Review

Authors: Andreas Barthel, Georg Benker, Kai Berens...

Addison's disease - the traditional term for primary adrenal insufficiency (PAI) - is defined as the clinical manifestation of chronic glucocorticoid- and/or mineralocorticoid deficiency due to failure of the adrenal cortex which may result in an adrenal crisis with potentially life-threatening consequences. Even though efficient and safe pharmaceutical preparations for the substitution of endogenous gluco- and mineralocorticoids are established in therapy, the mortality in patients with PAI is still increased and the health-related quality of life (HRQoL) is often reduced.PAI is a rare disease but recent data report an increasing prevalence. In addition to the common "classical" causes of PAI like autoimmune, infectious, neoplastic and genetic disorders, other iatrogenic conditions - mostly pharmacological side effects (e. g., adrenal haemorrhage associated with anticoagulants, drugs affecting glucocorticoid synthesis, action or metabolism and some of the novel anti-cancer checkpoint inhibitors) are contributing factors to this phenomenon.Due to the rarity of the disease and often non-specific symptoms at least in the early stages, PAI is frequently not considered resulting in a delayed diagnosis. Successful therapy is mainly based on adequate patient education as a cornerstone in the prevention and management of adrenal crisis. A focus of current research is in the development of pharmacokinetically optimized glucocorticoid preparations as well as regenerative therapies.

Topics: Addison Disease; Humans

PubMed: 30562824
DOI: 10.1055/a-0804-2715

Review

Authors: E S Husebye, B Allolio, W Arlt...

Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow-up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21-hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life-threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow-up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self-adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow-up.

Topics: Acute Disease; Addison Disease; Adrenal Cortex; Adrenal Insufficiency; Algorithms; Autoantibodies; Autoimmunity; Chronic Disease; Consensus; Cortisone; Diagnosis, Differential; Drug Administration Schedule; Drug Interactions; Emergency Treatment; Europe; Female; Humans; Hydrocortisone; Male; Prednisolone; Pregnancy; Pregnancy Complications; Steroid 21-Hydroxylase

PubMed: 24330030
DOI: 10.1111/joim.12162

Review

Authors: Anette S B Wolff, Isil Kucuka, Bergithe E Oftedal...

The adrenal glands are small endocrine glands located on top of each kidney, producing hormones regulating important functions in our body like metabolism and stress. There are several underlying causes for adrenal insufficiency, where an autoimmune attack by the immune system is the most common cause. A number of genes are known to confer early onset adrenal disease in monogenic inheritance patterns, usually genetic encoding enzymes of adrenal steroidogenesis. Autoimmune primary adrenal insufficiency is usually a polygenic disease where our information recently has increased due to genome association studies. In this review, we go through the physiology of the adrenals before explaining the different reasons for adrenal insufficiency with a particular focus on autoimmune primary adrenal insufficiency. We will give a clinical overview including diagnosis and current treatment, before giving an overview of the genetic causes including monogenetic reasons for adrenal insufficiency and the polygenic background and inheritance pattern in autoimmune adrenal insufficiency. We will then look at the autoimmune mechanisms underlying autoimmune adrenal insufficiency and how autoantibodies are important for diagnosis. We end with a discussion on how to move the field forward emphasizing on the clinical workup, early identification, and potential targeted treatment of autoimmune PAI.

Topics: Humans; Addison Disease; Adrenal Insufficiency; Adrenal Glands; Autoantibodies; Kidney

