant (n = 73), endocrine (n = 64), respiratory (n = 45), and infectious diseases (n = 12). The relative death rate from cardiovascular and malignant diseases was increased in both men and women ( Fig. 2 ). Ischemic heart disease was the most common cardiovascular cause of death (n = 133) followed by cerebrovascular disease (n = 46). No clustering of cancer type or cancer from a specific organ system was observed ( Table 2 ).

The RR and 95% CI for all-cause mortality in patients with Addison’s disease in Sweden from 1987–2001. This was calculated for men and women separately, taking age and calendar time into account. Obs. no., Observed number; Exp. no., expected number.

The RR and 95% CI for cardiovascular mortality and mortality from neoplastic disorders in patients with Addison’s disease in Sweden from 1987–2001. This was calculated for men and women separately, taking age and calendar time into account. Obs. no., Observed number; Exp. no., expected number.

The number of deaths from the various forms of malignant diseases among the patients with Addison’s disease in Sweden between 1987–2001

An increased risk of death from infectious disease was found in both men and women and from respiratory disorders in women only ( Fig. 3 ). If patients who died from infectious disease from all disease categories were counted together, a total of 35 patients died from infection, the majority (66%) from pneumonia. One death was related to tuberculosis.

The RR and 95% CI for mortality from infectious and respiratory disorders in patients with Addison’s disease in Sweden from 1987–2001. This was calculated for men and women separately, taking age and calendar time into account. Obs. no., Observed number; Exp. no., expected number.

Thirty-six patients were reported to have died from adrenal insufficiency, five of those died within 2 d and five within 3 wk of hospitalization. No patient was reported to have died from adrenal crisis according to ICD 10. The ICD 9 classification does not allow for a differentiation between primary adrenal insufficiency and adrenal crisis.

Impact of concurrent DM

At the time of the initial identification in the register, 12.6% of the men and 11.4% of the women had a concomitant diagnosis of DM ( Table 1 ). The RR for death was 1.82 (CI 1.29–2.06) for men and 1.52 (CI 1.11–2.07) for women with Addison’s disease and DM compared with those patients with Addison’s disease without DM. Therefore, DM had a significant influence on total mortality in both men and women.

However, the impact of DM on the excess mortality of the whole group of Addison’s patients was limited. The RR of death for patients with Addison’s disease without DM was 2.04 (CI 1.74–2.37) for men and 2.68 (CI 2.36–3.04) for women as compared with the background population, i.e . 7% less for men and women than the ratios obtained for the whole cohort. The excess mortality among patients with Addison’s disease with and without concomitant DM was most pronounced in the time period close to the initial detection ( Fig. 4 ).

The figure demonstrates an example of the annual incidence of death for female patients at the age of 65 yr during the calendar year of 1997 with Addison’s disease with and without concomitant DM. The dotted line depicts the risk of death in the background population, the banded line depicts women with primary adrenal failure, and the solid line represents the risk of death for patients with both DM and primary adrenal failure. The Poisson regression model demonstrated an excess mortality compared with the general population most pronounced during the first time after detection of Addison’s disease. However, substantial excess remained for many years. An example of men demonstrated similar results.

Using wider search criteria than in the national study, we identified 122 patients; of these, 105 were included in the analysis. The remaining 17 patients were excluded due to secondary adrenal insufficiency (two), tertiary adrenal insufficiency (three), Waterhouse-Friedrichsen syndrome (one), adrenalectomy due to Cushing’s disease (four) or due to malignant disease (two), miscoded diagnosis (two), and insufficient medical records (three). Therefore, depending on whether using ICD 9 or ICD 10 coding, seven (6%) or six (5%) patients, respectively, who did not have Addison’s disease could have been included in our national cohort.

Only one patient was diagnosed with certainty in the outpatient clinic. Eighty-two percent of the patients (86 of 105) were hospitalized when the diagnosis of Addison’s disease was confirmed. In 18 cases, information on whether patients were diagnosed in an outpatient unit or during hospitalization was unavailable.

