Addison's disease

Source:
Clinical Knowledge Summaries
Publication date:
01 March 2016

Abstract

Addison's disease Last revised in March 2016 Next planned review by December 2021 Summary Back to topAddison's disease: Summary Addison's disease (primary adrenal insufficiency) is caused by destruction of the adrenal cortex. This results in reduced production of glucocorticoids (such as cortisol), mineralocorticoids (such as aldosterone), and adrenal androgens (such as dehydroepiandrosterone).Adrenal insufficiency may also be caused by long-term administration of corticosteroids or disorders of the hypothalamus or pituitary gland, but this is not Addison's disease.In the developed world, Addison's disease is most commonly caused by autoimmune disease. Worldwide, tuberculosis is the most common cause of Addison's disease.Addison's disease is rare. About 8,400 people are currently diagnosed with Addison's disease in the UK.Diagnosis of Addison's disease is often delayed because symptoms are non-specific, common, and overlap with many other conditions.A person with Addison's disease may present with a sudden crisis precipitated by intercurrent infection or stress. Features include hypotension, hypovolaemic shock, acute abdominal pain, low-grade fever, and vomiting.Addison's disease should also be considered in a person with persistent, non-specific symptoms, such as: fatigue; hyperpigmentation; gastrointestinal symptoms; cravings for salt, soy sauce, or liquorice; musculoskeletal symptoms; or postural dizziness due to hypotension.The possibility of Addison's disease should also be considered in people with: hypothyroidism whose symptoms worsen when thyroxine is started; type 1 diabetes mellitus with recurrent unexplained hypoglycaemic episodes; other autoimmune diseases; or low sodium and high potassium levels on blood biochemistry.In adults, if adrenal insufficiency is suspected on the basis of clinical features, a serum cortisol level and urea and electrolytes should be requested. As a general guide:If the serum cortisol level is less than 100 nanomol/L, the person should be admitted to hospital. Adrenal insufficiency is highly likely.If the serum cortisol level is 100–500 nanomol/L, the person should be referred to an endocrinologist for further investigations.If the serum cortisol level is more than 400 nanomol/L, the diagnosis of Addison's disease is unlikely.If the person is acutely unwell or hypotensive, the person should be admitted to hospital. Serum cortisol values are not reliable in this situation, as they increase during illness.In children, investigations should be urgently carried out in secondary care if adrenal insufficiency is suspected. Admission to hospital may be required depending on the clinical picture and clinical judgement.The diagnosis of Addison's disease is usually confirmed in secondary care. An adrenocorticotrophic hormone stimulation (Synacthen®) test should be done.Treatment for Addison's disease is usually initiated and adjusted by a specialist endocrinologist, but repeat prescriptions may be provided in primary care under a shared care arrangement.Hydrocortisone is usually used for glucocorticoid replacement, but longer-acting glucocorticoids, such as prednisolone and dexamethasone, are sometimes used to avoid the peaks and troughs which may occur with hydrocortisone.Fludrocortisone is usually used for mineralocorticoid replacement.Dehydroepiandrosterone (unlicensed) may be prescribed by some specialists for androgen replacement.It is important for people with Addison's disease to increase their corticosteroid cover if they are under physical stress, such as illness.If an adrenal crisis is suspected, emergency admission to hospital should be arranged.Hydrocortisone intramuscularly or intravenously should be administered before transfer to hospital.Emergency administration of fludrocortisone is not required. Have I got the right topic? Back to topHave I got the right topic? From age 1 month onwards.This CKS topic is largely based on guidelines developed by the Addison's Clinical Advisory Panel on behalf of the Addison's Disease Self Help Group: Diagnosing Addison's: a guide for GPs [Addison's Clinical Advisory Panel, 2013]; Surgical guidelines for Addison's disease and other forms of adrenal insufficiency [Addison's Clinical Advisory Panel, 2014]; and Caring for the patient with Addison's: information for GPs [Addison's Clinical Advisory Panel, 2015].This CKS topic covers the management of people with primary adrenal insufficiency (Addison's disease).This CKS topic does not cover the management of people with secondary or tertiary adrenal insufficiency (due to a disorder of the hypothalamus or pituitary glands, or from long-term use of corticosteroids).There are separate CKS topics on Corticosteroids - oral, Depression, and Tiredness/fatigue in adults.The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare. How up-to-date is this topic? Back to topHow up-to-date is this topic? Back to top Changes Changes February to March 2016 — reviewed. A literature search was conducted in January 2016 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials published since the last revision of this topic. There have been minor changes to the recommendations on corticosteroid dosing during intercurrent illness, and it is now recommended that an adrenocorticotrophic hormone stimulation (Synacthen®) test should be carried out in secondary care. Back to top Previous changes Previous changes May 2014 — minor update. Change to the section on choice of hydrocortisone preparation for the treatment of adrenal crisis.October 2010 — minor update. Text regarding DHEA replacement therapy (unlicensed) reworded to reflect that this may be prescribed by some specialists. Issued in October 2010.May to September 2010 — this is a new CKS topic. The evidence-base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence. Back to top Update Update Back to top New evidence New evidence Evidence-based guidelinesNo new evidence-based guidelines since 1 March 2016.HTAs (Health Technology Assessments)No new HTAs since 1 March 2016.Economic appraisalsNo new economic appraisals relevant to England since 1 March 2016.Systematic reviews and meta-analysesNo new systematic review or meta-analysis since 1 March 2016.Primary evidenceNo new randomized controlled trials published in the major journals since 1 March 2016. Back to top New policies New policies No new national policies or guidelines since 1 March 2016. Back to top New safety alerts New safety alerts No new safety alerts since 1 March 2016. Back to top Changes in product availability Changes in product availability No changes in product availability since 1 March 2016. Goals and outcome measures Back to topGoals and outcome measures Back to top Goals Goals To support primary healthcare professionals to:Suspect Addison's disease in people with symptoms suggestive of adrenal insufficiency.Appropriately manage the person with suspected Addison's disease.Support the secondary care management plan of a person with confirmed Addison's disease and liaise with specialists when appropriate.Advise the person and their family on managing long-term replacement medication and to ensure they are aware of sick-day rules and the emergency management of an adrenal