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See related separate article Adrenal Crisis.
Adrenal insufficiency leads to a reduction in the output of adrenal hormones, ie glucocorticoids and/or mineralocorticoids. There are two types of adrenal insufficiency:
- Primary insufficiency - there is an inability of the adrenal glands to produce enough steroid hormones (Addison's disease is the name given to the autoimmune cause of this insufficiency). Glucocorticoid and often mineralocorticoid hormones are lost.
- Secondary insufficiency - there is inadequate pituitary or hypothalamic stimulation of the adrenal glands.
- Primary insufficiency - this is a relatively rare condition. The annual incidence is about 1 in 10,000 people, with a prevalence in the UK of about 8,400. All age groups can be affected but the most common onset is between 30 and 50 years. More women than men are affected.
- Secondary insufficiency - bearing in mind the many factors that can lead to suppression of the hypothalamic-pituitary axis (of which the most common is exogenous steroid use) it is not surprising that this is a relatively common condition. One American study found that 31% of patients admitted to a Critical Care Unit were suffering from secondary adrenal insufficiency.
Addison's disease is the term used to describe adrenal insufficiency but it can have many causes. 70-90% of cases of Addison's disease have an autoimmune basis. This is characterised by progressive destruction of the adrenal glands - most likely the result of cytotoxic T lymphocytes, although 50% of patients have circulating adrenal antibodies.. Clinical and biochemical insufficiency only occurs once >90% of the gland is destroyed.
|Causes of adrenal insufficiency|
Primary adrenal insufficiency
Secondary adrenal insufficiency
|Anatomic destruction of the gland (acute or chronic):
|Metabolic failure in hormone production:
||Suppression of hypothalamic-pituitary axis:
Children and adrenal insufficiency
- Adrenal insufficiency is rare in children.
- Presentation is nonspecific and thus there is a often delay in diagnosis.
- The most common causes are congenital adrenal hyperplasia (72% of cases), adrenoleukodystrophy (15% of cases) and autoimmune adrenalitis (13% of cases).
See separate Congenital Adrenal Hyperplasia article for more details.
- Can have cytomegalovirus (CMV) necrotising adrenalitis; also, Mycobacterium avium-intracellulare and cryptococcal infection.
- Adrenal tests are commonly abnormal in patients with HIV.
- These abnormalities may be due to drug interactions, eg phenytoin, ketoconazole.
Critically ill patients
- Patients who are critically ill are increasingly recognised to be at risk of adrenal dysfunction. It is also known as critical illness-related corticosteroid insufficiency (CIRCI).
- Furthermore, non-survivors are more likely to have higher baseline cortisol levels which do not respond to adrenocorticotropic hormone (ACTH) stimulation.
- It should be considered in patients who are pressor-dependent or have biochemical clues.
- ACTH testing may be unhelpful.
- Etomidate influences ACTH results.
- A trial of steroids may be indicated.
Patient mortality is reduced by prevention of adrenal crises.
- Adrenal crises on top of chronic insufficiency, eg sepsis, gastroenteritis or stress.
- Sepsis with Pseudomonas spp. or meningococcaemia (Waterhouse-Friderichsen syndrome).
- Haemorrhage, eg pregnancy, complication of venography.
- Drugs, eg phenytoin.
- Sudden severe back and abdominal pain.
- Diarrhoea and vomiting.
- This begins with adequate resuscitation, eg intravenous fluids, intravenous glucose.
- Intravenous (IV) hydrocortisone 100 mg, which should be continued four times daily afterwards until the patient can take oral medication. Intramuscular (IM) may be better, as an IV dose is rapidly removed from the circulation (but the initial dose should be IV).
- Adrenal insufficiency should be considered in any patient who presents with a collapse or hypotension.
- A short ACTH stimulation test may be carried out to confirm adrenal insufficiency (dexamethasone can be given in place of hydrocortisone for the duration of this) but IV hydrocortisone should not be withheld whist awaiting the results.
NB: advanced adrenal insufficiency is easier to diagnose compared with recognition of early cases, which is more difficult to diagnose.
Presentation in part depends on the rapidity of adrenal hypofunction
- Acute - for example, Waterhouse-Friderichsen syndrome (infarction secondary to septicaemia, eg meningococcal); presents with collapse and shock.
- Chronic - symptoms develop insidiously and may be mild.