The mean age at diagnosis was 37.3 yr ( sd 15.5); 42.1 (14.7) in women and 31.1 (14.3) in men. Fifty-two percent (55 of 105) had other endocrine disorders. Forty-one percent (43 of 105) had primary hypothyroidism and 11% (12 of 105) had DM (four type 1, five type 2, and three unknown type). One hundred and two patients received cortisone acetate and three patients received hydrocortisone as replacement therapy. The median daily cortisone acetate dose was 50 mg (range, 18.8–75 mg) administered twice daily in 85% (89 of 105) of the patients. Ninety-four percent (99 of 105) of the patients also received fludrocortisone with a median daily dose of 0.1 mg (range, 0.025–0.2 mg).

This study shows that patients with primary adrenal insufficiency identified by the use of the National Hospital Register in Sweden have a mortality rate which is 2-fold greater than that of the background population. The excess mortality was greatest close to the time of hospitalization and was mainly attributed to cancer and cardiovascular and infectious disease.

A possible explanation for an increased mortality rate in Addison’s patients is inappropriate glucocorticoid replacement therapy in the case of both excess and inadequate glucocorticoid exposure in response to stress and concurrent illnesses. Excess glucocorticoid exposure can induce hypertension, obesity with abdominal fat distribution, and DM; all strong independent risk factors for cardiovascular disease ( 21 , 22 ). In addition, an attenuated diurnal variation in the serum cortisol profile has been associated with abdominal obesity and the metabolic syndrome supporting the importance of the diurnal profile ( 23 ). Finally, a thorough reevaluation of patients undergoing glucocorticoid replacement therapy revealed that doses were too high and could be reduced in the case of more than half of the patients ( 24 ). Therefore, it is likely that many patients in the national cohort were receiving overly high doses of glucocorticoids delivered in a nonphysiological pattern, as indicated by the local study.

The increased frequency of other endocrine disorders in patients with autoimmune primary adrenal insufficiency such as mineralocorticoid insufficiency, primary hypothyroidism, and type 1 DM may also compromise survival in these patients. Overly high doses of fludrocortisone, which result in an increase in the activity of the mineralocorticoid receptor, may have deleterious effects on the heart and vascular system ( 25 ). Also, untreated hypothyroidism is associated with an increased risk of atherosclerotic disease ( 26 ), which may have contributed to increased cardiovascular mortality in our patient cohort if the thyroid status was inadequately monitored and treated. Untreated dehydroepiandrosterone deficiency could also be a contributing factor to the poor outcome in patients with Addison’s disease as indicated in recent dehydroepiandrosterone replacement trials ( 27 – 29 ).

In the national cohort, the frequency of DM among patients with primary adrenal failure was 12.0%, which is similar to that found in a recent survey ( 3 ). This is three to four times higher than the expected prevalence of 2.7–4.3% reported in the Swedish population ( 30 , 31 ). We were not able to determine the proportion of type 1 and 2 DM in the national cohort, but others have demonstrated an increased frequency of type 1 DM among patients with Addison’s disease ( 3 ). The relative risk of death for patients with DM is 3.8 in Sweden ( 31 ). Having DM and primary adrenal insufficiency significantly increased the risk of death when compared with having adrenal insufficiency alone. However, the overall impact of concomitant DM on the total mortality was minor. By excluding patients with DM, the overall mortality rate reduced only by 7% in men and women, demonstrating the independent influence of Addison’s disease on the increased relative risk of death.

The relative risk of death from cancer was increased in both men and women. The increased cancer mortality may be an effect of obesity associated with an inadequate replacement therapy or it may be due to the underlying autoimmune disorder. However, the absence of clustering of cancer types such as colon, rectum, breast, endometrial, and kidney cancer, which are associated with obesity ( 32 ), or non-Hodgkin’s lymphoma, which is associated with autoimmunity ( 33 ), does not support such a notion.

The mortality rate resulting from infectious diseases was more than five times that expected. This is an uncommon cause of death in the age-adjusted background population, and, therefore, the numbers are small. The goal should be to prevent these cases through continuous education of patients and a constant awareness of this risk in the overall care of patients with adrenal insufficiency( 15 ). Tuberculosis did not contribute to the increased mortality rate because only one case was identified.

Published mortality data in patients with hypopituitarism where the majority have secondary adrenal insufficiency have demonstrated increased relative risk of death of approximately 1.8 ( 13 ). This increased risk has not been associated statistically with the presence of secondary adrenal insufficiency ( 14 ). However, as the excess mortality is of similar magnitude as demonstrated in this study, it might therefore be speculated that adrenal insufficiency is a contributing factor to the increased mortality rate also in hypopituitarism.