crisis.Treat an adrenal crisis and to have the appropriate drugs available. Back to top Outcome measures Outcome measures No outcome measures were found during the review of this topic. Back to top Audit criteria Audit criteria No audit criteria were found during the review of this topic. Back to top QOF indicators QOF indicators No QOF indicators were found during the review of this topic. Back to top QIPP - Options for local implementation QIPP - Options for local implementation No QIPP indicators were found during the review of this topic. Back to top NICE quality standards NICE quality standards No NICE quality standards were found during the review of this topic. Background information Back to topBackground information Back to top Definition What is it? Addison's disease (primary adrenal insufficiency) is a result of destruction of the adrenal cortex.This causes reduced production of glucocorticoids (such as cortisol), mineralocorticoids (such as aldosterone), and adrenal androgens (such as dehydroepiandrosterone).The absence of cortisol leads to increased production of adrenocorticotrophic hormone (ACTH) because negative feedback to the pituitary gland is reduced.Adrenal insufficiency may also be caused by long-term administration of corticosteroids or disorders of the hypothalamus or pituitary gland, but this is not Addison's disease.Secondary adrenal insufficiency occurs when pituitary ACTH production is insufficient; this leads to adrenal atrophy. Causes include intracranial disorders, such as pituitary tumour, subarachnoid haemorrhage, and traumatic brain injury.Tertiary adrenal insufficiency results from disruption to the production of corticotropin-releasing hormone from the hypothalamus, which affects ACTH production from the anterior pituitary. [Vaidya et al, 2009; Wallace et al, 2009; Chakera and Vaidya, 2010; Stewart, 2010] Back to top Causes What causes it? In the developed world, Addison's disease is most commonly caused by autoimmune disease, accounting for around 70–90% of cases. Of these, the adrenal gland is affected in isolation in 40% of cases, with 60% being part of a multi-organ autoimmune polyendocrine syndrome [Arlt and Allolio, 2003; Jones et al, 2008; Vaidya et al, 2009; Stewart, 2010].Worldwide, tuberculosis is the most common cause of Addison's disease [Vaidya et al, 2009].Other causes are rare, but include [Arlt and Allolio, 2003; Holcomb, 2006; Stewart, 2010]:Adrenal metastases.      Adrenal haemorrhage.Infections, such as histoplasmosis, cryptococcosis, cytomegalovirus, and HIV.Amyloidosis and haemochromatosis.Congenital adrenal hyperplasia.Bilateral adrenalectomy.Congenital or neonatal primary adrenal insufficiency (accounts for only 1% of cases).Genetic causes, particularly adrenoleukodystrophy. Back to top Prevalence How common is it? Addison's disease is rare.The prevalence is around 1 per 20,000 people in western Europe and the US [Michels, 2014], and about 8400 people are currently diagnosed with Addison's disease in the UK [Addison's Clinical Advisory Panel, 2013].The annual incidence of Addison's disease is 4 in 1,000,000 people in Western populations [Chakera and Vaidya, 2010].Addison's disease can affect all age groups, but the most common onset is at 30–50 years of age [Addison's Clinical Advisory Panel, 2013].More women than men are affected [Jones et al, 2008]. Back to top Associated conditions What conditions are associated with Addison's disease? Addison's disease is associated with other autoimmune conditions (for example hypothyroidism and type 1 diabetes mellitus) [Addison's Clinical Advisory Panel, 2013]. These affect about 50%  of people with Addison's disease [O'Connell and Siafarikas, 2010].Of people with autoimmune Addison's disease, about 60% have an autoimmune polyendocrine syndrome [Arlt and Allolio, 2003]:Polyglandular autoimmune syndrome type 1 (up to 15% of people with Addison's disease, but probably less in the UK population).Autosomal recessive.Typically presents in childhood.Triad of Addison's disease, hypoparathyroidism, and chronic candidiasis.May also be associated with type 1 diabetes mellitus, hypogonadism, pernicious anaemia, autoimmune thyroid disease, chronic active hepatitis, immunoglobulin A deficiency, chronic atopic dermatitis, keratoconjunctivitis, vitiligo, and alopecia.Polyglandular autoimmune syndrome type 2 (more common).Complex genetic trait with links to human leukocyte antigen (HLA) major histocompatibility complex (especially HLA DR3 and DR4).Usually involves Addison's disease and autoimmune thyroid disease or type 1 diabetes mellitus. Premature ovarian insufficiency may also be found.May also include vitiligo, chronic atrophic gastritis and vitamin B12 deficiency, coeliac disease, and hypoparathyroidism.[Arlt and Allolio, 2003; Jones et al, 2008; Chakera and Vaidya, 2010; Stewart, 2010; Michels, 2014] Back to top Prognosis What is the prognosis? If untreated, Addison's disease is always fatal.People with Addison's disease require lifelong treatment.Even when treated, people with Addison's disease may be at increased risk of premature death.A Swedish study prospectively followed up 1675 people with Addison's disease over an average of 6.5 years [Bergthorsdottir et al, 2006]. The risk ratio for all-cause mortality was 2.19 for men (95% CI 1.91 to 2.51) and 2.86 for women (95% CI 2.54 to 3.20). Cardiovascular disease, cancer, and infectious diseases contributed to the excess mortality.Another Swedish cohort study assessed data from 3299 people with Addison's disease over 40 years [Bensing et al, 2008]. This showed an increased standardized mortality ratio of 2.9 in women (95% CI 2.7 to 3.0) and 2.5 in men (95% CI 2.3 to 2.7). [Baker and White, 2003; Chakera and Vaidya, 2010; Addison's Clinical Advisory Panel, 2013] Back to top Complications What are the complications? The most serious complication of Addison's disease is adrenal crisis.This occurs when a person with Addison's disease experiences severe physical stress. The adrenal glands cannot supply the extra corticosteroids needed to cope with the stress, and life-threatening symptoms develop [Baker and White, 2003; Chakera and Vaidya, 2010].Even if the person is young and otherwise fit, adrenal crisis may precipitate severe dehydration, hypotension, hypovolaemic shock, altered consciousness, seizures, stroke, or cardiac arrest [Vaidya et al, 2009; O'Connell and Siafarikas, 2010; Addison's Clinical Advisory Panel, 2013]. These complications may result in death or permanent disability.Children with adrenal crisis are more susceptible to hypoglycaemia. If this is not recognized and treated, permanent brain damage can be a consequence [Addison's Clinical Advisory Panel, 2013].Quality of life may also be reduced by Addison's disease, even when treated [Reisch and Arlt, 2009].    