See related article Adrenal Crisis.

Description

Adrenal insufficiency leads to a reduction in the output of adrenal hormones, i.e. glucocorticoids and/or mineralocorticoids. There are two types of adrenal insufficiency:¹

1. 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.
2. Secondary insufficiency - there is inadequate pituitary or hypothalamic stimulation of the adrenal glands.

Epidemiology

• Primary insufficiency - rare 0.8 per 100,000; affects both sexes equally and can occur at any age.²
• Secondary insufficiency - relatively common compared with the primary type as exogenous steroid use is frequent leading to suppression of the hypothalamic-pituitary axis.

Aetiology

80% of the cases of adult adrenal insufficiency have an autoimmune basis.²

Children and adrenal insufficiency

• Adrenal insufficiency is rare in children
• Presentation is nonspecific and thus often there is a delay in diagnosis
• The most common causes are congenital adrenal hyperplasia (72% of cases), adrenoleukodystrophy (15% of cases) and autoimmune adrenalitis (13% of cases)³

Critically ill patients

• Patients who are critically ill are increasingly recognised to be at risk of adrenal dysfunction
• Furthermore, nonsurvivors are more likely to have higher baseline cortisol levels which does not respond to adrenocorticotropic hormone (ACTH) stimulation⁴
• It should be considered in patients who are pressor dependent or have biochemical clues
• ACTH testing may be unhelpful⁵
• Etomidate influences ACTH results⁴
• A trial of steroids may be indicated

Presentation

Note: 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, e.g. meningococcal); presents with collapse and shock²
• Chronic - symptoms develop insidiously and may be mild

Symptoms

• Fatigue and weakness
• Anorexia
• Nausea
• Vomiting
• Weight loss
• Abdominal pain
• Diarrhoea
• Constipation
• Syncope
• Dizziness
• Confusion
• Personality change
• Irritability
• Amenorrhoea

Signs

• Cutaneous and mucosal pigmentation - look at mucosa and in new scars
• Hypotension
• Postural hypotension

Pathogenesis

Addison's disease is characterised by progressive destruction of the adrenal glands. This is usually autoimmune based and most likely the result of cytotoxic T lymphocytes, although 50% of patients have circulating adrenal antibodies.² Clinical and biochemical insufficiency only occurs once >90% of the gland is destroyed.

AIDS patients

• 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, e.g. phenytoin, ketoconazole

Investigations

In the early period of adrenal insufficiency, investigations may be normal; however, patients have no reserve when faced with stress.

Other investigations

• Insulin tolerance test¹ - 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, e.g. tuberculosis
• ECG - PR and QT interval prolongation
• CXR - lung neoplasm
• Abdominal X-ray - any adrenal calcification which may indicate previous TB infection
• Specific investigations, e.g. CT scan of adrenals
• It may be appropriate to test other hormones of the hypothalamic-pituitary axis, e.g. TSH, prolactin, FSH/LH

Hormonal abnormalities

• Low baseline (09:00 am) cortisol (<100 nmol/L) is strongly suggestive; >220 nmol/L excludes diagnosis
• 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

• 0 min. - baseline blood for cortisol; follow by 250 micrograms synacthen® IV/IM
• 30-60 min. - cortisol level
• 95% sensitivity and 97% specificity
• Less useful alone in secondary adrenal insufficiency⁷

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.

Distinguish between primary and secondary insufficiency by measuring the ACTH level

• Primary insufficiency - ACTH increased
• Secondary insufficiency - ACTH decreased

Associated diseases

Other autoimmune illnesses may also be present, e.g. thyroid disorders, pernicious anaemia, vitiligo and premature ovarian failure. In these patients it is important to consider the possibility of polyglandular autoimmune syndrome.

Management

Patient education

• Information about the condition
• MedicAlert® bracelet
• Steroid card¹⁰
• 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

Hormone replacement

• Glucocorticoid replacement - hydrocortisone is the mainstay of treatment; dose divided into 2/3s in the morning and 1/3 in the late afternoon (thus stimulating the normal diurnal adrenal rhythm).
• If there is coexistent thyroid deficiency then thyroid hormones should not be replaced before glucocorticoids, as a crisis may be precipitated.¹
• 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).

Secondary adrenocortical insufficiency

• This may selectively affect adrenocorticotropic hormone (ACTH) or may involve multiple deficiencies, i.e. 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, e.g. surgical removal of a pituitary tumour.

Prognosis

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 retrospective observational study in Sweden reported the risk of death for patients with Addison's disease was two-fold higher.¹¹ The cause of this extra mortality was cardiovascular, malignant and infectious disease-related.

History

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).

Document references

1. Salvatori R; Adrenal insufficiency. JAMA. 2005 Nov 16;294(19):2481 [abstract]
2. Ten S, New M, Maclaren N; Clinical review 130: Addison's disease 2001. J Clin Endocrinol Metab. 2001 Jul;86(7):2909 [abstract]
3. Shulman DI, Palmert MR, Kemp SF; Adrenal insufficiency: still a cause of morbidity and death in childhood. Pediatrics. 2007 Feb;119(2):e484 [abstract]
4. Lipiner, Sprung CL, Laterre PF, et al; Adrenal function in sepsis: the retrospective Corticus cohort study. Crit Care Med. 2007 Apr;35(4):1012 [abstract]
5. Shenker Y, Skatrud JB; Adrenal insufficiency in critically ill patients. Am J Respir Crit Care Med. 2001 Jun;163(7):1520
6. 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. [abstract]
7. Dorin RI, Qualls CR, Crapo LM; Diagnosis of adrenal insufficiency. Ann Intern Med. 2003 Aug 5;139(3):194 [abstract]
8. Betterle C, Greggio NA, Volpato M; Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab. 1998 Apr;83(4):1049
9. Majeroni BA, Patel P; Autoimmune polyglandular syndrome, type II. Am Fam Physician. 2007 Mar 1;75(5):667 [abstract]
10. CSM; Current Problems In Pharmacovigilance: Focus on Corticosteroids. Volume 24, (Pages 5-10) May 1998.
11. Bergthorsdottir R, Leonsson, Oden A, et al; Premature mortality in patients with Addison's disease: a population J Clin Endocrinol Metab. 2006 Dec;91(12):4849 [abstract]

Internet and further reading

• Klauer K; Adrenal Insufficiency and Adrenal Crisis, eMedicine, Dec 2009.

Acknowledgements