Although the study is based on official registers that have a very high yield, there are some limitations to be considered. Patients enter the study when being hospitalized, and this may occur when the diagnosis is first made; however, a patient in whom Addison’s disease has previously been diagnosed can also enter the study because of a concurrent illness. Selection of subjects by this means may explain the higher average age in the national cohort as compared with the mean age at the time of diagnosis in the local survey and in previous cross-sectional studies ( 3 ). Very rare causes of primary adrenal failure are likely to be represented within the national cohort, but the contribution to overall mortality is probably small. Furthermore, the study does not allow the detection of patients dying from adrenal insufficiency before diagnosis, which would increase the relative risk of death further. In addition, an unavoidable aspect of the study is that a small proportion of cases may have been incorrectly coded, which is more likely to have occurred in ICD 9 than in ICD 10.

The strength of this study is its size: it is the largest cohort of primary adrenal insufficiency reported in the literature. Moreover, the analysis included a longitudinal follow-up from initial detection to either death or to the end of the study period. Finally, because the majority of new cases were diagnosed during hospitalization in the local study, detection of cases in the national study was evenly distributed within the country and throughout the study period and suggests a high yield of all newly diagnosed cases during the 14-yr study period.

This study has demonstrated that the relative risk of death is more than 2-fold greater in patients with primary adrenal failure. The excess mortality was highest in the period immediately after detection and hospitalization. The excess mortality from infectious diseases may be prevented by adequately educating patients and health care workers and through other safety measures. An unexpected finding was the excess mortality observed as a result of cardiovascular disease and cancer. This could be due to overly high doses of glucocorticoids and a nonphysiological serum cortisol profile associated with the currently available replacement therapy. Concomitant endocrine disorders may have a significant impact on the outcome of this patient group, although our analysis of the impact of DM only explained the increased death rate to a minor extent. The results of this study should pave the way for improvements in the overall care of patients with adrenal insufficiency.

We thank the Swedish National Board of Health and Welfare (Fereshte Ebrahim) for the support it provided in the collection of data for this study.

The study received grants from the Health and Medical Care Committee of the Region Västra Götaland and the Sahlgrenska Academy, University of Göteborg, Sweden.

Disclosure statement: The authors have nothing to disclose.

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Addison’s disease: identification and management in primary care

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• Figures & Data
• INTRODUCTION

Addison’s disease (AD), also known as primary adrenal insufficiency, is a deficiency of glucocorticosteroids and mineral corticosteroids. 1 This can result in an insidious, protracted presentation. Therefore, unsurprisingly, the diagnosis is often delayed 2 and 60% of patients have seen two or more clinicians before the diagnosis is considered. 3 Around one-half of patients with AD are diagnosed after an acute adrenal crisis, 4 which can be rapidly fatal. 5 Although tuberculosis is the most common cause of AD worldwide, 1 in the developed world, autoimmune disease is the predominant cause. 3 In the latter context, AD is often linked to other autoimmune diseases, such as, vitiligo. 6

• EPIDEMIOLOGY

Addison’s disease is estimated to affect 1 in 10 000 people in the UK, 5 and throughout Europe. 7 The female:male ratio is 1.8 and adults of all ages are affected. 6 Incidence from Norwegian data is 0.44 per 100 000 population per year and there is some evidence of clustering within families. 6 Annually, in the UK, 1–2 consultations per 10 000 people are undertaken for adrenal gland disorders, compared to between 80–125 per 10 000 for acquired hypothyroidism. 8

At the authors’ practice of 11 000 patients, seven are registered with primary or secondary adrenal insufficiency. One such patient presented in Autumn 2013 (see Figures 1 and 2 demonstrating vitiligo of the face and hands). A 4-month delay in diagnosis occurred due to an extended period of primary care investigation for other (gastrointestinal) causes for the presenting symptoms. The diagnosis was made following an acute admission due to features of an Addisonian crisis including hypotension, vomiting, debilitating fatigue, and hyperkalaemia.

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Patient with Addison’s disease on a background of vitiligo (face).

Patient with Addison’s disease on a background of vitiligo (hands).

• CLINICAL FEATURES

A major problem with identifying people with AD is the non-specific nature of many of the presenting symptoms, at least in pre-crisis stages. Common symptoms, signs, and laboratory results are shown in Table 1 , and all can be associated with other, often more common, differential diagnoses.