Factors that affect quality of life include fatigue, loss of energy, depression, anxiety, reduced ability to cope with daily activities, and loss of libido (particularly in women).People with adrenal insufficiency have a reduced capacity for full-time work. Diagnosis Back to topDiagnosis of Addison's disease Back to top Suspecting Addison's disease When should I suspect Addison's disease? Diagnosis of Addison's disease is often delayed because symptoms are non-specific, common, and overlap with many other conditions.More than half of people with Addison's disease have symptoms and signs for more than 1 year before diagnosis.A person with Addison's disease may present with a sudden crisis precipitated by intercurrent infection or stress.Features include hypotension, hypovolaemic shock, acute abdominal pain, low-grade fever, and vomiting.Also consider Addison's disease in a person with persistent, non-specific symptoms, such as:Fatigue — this affects most people with Addison's disease.Hyperpigmentation (due to increased pituitary adrenocorticotrophic hormone) — this affects 92% of people with Addison's disease, particularly in sun-exposed areas, recent scars, pressure points, areas of friction, palmar creases, and mucous membranes.Gastrointestinal symptoms — weight loss; loss of appetite and premature satiety; nausea and vomiting; abdominal pain; cravings for salt, soy sauce, or liquorice.Musculoskeletal symptoms — muscle weakness and cramps; joint pains.Cardiovascular symptoms — postural dizziness due to hypotension (blood pressure decrease of 20 mmHg between sitting and standing measurements).Other symptoms — headache, low-grade fever, increased thirst or urination, loss of axillary or pubic hair in women, delayed puberty in children.In addition, consider the possibility of Addison's disease in people with:Hypothyroidism whose symptoms worsen when levothyroxine is started.Type 1 diabetes mellitus who experience recurrent unexplained hypoglycaemic episodes.Other autoimmune diseases, such as vitiligo, pernicious anaemia, chronic active hepatitis, alopecia, and coeliac disease.Hyponatraemia and hyperkalaemia on blood biochemistry — hyponatraemia is present in 90% and hyperkalaemia in 65% of people with established Addison's disease. However, these abnormalities are not diagnostic of Addison's disease, as electrolytes may be borderline or normal if the person is not in crisis. Back to top Basis for recommendation Basis for recommendation Delay in diagnosisThe statement that the diagnosis of Addison's disease is often delayed is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013] and expert opinion in review articles [Vaidya et al, 2009; Michels, 2014; Nenke and Torpy, 2014]. Clinical features of Addison's diseaseThe information on clinical features of Addison's disease is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013] and expert opinion in review articles [Arlt and Allolio, 2003; Dorin et al, 2003; Jones et al, 2008; Vaidya et al, 2009; Chakera and Vaidya, 2010; O'Connell and Siafarikas, 2010; Michels, 2014; Nenke and Torpy, 2014]. Back to top Differential diagnosis What else might it be? Symptoms of Addison's disease may mimic:Acute abdomen — severe dehydration, circulatory shock, nausea, vomiting, and abdominal pain of an adrenal crisis can be mistaken for an acute abdominal emergency.Gastroenteritis — nausea and vomiting are key features of adrenal crisis. For more information, see the CKS topic on Gastroenteritis.Depression — chronic fatigue, malaise, and anorexia may mimic depression. It is not uncommon for the symptoms of Addison's disease to be wrongly diagnosed as mental health problems. If Addison's disease is not recognized, an adrenal crisis may be precipitated by antidepressant drug treatment, as some antidepressants are sodium depleting. For more information, see the CKS topic on Depression.Eating disorders — unintentional weight loss, nausea, vomiting, and vague abdominal pain may be confused with symptoms of an eating disorder. For more information, see the CKS topic on Eating disorders.Type 1 diabetes mellitus — fatigue, unexplained weight loss, and thirst may occur in either condition. However, blood glucose is usually normal or low in adrenal failure. For more information, see the CKS topic on Diabetes - type 1.Chronic fatigue syndrome — fatigue is a predominant feature in many people with Addison's disease. For more information, see the CKS topic on Tiredness/fatigue in adults.Hyperemesis and chloasma of pregnancy — symptoms of Addison's disease may be attributed to vomiting and pigment changes associated with pregnancy. For more information see the CKS topic on Nausea/vomiting in pregnancy. Back to top Basis for recommendation Basis for recommendation This information on differential diagnosis is based on the expert opinion of the Addison's Disease Self Help Group [Addison's Clinical Advisory Panel, 2013] and expert opinion in review articles [Vaidya et al, 2009; Chakera and Vaidya, 2010]. Back to top Investigations - suspected adrenal insufficiency How should I investigate suspected adrenal insufficiency in primary care? In adults, if adrenal insufficiency is suspected on the basis of clinical features, request a serum cortisol level and urea and electrolytes.The serum cortisol level should ideally be obtained at 8–9 am. Random serum cortisol levels have a low sensitivity for Addison's disease because there is a diurnal variation in cortisol levels (highest in the early morning and lowest late in the evening).Sodium levels may be low and potassium levels high in Addison's disease, but normal serum sodium and potassium levels do not exclude the diagnosis. Seek specialist advice if there is electrolyte disturbance.Seek specialist advice from an endocrinologist before obtaining a serum cortisol level in: People who work shifts — it is uncertain when the best time to obtain a serum cortisol level is, and interpretation of the results can be difficult. An adrenocorticotrophic hormone stimulation (Synacthen) test may be required.People receiving long-term corticosteroid treatment — interpretation of results can be difficult, and an adrenocorticotrophic hormone stimulation (Synacthen) test may be required.People receiving oestrogen treatment — results may be difficult to interpret because oestrogens increase hepatic production of cortisol-binding globulin, and therefore increase cortisol levels.When interpreting cortisol results, be aware that laboratories use many different assays, so check local reference ranges. As a general guide, if the serum cortisol level is:Less than 100 nanomol/L, admit the person to hospital. Adrenal insufficiency is highly likely.100–500 nanomol/L, refer the person to an endocrinologist for further investigations, including an adrenocorticotrophic hormone stimulation (Synacthen) test. The urgency of referral depends on the severity of symptoms and the serum cortisol level. Postural hypotension and/or electrolyte disturbance are indications for urgent referral or admission.If the person is acutely unwell or hypotensive, admit to hospital. Serum cortisol values are not reliable, as they increase during illness.In children, urgently arrange for investigations to be carried out in secondary care if adrenal insufficiency is suspected. Admission to hospital may be required depending on the clinical picture — use clinical judgement. Back to top Basis for recommendation Basis for recommendation Checking the serum cortisol levelThese recommendations are largely based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013] and expert opinion in review articles [Oelkers, 1996; Arlt and Allolio, 2003; Vaidya et al, 2009; Wallace et al, 2009; Michels, 2014].Shift workers — CKS found no guidelines or published expert opinion on when to test