PubMed: 38027140
DOI: 10.3389/fendo.2023.1285901

Review

Authors: Federica Buonocore, John C Achermann

Primary adrenal insufficiency (PAI) is a potentially life-threatening condition that requires urgent diagnosis and treatment. Whilst the most common causes are congenital adrenal hyperplasia (CAH) in childhood and autoimmune adrenal insufficiency in adolescence and adulthood, more than 30 other physical and genetics cause of PAI have been reported. Reaching a specific diagnosis can have implications for management and for monitoring associated features, as well as for counselling families about recurrence risk in siblings and relatives. Here, we describe some recent insights into the genetics of adrenal insufficiency and associated molecular mechanisms. We discuss (a) the role of the nuclear receptors DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human adrenal and reproductive dysfunction; (b) multisystem growth restriction syndromes due to gain-of-function in the growth repressors CDKN1C (IMAGE syndrome) and SAMD9 (MIRAGE syndrome), or loss of POLE1; (c) nonclassic forms of STAR and P450scc/CYP11A1 insufficiency that present with a delayed-onset adrenal phenotype and represent a surprisingly prevalent cause of undiagnosed PAI; and (d) a new sphingolipidosis causing PAI due to defects in sphingosine-1-phosphate lyase-1 (SGPL1). Reaching a specific diagnosis can have life-long implications for management. In some situations, milder or nonclassic forms of these conditions can first present in adulthood and may have been labelled, "Addison's disease."

Topics: Addison Disease; Humans

PubMed: 31610036
DOI: 10.1111/cen.14109

Authors: Aaron Michels, Nicole Michels

Primary adrenal insufficiency, or Addison disease, has many causes, the most common of which is autoimmune adrenalitis. Autoimmune adrenalitis results from destruction of the adrenal cortex, which leads to deficiencies in glucocorticoids, mineralocorticoids, and adrenal androgens. In the United States and Western Europe, the estimated prevalence of Addison disease is one in 20,000 persons; therefore, a high clinical suspicion is needed to avoid misdiagnosing a life-threatening adrenal crisis (i.e., shock, hypotension, and volume depletion). The clinical manifestations before an adrenal crisis are subtle and can include hyperpigmentation, fatigue, anorexia, orthostasis, nausea, muscle and joint pain, and salt craving. Cortisol levels decrease and adrenocorticotropic hormone levels increase. When clinically suspected, patients should undergo a cosyntropin stimulation test to confirm the diagnosis. Treatment of primary adrenal insufficiency requires replacement of mineralocorticoids and glucocorticoids. During times of stress (e.g., illness, invasive surgical procedures), stress-dose glucocorticoids are required because destruction of the adrenal glands prevents an adequate physiologic response. Management of primary adrenal insufficiency or autoimmune adrenalitis requires vigilance for concomitant autoimmune diseases; up to 50% of patients develop another autoimmune disorder during their lifetime.

Topics: Addison Disease; Adrenal Glands; Diagnosis, Differential; Hormone Replacement Therapy; Humans

PubMed: 24695602
DOI: No ID Found

Review

Authors: Magdalena J Glebocka, Alisdair Boag

PRACTICAL RELEVANCE

Addison's disease is a very rare condition in cats, with only approximately 40 cases documented in the past 40 years since it was first described in 1983.

CLINICAL CHALLENGES

While canine hypoadrenocorticism is a well-recognised disorder with clear diagnostic and treatment guidelines, feline hypoadrenocorticism remains a challenge because of its rarity and waxing and waning clinical signs. Furthermore, empirical treatment with corticosteroids, resulting in clinical improvement, contributes to delays in achieving the diagnosis and initiating treatment. Feline hypoadrenocorticism is diagnosed with an adrenocorticotropic hormone (ACTH) stimulation test; a low resting cortisol concentration with an inadequate or absent response to synthetic ACTH is diagnostic. Various ACTH stimulation-testing protocols are reported in published cases, with the majority using three time-limited blood samples. This can be limiting clinically, depending on cats' clinical presentation and behaviour at the veterinary practice and tolerance for procedures. Long-term treatment, similar to canine hypoadrenocorticism, consists of oral corticosteroids, with several formulations licensed in the UK, and mineralocorticoids (desoxycorticosterone pivalate), of which the only available formulation (Zycortal; Dechra) is licensed for dogs and its safety has not been assessed in cats.

GLOBAL IMPORTANCE

Feline hypoadrenocorticism occurs worldwide. Although no breed, sex or age association has been reported, cats aged <6 years are overrepresented.

Topics: Animals; Cats; Cat Diseases; Adrenal Insufficiency; Adrenocorticotropic Hormone; Addison Disease; Adrenal Cortex Hormones

PubMed: 39325772
DOI: 10.1177/1098612X241248381

Authors: Margret Einarsdottir, Per Dahlqvist, Sophie Bensing...