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Symptoms, clinical signs, and laboratory results associated with Addison’s disease

A rapid appraisal of presentations of AD, conducted though MEDLINE ® via NHS Evidence, yielded many disparate presenting symptoms. In summary, diagnostic pitfalls to be aware of include a chronic presentation which may be misdiagnosed as one of a number of other problems, often based on a mental health diagnosis, for example anxiety or depression; precipitation into crisis through use of antidepressants (as sodium-depleting) or through use of steroids for a comorbidity; evolution in pregnancy may be mistaken for chloasma and interpretation of serum cortisol measurement is harder in pregnancy, so if AD is suspected referral to endocrinology is essential; and erratic diabetes control, either recurrent hypoglycaemia or diabetic ketoacidosis.

• INVESTIGATION

A high index of suspicion is needed as AD crises can be rapidly fatal. If suspected (features of persistent vomiting, muscle weakness, dehydration, hypotension, headache, extreme fatigue, and shock), 5 the patient should be admitted as a medical emergency. Otherwise, consider measuring urea and electrolytes (U&E) as sometimes, although by no means always, a low sodium and high potassium will be found, and a 9 am serum cortisol level. Local reference ranges should be checked but generally, a serum cortisol result >500 nmol/l makes AD very unlikely, <100 nmol/l is definitely abnormally low 9 requiring rapid investigation. Results lying between these values are indeterminate and should prompt a short synacthen test. Additional relevant secondary care tests at the time of diagnosis include plasma adrenocorticotropic hormone and renin, and serum dehydroepiandrosterone sulfate; other hypothalamic-pituitary axis investigation may be warranted if secondary AD is suspected. 7 Further screening for other autoimmune conditions should be considered and are summarised in Box 1 .

Potentially coexistent autoimmune diseases and a proposed annual surveillance programme for patients with Addison’s disease

Annual surveillance for other autoimmune disorders is recommended. Some authorities recommend annual screening for the autoantibodies listed above, 7 instead of the proposed stepped approach of investigation. Anti-TPO = anti-thyroid peroxidase. Anti TTG = anti tissue transglutaminase. B12 = vitamin B12 level. FBC = full blood count. HbA1c = glycated haemoglobin.LFT = liver function tests. PTH = parathyroid hormone. TSH = thyroid stimulating hormone. T4 = thyroxine. U+E = urea and electrolytes.

• ONGOING MANAGEMENT

Lifelong oral steroid supplementation is usually initiated and adjusted in secondary care by an endocrinologist and typically includes glucocorticoid (hydrocortisone) and mineralocorticoid (fludrocortisone) replacement. Under-replacement may be indicated by persisting symptoms or signs and over-replacement by hypertension, thin skin, striae, easy bruising, glucose intolerance, hyperglycaemia, and electrolyte imbalance. Patients with AD should be informed that they are eligible for free prescriptions in the UK.

Individualised sick day rules need to be highlighted to patients, and flagged on primary care computer systems. Resources to assist with providing this information can be found at http://www.addisons.org.uk/ . Self-administered injectable steroids may be provided in situations where rapid access to supportive treatment in a crisis is not guaranteed. 9

There is no well-established guidance for primary care follow-up of people with AD. We suggest a disease register with annual recall for review with investigations as shown in Box 1 .

AD is an infrequently occurring mimic of many other more common conditions encountered in primary care. Despite multiple useful reviews of AD in the literature, we have personal recent experience of delays in diagnosis and there remains a need to raise the clinical profile in primary and secondary care of this highly treatable but life-threatening disease. Research into a formal diagnostic algorithm would be helpful, as would further epidemiological work to examine clustering of cases in time and place.

Further resources

http://cks.nice.org.uk/addisons-disease

https://www.endocrinology.org/policy/docs/11-03_Adrenal%20insufficiency.pdf

Patient consent

The patient gave consent for publication of this article and the images

Claire Burton is funded by a National Institute for Health Research (NIHR) In-Practice Fellowship (IPF 07/002). Components of this report are from independent research arising from this Fellowship. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.

Freely submitted; externally peer reviewed.

Competing interests

The authors have declared no competing interests.