shift workers and how to interpret the results. This recommendation is based on expert opinion from previous reviewers of this CKS topic.People receiving long-term corticosteroid treatment — CKS found no guidelines or published expert opinion on when to test people on long-term corticosteroid treatment and how to interpret the results. This recommendation is based on expert opinion from previous reviewers of this CKS topic.People receiving oestrogen treatment — this advice is extrapolated from expert opinion in review articles [Oelkers, 1996; Arlt and Allolio, 2003; Wallace et al, 2009].Checking electrolyte levelsThe recommendation to check electrolyte levels is based on advice from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013] and previous expert reviewers of this CKS topic. Typical findings in Addison's disease are a low sodium level and high potassium level, although if the person is not in adrenal crisis, electrolyte levels may be borderline or normal [Addison's Clinical Advisory Panel, 2013].Checking local reference ranges of cortisol levelsExpert opinion in a review article on the diagnosis and investigation of adrenal insufficiency is that the use of serum cortisol levels in the evaluation of possible adrenal insufficiency is limited by methodological imprecision, accuracy, lack of standardization, and choice of cut-off limits. Ideally, the cut-off should be determined based on the local assay method [Wallace et al, 2009].Arranging admission to hospitalThe recommendation to admit to hospital if the cortisol level is less than 100 nanomol/L is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013].The Addison's Clinical Advisory Panel states that if a person is unwell, the diagnosis of adrenal insufficiency cannot be excluded by a normal serum cortisol level; and if the person is hypotensive and vomiting an immediate and urgent referral is required [Addison's Clinical Advisory Panel, 2013]. CKS therefore recommends admission to hospital in this situation.Endocrinology referralExpert opinion varies regarding the serum cortisol level at which adrenal insufficiency can be excluded.The Addison's Clinical Advisory Panel suggests that adrenal insufficiency is unlikely if the 8–9 am serum cortisol level is more than 400 nanomol/L and that further testing should be undertaken for people with a serum cortisol level of 100–400 nanomol/L [Addison's Clinical Advisory Panel, 2013]. Other experts suggest a cut-off value of around 500 nanomol/L [Arlt and Allolio, 2003; Wallace et al, 2009].Taking this information and the expert opinion of previous reviewers of this topic into account, CKS recommends referral if the serum cortisol level is 100–500 nanomol/L. Back to top Confirming the diagnosis How is the diagnosis of Addison's disease confirmed? The diagnosis of Addison's disease is usually confirmed in secondary care.For adults, refer the person to a specialist endocrinology unit.For children, urgently refer to a paediatrician (preferably one with an interest in endocrinology).An adrenocorticotrophic hormone stimulation (Synacthen) test should be done in secondary care to confirm the diagnosis, as it has a high sensitivity in Addison's disease.Other tests that can help differentiate primary from secondary adrenal insufficiency include:Adrenocorticotrophic hormone (ACTH) levels — serum ACTH levels are high in Addison's disease (primary adrenal insufficiency) but are low in secondary adrenal insufficiency.Plasma renin and aldosterone levels — renin levels are typically high and aldosterone levels low in Addison's disease. In secondary adrenal insufficiency, the renin-angiotensin system can function normally. Back to top Adrenocorticotrophic hormone stimulation (Synacthen®) test Adrenocorticotrophic hormone stimulation (Synacthen®) test For the adrenocorticotrophic hormone (ACTH) stimulation (Synacthen®) test (usually done in secondary care):Blood samples are obtained to check serum cortisol levels before and 30 minutes after administering 250 micrograms of tetracosactide (a synthetic analogue of ACTH) intravenously or intramuscularly.This test can be performed at any time of day, as the post-stimulation value is used for diagnostic purposes.A normal response to the ACTH stimulation test is an increase in the serum cortisol level.  In people with normal adrenal reserve, cortisol levels increase to more than 500–550 nanomol/L after 30 or 60 minutes.In people with adrenal insufficiency, serum cortisol levels do not increase adequately in response to tetracosactide because the adrenal cortex is already receiving maximum stimulation from endogenous ACTH.[Arlt and Allolio, 2003; Bornstein, 2009; Vaidya et al, 2009; Wallace et al, 2009; Chakera and Vaidya, 2010] Back to top Additional investigations in secondary care Additional investigations in secondary care Additional investigations to determine the cause of adrenal insufficiency may include:Autoantibody levels — adrenal cortex autoantibodies or antibodies against 21-hydroxylase are present in more than 80% of people with recent-onset autoimmune adrenalitis.Imaging — computed tomography (CT) or magnetic resonance imaging (MRI) is not usually required if autoimmune adrenalitis is likely, but it may be requested if tuberculosis or other infection, haemorrhage, infiltration, or neoplastic disease is suspected. [Arlt and Allolio, 2003; Marzotti and Falorni, 2004; Jones et al, 2008; Michels, 2014] Back to top Basis for recommendation Basis for recommendation Confirmation of the diagnosis of Addison's disease in secondary careCKS recommends that the diagnosis of Addison's disease in adults should be confirmed in secondary care, based on expert opinion from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013] and a review article [O'Connell and Siafarikas, 2010].CKS considers it good clinical practice that children be referred to a paediatrician for further investigation, because the time and expertise to perform and interpret these tests in children are not available in primary care.Choice of tests to confirm the diagnosis The adrenocorticotrophic hormone (ACTH) stimulation (Synacthen®) test is widely recommended by experts because it has a high sensitivity in Addison's disease (primary adrenal insufficiency) [Dorin et al, 2003; Wallace et al, 2009].Expert opinion in review articles also suggests that ACTH levels and plasma renin and aldosterone levels may be useful for differentiating primary from secondary adrenal insufficiency [Arlt and Allolio, 2003; Vaidya et al, 2009; Wallace et al, 2009]. Management Back to topManagement Scenario: Management: covers self-care advice, maintenance treatment (usually initiated in secondary care) and its monitoring, follow up, adjustment of corticosteroid doses to cover medical and dental procedures, and the emergency management of an adrenal crisis. Back to top Scenario: Management Scenario: Management From age 1 month onwards. Back to top Treatment How is Addison's disease treated? Treatment regimens for Addison's disease are usually initiated and adjusted by a specialist endocrinologist, but repeat prescriptions may be provided in primary care under a shared-care arrangement. Both glucocorticoid and mineralocorticoid replacement are needed, but androgen replacement is not routinely prescribed in the