- Fatigue and weakness.
- Weight loss.
- Abdominal pain.
- Personality change.
- Cutaneous and mucosal pigmentation - look at mucosa and in new scars.
- Postural hypotension.
In the early period of adrenal insufficiency, investigations may be normal; however, patients have no reserve when faced with stress.
- Insulin tolerance test - hypoglycaemia is induced by an insulin infusion and the cortisol response is monitored; this is not regularly performed due to safety issues.
- Adrenal autoantibodies - if negative, consider investigating for other causes, eg TB.
- ECG - PR and QT interval prolongation.
- CXR - lung neoplasm.
- Abdominal X-ray - any adrenal calcification which may indicate previous TB infection.
- Specific investigations, eg CT scan or MRI of adrenals.
- It may be appropriate to test other hormones of the hypothalamic-pituitary axis, eg TSH, prolactin, FSH/LH.
- Low baseline (9.00 am) cortisol (<100 nmol/L) is strongly suggestive; >220 nmol/L excludes diagnosis
- Specialist advice should be sought in interpreting patients on shift work (diurnal variation may be altered), people taking oestrogen (can increase cortisol-binding globulin production by the liver) and patients on long-term steroids (may need a Synacthen® test).
- Plasma renin and aldosterone levels - will give an indication of mineralocorticoid activity.
- Diagnosis requires adrenocorticotropic hormone (ACTH) stimulation to assess adrenal reserves.
Short Synacthen® test
This may be performed in primary care if there is sufficient expertise and time. Otherwise, referral to secondary care is appropriate. All children with suspected adrenal insufficiency should be referred for an urgent paediatric opinion.
- 0 minutes - baseline blood for cortisol; followed by 250 micrograms Synacthen® IV/IM.
- 30-60 minutes - cortisol level.
- 95% sensitivity and 97% specificity.
- Less useful alone in secondary adrenal insufficiency.
Interpreting results of the short Synacthen® test
If initial cortisol is >140 nmol/L and second cortisol is >400-500 nmol/L, this excludes Addison's disease. The test can be performed at any time of day, as it is the post-stimulation increase that is diagnostic and this occurs irrespective of any physiological variation.
Distinguish between primary and secondary insufficiency by measuring the ACTH level
This involves an intravenous infusion of 250 mg ACTH per day for three-five days. Daily urine samples are checked for 17-hydroxysteroid levels. A three- to five-fold increase in normal levels is diagnostic of secondary insufficiency. In primary insufficiency, the level does not change.
Other autoimmune illnesses may also be present, eg thyroid disorders, pernicious anaemia, vitiligo and premature ovarian failure. In these patients it is important to consider the possibility of polyglandular autoimmune syndrome.
|Polyglandular autoimmune syndrome|
|Age of onset:||Children.||Adults - women more than men.|
|Diagnosis:||At least two of the following:
||Autoimmune adrenal insufficiency and:
|Aetiology:||Mutant gene on chromosome 6 associated with HLA alleles B8 and DR3.|
- Information about the condition.
- MedicAlert® bracelet.
- Steroid card.
- Importance of not missing steroids.
- Intercurrent illness - if tolerating oral medication then the dose should be doubled until better. If the patient is so unwell that they are unable to take the medication orally then they will need to take it parenterally - thus, they will need to be given IM hydrocortisone and be taught how to administer it.
- Seek medical help if requiring parenteral therapy.
- Glucocorticoid replacement - hydrocortisone is the mainstay of treatment; dose divided into two thirds in the morning and one third in the late afternoon (thus stimulating the normal diurnal adrenal rhythm). A modified-release once-daily preparation is now available for use in Europe but is not yet licensed for use in the UK.
- If there is co-existent thyroid deficiency then thyroid hormones should not be replaced before glucocorticoids, as a crisis may be precipitated.
- Mineralocorticoid replacement - this is usually required in primary adrenal insufficiency.
- Fludrocortisone is used and adequacy of therapy involves measuring blood pressure and looking for postural hypotension and normalising of serum electrolytes (Na and K).
- This may selectively affect adrenocorticotropic hormone (ACTH) or may involve multiple deficiencies, ie panhypopituitarism.
- Other causes include ACTH suppression by sodium valproate, metastases, craniopharyngioma, tuberculosis, postpartum pituitary necrosis (Sheehan's syndrome), trauma and following radiotherapy or surgery.