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• Received February 20, 2015.
• Revision requested March 26, 2015.
• Accepted April 6, 2015.
• © British Journal of General Practice 2015
• Chakera AJ ,
• Howlett T ,
• Erichsen MM ,
• Skinningsrud B ,
• Husebye ES ,
• Allolio B ,
• RCGP Birmingham Research Unit
• National Institute for Health and Care Excellence
• Bleicken B ,

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• DOI: 10.1016/j.amjmed.2009.12.017
• Corpus ID: 8929580

Addison disease in adults: diagnosis and management.

• A. Chakera , B. Vaidya
• Published in American Journal of Medicine 1 May 2010

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50 Citations

Addison’s disease: a rare case report, addison’s disease, diagnosis and management of addison's disease: insights gained from a large south african cohort, addison's disease and its associations, diagnostic difficulties of addison's disease in children: a case report, a case of late manifestation of primary adrenal insufficiency in the autoimmune polyglandular syndrome type 1, diagnosis and management of addison's disease in a nulliparous woman followed by successful pregnancy outcome in a rural tertiary hospital: a case report, addison's disease in evolution: an illustrative case and literature review., addison’s disease presenting only with hyperpigmentation – a rare case report, clinical approach to adrenal insufficiency in hospitalised patients, 7 references, italian addison network study: update of diagnostic criteria for the etiological classification of primary adrenal insufficiency., premature mortality in patients with addison's disease: a population-based study., clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a norwegian registry., a systematic review and meta-analysis of randomized placebo-controlled trials of dhea treatment effects on quality of life in women with adrenal insufficiency., modified-release hydrocortisone to provide circadian cortisol profiles., adrenal insufficiency., related papers.

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An Update on Addison's Disease

Affiliations.

• 1 Medicover, Bochum, Germany.
• 2 Department of Medicine III, University Hospital Carl Gustav Carus, Dresden, Germany.
• 3 Medicover, Berlin-Mitte, Germany.
• 4 Medicover, Ulm and Neu-Ulm, Germany.
• 5 University of Calgary, Calgary, AB,Canada.
• 6 Division of Diabetes & Nutritional Sciences, Faculty of Life Sciences & Medicine, King's College London, London, United Kingdom.
• 7 Department of Medicine I, Würzburg University Hospital, Würzburg, Germany.
• 8 Klinik für Endokrinologie, Diabetologie und Klinische Ernährung, University Hospital, Zürich, Switzerland.
• 9 Lee Kong Chian School of Medicine, NTU Nanyang Technological University, Singapore, Singapore.
• 10 Endocrine and Metabolic Unit, Royal Adelaide Hospital, University of Adelaide, Adelaide SA, Australia.
• PMID: 30562824
• DOI: 10.1055/a-0804-2715

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.

© Georg Thieme Verlag KG Stuttgart · New York.

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Case Report

Addison's disease and its associations, amar puttanna.

1 Russells Hall Hospital, Dudley, UK

Alana Rosaleen Cunningham

2 Walsall Manor Hospital, Walsall, UK

Philip Dainty

3 Department of Acute Medicine, Wolverhampton New Cross Hospital, Wolverhampton, UK

Addison's disease is a relatively rare endocrine condition resulting from adrenal insufficiency due to various causes. Weight loss is a common feature; however, patients may be seen by a variety of specialists, even requiring acute admission before the diagnosis is made. Addison's disease is commonly associated with other autoimmune diseases. In some cases such as autoimmune polyendocrine syndromes (APS) types 1 and 2, these associations are more commonly found. We present a case of one such patient who presented to the acute medical team having been referred to the gastrointestinal services in the previous year for persistent vomiting and weight loss. On review of history, the cause of vomiting and weight loss was questioned and combined with subsequent biochemical testing a diagnosis of Addison's disease was made. The patient was also noted to have other associated endocrine and autoimmune conditions.

Addison's disease is not as common as other endocrine conditions such as diabetes or thyroid disease. However, it is an important consideration in acute admissions due to the associated significant morbidity and mortality. 1 It can be very difficult to diagnose due to its varied presentation and often referrals to various specialties occur before a diagnosis is made. Many patients are only diagnosed once acutely admitted in Addison's crisis, which makes prompt diagnosis all the more important. Crisis can also be triggered by sepsis which can also mask symptoms and make the diagnosis difficult. Addison's disease is known to have associations with other conditions; therefore, knowledge of this can lead to prompt diagnosis and earlier management once this diagnosis is made.