UK.Glucocorticoid replacement — hydrocortisone is usually used, but longer-acting glucocorticoids, such as prednisolone and dexamethasone, are sometimes used to avoid the peaks and troughs which may occur with hydrocortisone.The daily adult dosage of hydrocortisone is usually 15–30 mg in divided doses. Dosage depends on body weight, metabolism, and absorption.Ideally glucocorticoid replacement should resemble the natural cycle of corticosteroid release. Three divided doses are usually given (for example 10 mg on waking, 5 mg at noon, and 5 mg in the early evening), as this aims to provide even levels of glucocorticoid throughout the day. Two divided doses are also an option (for example 15 mg in the morning, and 10 mg in the afternoon or early evening), but this may lead to more variation in cortisol levels.For people doing shift work, doses of glucocorticoid should follow the person's daily routine, not the time on the clock. For example, the first dose should be given on getting up after sleep, even if this is not in the morning.Dosages in children are usually in the region of 8–10 mg/m2 daily in three divided doses, although the total daily dose may be divided into a larger morning dose and a smaller evening dose.Mineralocorticoid replacement — fludrocortisone, which has 125 times the mineralocorticoid action of hydrocortisone, is usually used.The daily adult dosage of fludrocortisone is usually 50–300 micrograms. Dosage depends on metabolism and exercise levels.Children have a much higher mineralocorticoid requirement (dosage depends on the age and weight of the child and the severity of the condition), and they may need salt supplementation.At high temperatures and humidity, the fludrocortisone dose may need to be increased to compensate for the increased salt loss from sweating.Androgen replacement — dehydroepiandrosterone (DHEA) is an androgen made in the adrenal cortex; therefore, levels are decreased in Addison's disease. DHEA replacement (unlicensed) may be prescribed by some specialists. Back to top Basis for recommendation Basis for recommendation Glucocorticoid replacementThe dosage information for glucocorticoid replacement is based on expert opinion in the British National Formulary (BNF) and the BNF for children [BNF 70, 2015; BNF for Children, 2015], a review article [Vaidya et al, 2009], and information for GPs from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015].The suggested regimens vary among sources but are based on expert opinion from review articles [Arlt and Allolio, 2003; Reisch and Arlt, 2009; Chakera and Vaidya, 2010; Michels, 2014], the Oxford textbook of medicine [Stewart, 2010], and expert opinion from previous reviewers of this CKS topic.The information on shift work is based on expert opinion in a review article [Reisch and Arlt, 2009].Mineralocorticoid replacementThe dosage information for mineralocorticoid replacement is based on the manufacturer's Summary of Product Characteristics for fludrocortisone [ABPI Medicines Compendium, 2015], expert opinion in the BNF [BNF 70, 2015],  and in review articles  [Reisch and Arlt, 2009; Nenke and Torpy, 2014], and information for GPs from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015].The information on children and neonates, and dosage changes at high temperatures or humidity are based on expert opinion in a review article [Reisch and Arlt, 2009].Androgen replacementThe information on dehydroepiandrosterone is based on expert opinion in review articles [Arlt and Allolio, 2003; Jones et al, 2008; Reisch and Arlt, 2009; Chakera and Vaidya, 2010; Michels, 2014]. Some studies suggest that it has a small beneficial effect on well-being and mood, particularly in women, but other studies suggest little effect [Alkatib et al, 2009]. DHEA is not available as a licensed medicinal product in the UK, but can be prescribed as an unlicensed product. Back to top Self-care advice What self-care advice should I give a person with Addison's disease? Ensure that the person with Addison's disease and their family or carers (if appropriate) are aware of:The need for lifelong glucocorticoid replacement treatment and the potentially life-threatening complications which may arise with inadequate glucocorticoid replacement, especially at times of illness and physical stress.How to adjust their replacement steroid medication during periods of illness (including fever), injury, or strenuous exercise. For more information, see the section on Intercurrent illness - adjustment of steroid dose.How to recognize the symptoms of an adrenal crisis and how to give intramuscular hydrocortisone in an emergency (a family member should also know how to do this). Clear instructions and pictures of how to self inject are available on the Addison's Disease Self Help Group website.The need to make the team responsible for their care aware that they may need extra glucocorticoid replacement if they are undergoing a procedure such as surgery, dental treatment, or endoscopy.The importance of carrying emergency information on their person, for example:MedicAlert® identification — this allows healthcare professionals to access a 24-hour helpline for more information on a person's condition in an emergency if they are not able to give information themselves.Steroid treatment card — this alerts healthcare professionals that the person is on steroid treatment which should not be stopped suddenly.Emergency crisis letter — the Addison's Disease Self Help Group website provides a letter for healthcare professionals that people with Addison's disease can carry with them in case of medical emergency. This is available in a variety of languages for people travelling abroad.Advise the person that:They are entitled to receive their medication free of charge. It is important to renew prescriptions in good time to avoid running out of medication.When travelling, they should take extra medication plus an emergency hydrocortisone injection kit. It may be necessary to supply a doctor's note for airport security explaining the need for medication, needles, and syringes in hand luggage.The Addison's Disease Self Help Group provides a manual for people with Addison's disease, covering issues including medication, diet, exercise, pregnancy, looking after children with Addison's disease, travelling, and managing adrenal crisis. This is available on their website: www.addisons.org.uk. Back to top Basis for recommendation Basis for recommendation Advice on managing medication and adrenal crisisThis recommendation is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2014; Addison's Clinical Advisory Panel, 2015] and review articles [Jones et al, 2008; Chakera and Vaidya, 2010].Carrying emergency informationThis recommendation is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2013], and review articles  [Jones et al, 2008; Chakera and Vaidya, 2010; O'Connell and Siafarikas, 2010; Wass and Arlt, 2012].Advice on prescriptions and travelThe recommendations on prescriptions and travel advice are based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015]. Back to top Follow up How should I follow up a person with Addison's disease? Follow up will usually be shared between primary and secondary care.Ensure that the following areas are covered by primary or secondary care:Asking