- Presentation is similar to primary insufficiency although there is usually no hyperpigmentation, as ACTH is low (hyperpigmentation results from metabolites of ACTH).
- Management involves hormone replacement and may also require more definitive treatment, eg surgical removal of a pituitary tumour.
The prognosis for any patient with adrenal insufficiency will depend on the underlying cause. In those patients in whom the prognosis is not affected by the underlying pathology, replacement therapy should result in a return to health with a normal life expectancy. However, a Norwegian study found an excess of mortality in patients diagnosed with Addison's disease at a young age, associated with acute adrenal failure, infection and sudden death.
Thomas Addison (1793-1860) first described the syndrome in 1855. He was a student of medicine in Edinburgh (1812-15) and went on to be one of the three 'giants' of Guy's Hospital (together with Richard Bright (1789-1858) and Thomas Hodgkin (1798-1866)). Life-saving replacement therapy only became available following the synthesis of cortisone (Kendall, Sarett and Reichstein in 1949).
Further reading & references
- Grossman AB; Clinical Review: The diagnosis and management of central hypoadrenalism. J Clin Endocrinol Metab. 2010 Nov;95(11):4855-63. Epub 2010 Aug 18.
- Neary N, Nieman L; Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):217-23.
- Liotta EA et al, Addison Disease, Medscape, Jun 2010
- Kirkland L, Adrenal Crisis, Medscape, Mar 2010
- Addison's disease; NICE CKS, September 2010
- Neary N, Nieman L; Adrenal insufficiency: etiology, diagnosis and treatment. Curr Opin Endocrinol Diabetes Obes. 2010 Jun;17(3):217-23.
- Ten S, New M, Maclaren N; Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab. 2001 Jul;86(7):2909
- Speiser PW et al, Pediatric Adrenal Insufficiency (Addison Disease), Medscape, Jun 2011
- Shulman DI, Palmert MR, Kemp SF; Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007 Feb;119(2):e484
- Griffing GT et al, Addison Disease, Medscape, Apr 2010
- Ekpebegh CO, Ogbera AO, Longo-Mbenza B, et al; Basal cortisol levels and correlates of hypoadrenalism in patients with human Med Princ Pract. 2011;20(6):525-9. Epub 2011 Oct 4.
- Marek P; Critical Illness-Related Corticosteroid Insufficiency, Chest,2009; 135(1): 181-193
- Moraes RB, Czepielewski MA, Friedman G, et al; Diagnosis of adrenal failure in critically ill patients. Arq Bras Endocrinol Metabol. 2011 Jun;55(5):295-302.
- Lipiner, Sprung CL, Laterre PF, et al; Adrenal function in sepsis: the retrospective Corticus cohort study. Crit Care Med. 2007 Apr;35(4):1012
- Nicolaides N et al; Adrenal Insufficiency, Endotext.com, 2012
- Marik PE, Pastores SM, Annane D, et al; Recommendations for the diagnosis and management of corticosteroid insufficiency Crit Care Med. 2008 Jun;36(6):1937-49.
- Salvatori R; Adrenal insufficiency. JAMA. 2005 Nov 16;294(19):2481
- Erichsen MM, Lovas K, Skinningsrud B, et al; Clinical, immunological, and genetic features of autoimmune primary adrenal J Clin Endocrinol Metab. 2009 Dec;94(12):4882-90. Epub 2009 Oct 26.
- Current Problems In Pharmacovigilance: Focus on Corticosteroids. Volume 24, (Pages 5-10), Medicines and Healthcare products Regulatory Agency (MHRA) - CSM (May 1998)
- Pocock N; Plenadren® (modified release hydrocortisone tablet) approved in the EU for adrenal insufficiency National electronic Library for Medicines, 2011
- Klauer KM, Adrenal Crisis in Emergency Medicine, Medscape, Mar 2012
- Erichsen MM, Lovas K, Fougner KJ, et al; Normal overall mortality rate in Addison's disease, but young patients are at Eur J Endocrinol. 2009 Feb;160(2):233-7. Epub 2008 Nov 14.
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|Original Author: Dr Gurvinder Rull||Current Version: Dr Laurence Knott||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 19/04/2012||Document ID: 1778 Version: 24||© EMIS|