Case presentation

A 20-year-old female patient was admitted in October with a 3-month history of persistent vomiting between 5 and 15 times a day and weight loss. She was dehydrated and unable to tolerate oral intake due to nausea and vomiting. Her bowel motions were normal; she had no problems with micturition or symptoms of infection, however had noticed significant weight loss in the preceding few months.

She had known hypothyroidism and had previously been referred directly to the gastroenterologists for persistent vomiting. She underwent an oesophagogastroduodenoscopy (OGD) which showed gastritis and therefore, she was started on proton pump inhibitor therapy. A blood test showed negative tissue transglutaminase antibodies, positive gastric parietal cell antibodies and she was scheduled for a CT enterograph.

Given this history she was treated as ongoing gastritis with vomiting secondary to the above. She had a sodium level of 133 mmol/L and low blood pressure and this was felt to be secondary to dehydration. This was treated with intravenous fluids and she was subsequently discharged on antiemetics.

The patient presented again 4 months later with persistent vomiting with some fresh blood at the end due to a Mallory-Weiss tear. She mentioned ongoing weight loss from 50 kg in August to 41 kg currently and ongoing lethargy. She described some right-sided abdominal pain and a pregnancy test was negative. She denied thyroxine abuse or forced vomiting. The patient was unsure about any relevant family history. She was a social smoker and denied any alcohol intake.

On examination she was very thin, hypotensive and tachycardic. She was clinically dehydrated and was noted to have some mild skin pigmentation.

Investigations

Her sodium levels were 129 mmol/L (normal 133–146 mmol/L), potassium levels normal at 4.9 mmol/L (3.4–5.3 mmol/L), C reactive protein (CRP) 16 (<5), haemoglobin 12.4 g/dL (12.5–16 g/dL), white cell count (WCC) 11.6 (4–11×10 9 /L) and she had a mild eosinophilia. Given the history and findings a random cortisol was requested which came back at 2 nmol/L (102–535 nmol/L). Liver and renal function tests were normal. Thyroid stimulating hormone (TSH) was 33 mU/L (0.27–4.2 mU/L) and blood glucose was 4.5 mmol/L (4–6 mmol/L).

Differential diagnosis

On the basis of the history and investigation results, the patient was diagnosed with Addison's disease. Given her history of hypothyroidism, Addison's disease and positive gastric parietal cell antibodies; the possibility of autoimmune polyendocrine syndrome was raised.

The patient was started on intravenous hydrocortisone 100 mg four times a day and fluids resulting in subsequent improvement.

Outcome and follow-up

A hormone profile revealed normal leutinising hormone (LH), follicle stimulating hormone (FSH), oestradiol, progesterone and prolactin with a low insulin-like growth factor (IGF). A pituitary MRI and an abdominal CT were normal with no adrenal changes.

The patient was discharged home on oral hydrocortisone and fludrocortisone tablets and educated about the importance of compliance. Unfortunately she was readmitted within the next 6 months with a further episode of Addison's crisis due to poor compliance.

The above case highlights the importance of reviewing previous admissions and to think of other differential diagnoses especially when the presenting symptom is similar. The patient had been initially referred to the gastroenterologists; therefore, subsequent admissions were put down to a gastrointestinal cause despite there being limited improvement in symptoms. However given the ongoing weight loss despite no underlying cause on previous investigations, it was important to rule out other diagnoses and eventually the diagnosis of Addison's disease was made almost 1 year after symptoms presented.

Addison's disease is a relatively rare condition with an annual incidence of 4 million in the western population. 2 It can be very difficult to diagnose and easily missed due to its presentation with non-specific symptoms. 3

The delay in diagnosis is not uncommon and patients can be seen by various healthcare professionals including gastroenterologists or psychiatrists before being correctly diagnosed. 4 5

The wide variety in symptoms means that the diagnosis can be attributed to other conditions and the more cardinal features such as skin or mucous membrane pigmentation may be missed although these may not always be present. 6

Anorexia or hypotension may be relevant however are again non-specific as they be explained by alternative diagnoses such as an underlying infection.