about any symptoms and general well-being.Reinforcing self-care advice, including how to increase corticosteroid cover during intercurrent illness or exercise.Providing hydrocortisone for injection with needles and syringes to treat adrenal crisis.Screening for other autoimmune disorders (such as pernicious anaemia, type 1 diabetes mellitus, and thyroid dysfunction), if Addison's disease is caused by an autoimmune process.In women of childbearing potential, asking about the regularity of their menstrual cycle to check for premature ovarian failure.For monitoring of medication:Treatment dose changes are made under specialist supervision, on the basis of clinical response. There are no objective measures for assessing the effectiveness of treatment.When reviewing a person with Addison's disease in primary care, look for clinical features of:Over-replacement — such as hypertension, thin skin, striae, easy bruising, impaired glucose regulation or hyperglycaemia, electrolyte abnormalities.Under-replacement — ongoing symptoms of Addison's disease, including fatigue, postural hypotension, nausea, weight loss, and salt craving.If over- or under-replacement is suspected, seek specialist advice from an endocrinologist, the urgency depending on clinical judgement. Back to top Basis for recommendation Basis for recommendation Primary care follow upCKS found no trial evidence on the primary care follow up of people with Addison's disease. The recommendations on considerations at follow up are based on expert opinion in a review article [Chakera and Vaidya, 2010].Checking for features of over- or under-replacement of corticosteroid medicationThis recommendation is based on expert opinion in review articles [Jones et al, 2008; Chakera and Vaidya, 2010]The features of over- and under-replacement with corticosteroid medication are based on expert opinion in review articles [Coursin and Wood, 2002; Reisch and Arlt, 2009]. Back to top Suspected adrenal crisis - management How should I manage a suspected adrenal crisis? If an adrenal crisis is suspected, arrange emergency admission to hospital. Do not delay admission by doing diagnostic tests.Give the person hydrocortisone intramuscularly or intravenously (if not already self-administered) and stabilise with an intravenous saline infusion (if available) before transfer to hospital.The preferred formulations of hydrocortisone are:Hydrocortisone sodium phosphate (Efcortesol®). This is licensed for the treatment of adrenal crisis and may be more suitable for self-injection kits because it is a solution and does not require reconstitution. However, there is a risk of pain and paraesthesia on intravenous injection and it is not recommended for use in children.Hydrocortisone sodium succinate (Solu-Cortef®). This is licensed for treating adrenal crisis, but it is in powder form requiring reconstitution and so may be less suitable.Do not use hydrocortisone acetate injection to treat an adrenal crisis.The dose of hydrocortisone depends on the person's age.Adults: 100 mg.Children 6 years of age or older: 50 mg to 100 mg (use clinical judgement depending on the age and size of the child).Children 1–5 years of age: 50 mg.Infants up to 1 year of age: 25 mg.Emergency administration of fludrocortisone is not required because high-dose hydrocortisone has a mineralocorticoid effect. Back to top Basis for recommendation Basis for recommendation Arranging emergency admission to hospitalThe recommendation to admit a person with suspected adrenal crisis to hospital as an emergency is based on the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015] and expert opinion in review articles [O'Connell and Siafarikas, 2010; Nenke and Torpy, 2014].Hydrocortisone injectionsThe choice of hydrocortisone preparation to treat suspected adrenal crisis is based on the manufacturers' Summaries of Product Characteristics (SPCs) for Efcortesol® [ABPI Medicines Compendium, 2014a] and Solu-Cortef® [ABPI Medicines Compendium, 2016], the expert opinion of the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015], the British National Formulary (BNF) [BNF 70, 2015] and the BNF for children [BNF for Children, 2015], and expert opinion in a review article [Jones et al, 2008].Hydrocortisone acetate injection is not recommended for the treatment of adrenal crisis because it is indicated for local treatment (intra-articular or peri-articular injection) of arthritic conditions and is not suitable for the production of systemic effects[ABPI Medicines Compendium, 2014b].The emergency dose for adults is widely recommended by experts, including the Addison's Disease Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015].CKS has extrapolated recommendations on emergency hydrocortisone doses for children from the BNF [BNF 70, 2015] and the SPC for Efcortesol® [ABPI Medicines Compendium, 2014a]. These are supported by expert opinion from previous reviewers of this CKS topic, particularly regarding the dose for children 6 years of age and older. Intravenous doses are recommended in the SPC, but for adults it states that intramuscular injection can be used, although the response is likely to be less rapid [ABPI Medicines Compendium, 2014a]. Expert opinion from previous reviewers of this CKS topic also supports the use of intramuscular injection in children.FludrocortisoneThe recommendation that fludrocortisone is not required in an emergency is based on expert opinion in a review article [Nenke and Torpy, 2014]. Back to top Medical and dental procedures - additional steroid cover How should I advise a person with Addison's disease who is to undergo a medical or dental procedure? Ensure that if the person is undergoing surgery, endoscopy, or dental treatment, the team responsible for their care are aware that extra glucocorticoid replacement may be required.Glucocorticoid cover for major surgery will be managed by the hospital. For primary care procedures, the Addison's Clinical Advisory Panel advise:Minor surgical procedures (for example skin lesion excision with local anaesthetic) — pre-operative glucocorticoid cover is not usually needed. An extra dose is only needed after the procedure if the person experiences hypoadrenal symptoms.Dental surgery without general anaesthetic (for example root canal work with local anaesthetic). The glucocorticoid dose should be doubled (up to 20 mg hydrocortisone) 1 hour before surgery. After the procedure, the dose of oral medication should be doubled for 24 hours, then returned to the normal dose.Minor dental procedures (for example replacement filling) — extra glucocorticoid is not usually needed. An extra dose is only needed after the procedure if the person experiences hypoadrenal symptoms.For more detailed information on corticosteroid cover for procedures (including investigations such as endoscopy, and major surgery), see the information published by the Addison's Disease Self Help Group on Glucocorticoid medication requirements for surgery and dentistry. Back to top Basis for recommendation Basis for recommendation The advice for people undergoing medical or dental procedures is based on expert opinion in guidelines from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2014; Addison's Clinical Advisory Panel, 2015]. Back to top Intercurrent illness - adjustment of