Topics: Addison Disease; Humans

PubMed: 35019146
DOI: No ID Found

Review

Authors: Stefania Marzotti, Alberto Falorni

Topics: Addison Disease; Autoantibodies; Biomarkers; Humans; Prognosis

PubMed: 15518054
DOI: 10.1080/08916930410001705466

Authors: Qiu-Hong Wang, Yang-Yang Wang, Jing Wang...

BACKGROUND

Addison's disease and X-linked adrenoleukodystrophy (X-ALD) (Addison's-only) are two diseases that need to be identified. Addison's disease is easy to diagnose clinically when only skin and mucosal pigmentation symptoms are present. However, X-ALD (Addison's-only) caused by ABCD1 gene variation is ignored, thus losing the opportunity for early treatment. This study described two patients with initial clinical diagnosis of Addison's disease. However, they rapidly developed neurological symptoms triggered by infection. After further genetic testing, the two patients were diagnosed with X-ALD.

METHODS

We retrospectively analyzed X-ALD patients admitted to our hospital. Clinical features, laboratory test results, and imaging data were collected. Whole-exome sequencing was used in molecular genetics.

RESULTS

Two patients were included in this study. Both of them had significantly increased adrenocorticotropic hormone level and skin and mucosal pigmentation. They were initially clinically diagnosed with Addison's disease and received hydrocortisone treatment. However, both patients developed progressive neurological symptoms following infectious disease. Further brain magnetic resonance imaging was completed, and the results suggested demyelinating lesions. Molecular genetics suggested variations in the ABCD1 gene, which were c.109_110insGCCA (p.C39Pfs*156), c.1394-2 A > C (NM_000033), respectively. Therefore, the two patients were finally diagnosed with X-ALD, whose classification had progressed from X-ALD (Addison's-only) to childhood cerebral adrenoleukodystrophy (CCALD). Moreover, the infection exacerbates the demyelinating lesions and accelerates the onset of neurological symptoms. Neither the two variation sites in this study had been previously reported, which extends the ABCD1 variation spectrum.

CONCLUSIONS

Patients with only symptoms of adrenal insufficiency cannot be simply clinically diagnosed with Addison's disease. Being alert to the possibility of ABCD1 variation is necessary, and complete genetic testing is needed as soon as possible to identify X-ALD (Addison's-only) early to achieve regular monitoring of the disease and receive treatment early. In addition, infection, as a hit factor, may aggravate demyelinating lesions of CCALD. Thus, patients should be protected from external environmental factors to delay the progression of cerebral adrenoleukodystrophy.

Topics: Humans; Adrenoleukodystrophy; Male; Retrospective Studies; ATP Binding Cassette Transporter, Subfamily D, Member 1; Child; Diagnostic Errors; Magnetic Resonance Imaging; Addison Disease

PubMed: 38956688
DOI: 10.1186/s13052-024-01669-y

Review

Authors: P Martín Martorell, B O Roep, J W A Smit...

Addison's disease has a low incidence and is most frequently the result of an autoimmune disease in developed countries. Addison's disease can present as an isolated entity or in combination with other autoimmune diseases: Addison's disease can be part of the distinct polyglandular autoimmune syndromes APS I and II. Autoantibodies in patients with isolated Addison's disease are directed against the enzymes involved in steroid synthesis, P45oc21, P45oscc and P45oc17. Addison's disease, both isolated and in the context of APS II, has been associated with the haplotype HLA-A1, -B8 and DR3. The value of the increased expression of these molecules on adrenocortical cells could point towards an infectious pathogenesis. Given the prevalence, up to 80 %, of autoantibodies in Addison's disease as well as the high predictive value for developing the disease when antibodies are present (41% in three years), we advise screening high-risk populations, such as patients with other autoimmune endocrinopathies or their relatives for the presence of these antibodies. The adrenocortical function of patients positive for antibodies should be followed yearly.

Topics: Addison Disease; Autoimmune Diseases; Autoimmunity; Humans; Polyendocrinopathies, Autoimmune

PubMed: 12430572
DOI: No ID Found