Investigations can provide many clues to the clinician to make them suspect Addison's disease. On routine blood tests the patient may have hyponatraemia and/or hyperkalaemia, hypoglycaemia, eosinophilia. 7

Raised TSH may be a feature and sometimes Addison's disease can be worsened by starting thyroxine. 8

A clinician may then suspect the diagnosis and consider a random cortisol level. However, this can be inaccurate due to the circadian rhythm of cortisol production with peak levels in the morning and low levels at midnight and also an increase in production in times of stress. 9 An unusually low cortisol in the presence of clinical features of Addison's disease should prompt a diagnosis and this may be confirmed by a trial of hydrocortisone.

The key test for diagnosis is a short synacthen test however this can be difficult in the crisis scenario as intravenous hydrocortisone should be started immediately. Cortisol and adrenocorticotropic hormone (ACTH) levels should also be taken prior to steroid administration.

In the non-acute setting, Synacthen or synthetic ACTH (also called tetracosactrin) can be administered either intravenously or intramuscularly. A typical test involves baseline cortisol levels taken (0 min) followed by administration of 250 μg tetracosactrin and then repeat cortisol levels taken at 30 min (and 60 min in some cases). The level suggesting intact adrenal gland function has varied from between 400 and 550 nmol/L but the generally agreed level is 525 nmol/L. 10 11

About half of the patients with Addison's disease are diagnosed only after an acute adrenal crisis. It is a medical emergency often precipitated by an infection or other forms of stress in an undiagnosed or inadequately treated patient with Addison's disease. In this condition, patients present acutely unwell with severe dehydration, hypotension or circulatory shock. 4

There are known autoimmune associations with Addison's disease. Thomas Addison described the presence of pernicious anaemia and vitiligo when describing his eponymous condition. 12 Fifty per cent of patients with Addison's disease have an associated autoimmune disease with the most common being thyroid disease. 13

Addison's disease can be associated with other autoimmunity therefore if a past medical history reveals conditions such as vitiligo, thyroid disease, coeliac disease or atrophic gastritis then this raises the suspicion of another autoimmune diagnosis. The above patient had hypothyroidism and positive gastric cell antibodies. This also suggested the possibility of autoimmune polyendocrine syndrome (APS).

Autoimmune polyendocrine syndrome

APS refers to multiple endocrine gland insufficiency associated with autoimmune disease 14 ; however, it is also used to describe syndromes characterised by the association of two or more organ specific disorders. 15

There is also the presence of genetic inheritance such as autoimmune regulator (AIRE) gene in APS type I or polygenic inheritance in APS type II. 16 Neufeld and Blizzard 17 further classified this syndrome into four main types based on clinical findings, however the main two syndromes are APS types I and II.

APS type I is an autosomal recessive condition and is characterised by the associations including mainly Addison's disease, hypoparathyroidism and chronic candidiasis. However, other associated features include pernicious anaemia, atrophic gastritis, hepatitis, vitiligo and type 1 diabetes mellitus. 18

APS type II (AKA Schmidt's syndrome) is more common than type I and is associated with conditions including Addison's disease, insulin dependant diabetes mellitus and autoimmune thyroid disease. It is associated with human leucocyte antigen (HLA)—HLA DR3 and HLA DR4.

Pernicious anaemia is also found but is more common in APS type I. 7 15

Table 1 below summarises the key associations with Addison's disease and APS. 7 12–18

Table 1

Table showing the conditions associated with Addison's disease and autoimmune polyendocrine syndromes (APS) types 1 and 2

Learning points

• Addison's disease is one differential to be excluded in patients with unexplained weight loss with or without persistent vomiting.
• It is sometimes important to question previous diagnoses and management especially if symptoms persist and to look for other causes of symptoms.
• The diagnosis of Addison's involves simple blood tests however, in the acute setting; a random cortisol can sometimes provide sufficient information. If in doubt, intravenous steroids can be given if there is a high index of suspicion without blood tests.
• If left untreated Addison's disease can be potentially fatal and prompt diagnosis can avoid unnecessary hospital admissions with a crisis.
• Owing to the association between autoimmune conditions, think of associated conditions in patient's diagnosed with Addison's disease including autoimmune polyendocrine syndromes (APS).

Contributors: All authors were involved in conception and design of the article, acquisition of the data, drafting the article and revising the article for publishing.

Competing interests: None.

Patient consent: Obtained.

Provenance and peer review: Not commissioned; externally peer reviewed.