steroid dose How should the corticosteroid dose be adjusted during intercurrent illness or exercise to prevent adrenal crisis? It is important for people with Addison's disease to increase their corticosteroid cover if they are under physical stress, such as during a period of illness or strenuous exercise, to reduce the risk of adrenal crisis. It is difficult to accurately predict the needs of each person, but as a guide for adults (for children, seek advice from their specialist):The person should double the normal dose of hydrocortisone (or alternative glucocorticoid) if they have a fever or are prescribed antibiotics for an infection until they are recovered.The person should take 20 mg hydrocortisone orally and sip oral rehydration solution (such as Dioralyte®) if they experience severe nausea (often with headache). If they are taking an alternative glucocorticoid (such as dexamethasone or prednisolone), consult their care plan, or seek advice from an endocrinologist regarding the dose.If the person has vomited, they should use their emergency hydrocortisone injection and seek immediate medical advice, emphasizing that it is an Addison's disease emergency — early self-administration of hydrocortisone intramuscularly will often stabilize an episode of vomiting or diarrhoea.After major injury, the person should take 20 mg hydrocortisone orally. If they are taking an alternative glucocorticoid (such as dexamethasone or prednisolone), consult their care plan, or seek advice from an endocrinologist regarding the dose.If the person has diarrhoea, seek specialist advice from their endocrinologist as to whether the glucocorticoid dose needs to be adjusted.If the person is undertaking strenuous exercise (such as a marathon), they will need to increase their medication. Up to double the normal dose of glucocorticoid and mineralocorticoid and increasing fluid intake is suggested.If a less strenuous activity (such as hiking) is being undertaken, the person should add 5 mg to 10 mg hydrocortisone to their normal regimen shortly before the activity. If they are taking an alternative glucocorticoid (such as dexamethasone or prednisolone), consult their care plan, or seek advice from an endocrinologist regarding the dose. Back to top Basis for recommendation Basis for recommendation CKS found no trial evidence on adjusting the dose of corticosteroid during intercurrent illness; therefore, this recommendation is mainly based on expert opinion from the Addison's Clinical Advisory Panel [Addison's Clinical Advisory Panel, 2015]. In addition:The recommendation that glucocorticoid cover for infection or sepsis should be doubled until the person is recovered is also based on expert opinion from review articles [Reisch and Arlt, 2009; Wass and Arlt, 2012].CKS found no evidence on whether to increase the dose of glucocorticoid if the person has diarrhoea, and expert opinion from previous reviewers of this CKS topic was divided. CKS therefore recommends seeking specialist advice from an endocrinologist in this situation.The recommendation on steroid cover for less strenuous activities is based on expert opinion in a review article [Arlt and Allolio, 2003]. Supporting evidence Back to topSupporting evidence This CKS topic is largely based on the expert opinion of the Addison's Clinical Advisory Panel in the guidelines: Diagnosing Addisons: a guide for GPs [Addison's Clinical Advisory Panel, 2013], Surgical guidelines for Addison's disease and other forms of adrenal insufficiency [Addison's Clinical Advisory Panel, 2014], and Caring for the patient with Addison's: information for GPs [Addison's Clinical Advisory Panel, 2015]. The rationale for individual recommendations in this topic is discussed in the relevant basis for recommendation sections. How this topic was developed Back to topHow this topic was developed This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website. Back to top Search strategy Search strategy Scope of searchA literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of Addison's disease.Search datesApril 2010 - February 2016.Key search termsVarious combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.Addisons disease/, addisons.tw.Sources of guidelines National Institute for Health and Care Excellence (NICE) Scottish Intercollegiate Guidelines Network (SIGN) Royal College of Physicians Royal College of General Practitioners Royal College of Nursing NICE Evidence Health Protection Agency World Health Organization National Guidelines Clearinghouse Guidelines International Network TRIP database GAIN NHS Scotland National Patient Pathways New Zealand Guidelines Group Agency for Healthcare Research and Quality Institute for Clinical Systems Improvement National Health and Medical Research Council (Australia) Royal Australian College of General Practitioners British Columbia Medical Association Canadian Medical Association Alberta Medical Association University of Michigan Medical School Michigan Quality Improvement Consortium Singapore Ministry of Health National Resource for Infection Control Patient UK Guideline links UK Ambulance Service Clinical Practice Guidelines RefHELP NHS Lothian Referral Guidelines Medline (with guideline filter) Driver and Vehicle Licensing Agency NHS Health at Work(occupational health practice)Sources of systematic reviews and meta-analyses The Cochrane Library: Systematic reviews Protocols Database of Abstracts of Reviews of Effects Medline (with systematic review filter) EMBASE (with systematic review filter)Sources of health technology assessments and economic appraisals NIHR Health Technology Assessment programme The Cochrane Library: NHS Economic Evaluations Health Technology Assessments Canadian Agency for Drugs and Technologies in Health International Network of Agencies for Health Technology AssessmentSources of randomized controlled trials The Cochrane Library: Central Register of Controlled Trials Medline (with randomized controlled trial filter) EMBASE (with randomized controlled trial filter)Sources of evidence based reviews and evidence summaries Bandolier Drug & amp; Therapeutics Bulletin TRIP database Central Services Agency COMPASS Therapeutic NotesSources of national policy Department of Health Health Management Information Consortium(HMIC)Patient experiences Healthtalkonline BMJ - Patient Journeys Patient.co.uk - Patient Support GroupsSources of medicines informationThe following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content. British National Formulary(BNF) electronic Medicines Compendium(eMC) European Medicines Agency(EMEA) LactMed Medicines and Healthcare products Regulatory Agency(MHRA) REPROTOX Scottish Medicines Consortium Stockley's Drug Interactions TERIS TOXBASE Micromedex UK Medicines Information Back to top Stakeholder engagement Stakeholder engagement Our policyThe external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:Clinical accuracy.Consistency with other providers of clinical knowledge for primary care.Accuracy of implementation of national guidance (in particular NICE guidelines).Usability.Principles of the consultation processThe process is inclusive and any individual may participate.To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.External reviewers are not paid for commenting on the draft topics.Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.All reviewers are invited to be acknowledged on the website.All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.StakeholdersKey stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.Stakeholders identified from the following groups are invited to review draft topics:Experts in the topic area.Professional organizations and societies(for example, Royal Colleges).Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer's Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.Guideline development groups where the topic is an implementation of a guideline.The British National Formulary team.The editorial team that develop MeReC Publications.Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.Patient engagementClarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:Topic selectionScoping of topicSelection of clinical scenariosFirst draft internal reviewSecond draft internal reviewExternal reviewFinal draft and pre-publicationOur lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals. Back to top Evidence exclusion criteria Evidence exclusion criteria Our policyScoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.Standard exclusions for scoping literature:Animal studiesOriginal research is not written in EnglishPossible exclusions for reviewed literature:Sample size too small or study underpoweredBias evident or promotional literaturePopulation not relevantIntervention/treatment not relevantOutcomes not relevantOutcomes have no clear evidence of clinical effectivenessSetting not relevantNot relevant to UKIncorrect study typeReview articleDuplicate reference Back to top Organizational, behavioural and financial barriers Organizational, behavioural and financial barriers Our policyThe CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.FeasibilityStudies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.Organizational and Financial Impact AnalysisStudies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.Eligible populationCurrent interventionsLikely uptake of new intervention or recommendationCost of the current or new intervention mixImpact on other costsCondition-related costsIn-direct costs and service impactsTime dependenciesCost-effectiveness or cost-benefit analysis studies are identified where available. We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation. Back to top Declarations of interest Declarations of interest Our policyClarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:Personal financial interestsPersonal family interestPersonal non-financial interestNon-personal financial gain or benefitAlthough particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons.An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.Who should declare competing interests?Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.Competing interests declared for this topic:None. References Back to topReferences ABPI (2014a) SPC for hydrocortisone 100 mg/mL or 500 mg/mL injection. Electronic Medicines Compendium. Datapharm Communications Ltd.. www.medicines.org.uk [Free Full-text] ABPI (2014b) SPC for Hydrocortistab injection 25 mg/mL. Datapharm Communications Ltd.. www.medicines.org.uk [Free Full-text] ABPI (2015) SPC for fludrocortisone acetate 0.1 mg tablets. Electronic Medicines Compendium. Datapharm Communications Ltd.. www.medicines.org.uk [Free Full-text] ABPI (2016) SPC for Solu-Cortef. Electronic Medicines Compendium. Datapharm Communications Ltd.. www.medicines.org.uk [Free Full-text] Wass, J., Howlett, T., Arlt, W., et al. (2013) Diagnosing Addison's: a guide for GPs. Addison's Self Help Group.. www.addisons.org.uk [Free Full-text] Wass, J., Howlett, T., Arlt, W. and Pearce, S. (2014) Surgical guidelines for Addison's disease and other forms of adrenal insufficiency. Addison's Self Help Group.. [Free Full-text] Wass, J., Howlett, T., Arlt, W., et al. (2015) Caring for the patient with Addison's: information for GPs. Addison's Self Help Group.. www.addisons.org.uk [Free Full-text] Alkatib,A.A., Cosma,M., Elamin,M.B., et al. (2009) A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. Journal of Clinical Endocrinology Metabolism. 94(10), 3676-3681. [Abstract] Arlt,W. and Allolio,B. (2003) Adrenal insufficiency. Lancet. 361(9372), 1881-1893. [Abstract] Baker, S. and White, K. (2003) Living with Addison's disease - an owner's manual for individuals with the condition.. www.addisons.org.uk/ [Free Full-text] Bensing,S., Brandt,L., Tabaroj,F., et al. (2008) Increased death risk and altered cancer incidence pattern in patients with isolated or combined autoimmune primary adrenocortical insufficiency. Clinical Endocrinology. 69(5), 697-704. [Abstract] Bergthorsdottir,R., Leonsson-Zachrisson,M., Oden,A. and Johannsson,G. (2006) Premature mortality in patients with Addison's Disease: a population-based study. Journal of Clinical Endocrinology & Metabolism. 91(112), 4879-4853. [Abstract] BNF 70 (2015) British National Formulary.70th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. BNF for Children (2015) British National Formulary for Children 2015-2016.London: British Medical Association and the Royal Pharmaceutical Society of Great Britain. Bornstein,S.R. (2009) Predisposing factors for adrenal insufficiency. New England Journal of Medicine. 360(22), 2328-2339. Chakera,A.J. and Vaidya,B. (2010) Addison disease in adults: diagnosis and management. American Journal of Medicine. 123(5), 409-413. [Abstract] Coursin,D.B. and Wood,K.E. (2002) Corticosteroid supplementation for adrenal insufficiency. Journal of the American Medical Association. 287(2), 236-240. Dorin,R.I., Qualls,C.R. and Crapo,L.M. (2003) Diagnosis of adrenal insufficiency. Annals of Internal Medicine. 139(3), 194-204. Holcomb,S.S. (2006) Do the clues add up to Addison's disease?. Hospital Nursing. 36(3), 1-4. Jones,D.A., Miras,A. and Tringham,J.R. (2008) Addison's disease: a diagnostic challenge. British Journal of Hospital Medicine. 69(12), 192-195. Marzotti,S. and Falorni,A. (2004) Addison's disease. Autoimmunity. 37(4), 333-336. Michels, A. and Michels, N. (2014) Addison Disease: Early Detection and Treatment Principles. American Family Physician. 89(7), 563-568. [Abstract] Nenke, M. and Torpy, D. (2014) Addison's disease. Managing 'sick days' to avoid crises. Endocrinology Today. 3(1), 26-31. O'Connell, S. and Siafarikas, A. (2010) Addison disease diagnosis and initial management. Australian Family Physician. 39(11), 834-837. [Abstract] Oelkers,W. (1996) Adrenal insufficiency. New England Journal of Medicine. 335(16), 1206-1212. Reisch,N. and Arlt,W. (2009) Fine tuning for quality of life: 21st century approach to treatment of Addison's disease. Endocrinology & Metabolism Clinics of North America. 38(2), 407-418. [Abstract] Stewart,P.M. (2010) Oxford textbook of medicine. In: Warrell,D.A., Cox,T.M., Firth,J.D. (Eds.) Adrenal disorders.Oxford: Oxford University Press., 1869-1900. Vaidya,B., Chakera,A.J. and Dick,C. (2009) Addison's disease. BMJ. 339, b2385. Wallace,I., Cunningham,S. and Lindsay,J. (2009) The diagnosis and investigation of adrenal insufficiency in adults. Annals of Clinical Biochemistry. 46(5), 351-367. [Abstract] Wass, J. and Arlt, W. (2012) How to avoid precipitating an acute adrenal crisis. British Medical Journal. 345. [Abstract]