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Addison's Disease

Definitions and Background

 

Adrenal insufficiency, or hypoadrenalism, is reduction in the output of adrenal hormones. These include glucocorticoids, mineralocorticoids, androgens and catecholamines.

Primary insufficiency is due to the inability of the adrenals to produce enough steroid hormones, through destruction of the adrenal tissue. Addison's Disease causes autoimmune destruction of the gland and accounts for 80-90% of cases. 

Secondary insufficiency is reduced adrenal function due hypothalamic-pituitary dysfunction i.e. the inability of the pituitary gland to regulate adrenal secretion either through lack of CRH production from the hypothalamus and/or lack of ACTH production from the anterior pituitary. This is most commonly due to suppression of the hypothalamic-pituitary axis due to exogenous steroids.

 

Hypothalamic - pituitary - adrenal axis

The hypothalamic-pituitary-adrenal axis, is shown to the left. It is a negative feedback loop, with CRH (corticotropin stimulating hormone) secreted from the hypothalamus, positively stimulating the anterior pituitary to release ACTH (adrenalcorticotropic  hormone), which acts on the adrenal glands to stimulate release of cortisol. High levels of cortisol negatively impacts CRH and ACTH secretion, reducing further cortisol release.

 In primary hypoadrenalism, low cortisol production from damaged adrenals stops the direct inhibition of CRH and ACTH production. Increased CRH stimulates high ACTH secretion which leads to the skin pigmentation seen in these patients. 

Primary hypoadrenalism is rare, with an incidence of around 6 per 100,000 in the UK. It is more common in females than males (2:1). 10% of primary hypoadrenalism is caused by tuberculosis infection.

 

 

Adrenal structure

 

The adrenals comprise of an outer cortex with three zones, the glomerulosa (secretes mineralocorticoids), the fasciculata (secretes  glucocorticoids) and the reticularis (secretes androgens) as well as the adrenal medulla, which synthesises, store and secretes catecholamines.

The adrenal hormones affected in Addison's Disease are the steroid hormones, (the medulla is usually spared). These are grouped into three classes, based on their physiological effects:

  • Glucocorticoids are so named due to their effect on carbohydrate metabolism. They increase hepatic gluconeogenesis, increase glycogen deposition, increase protein catabolism, affect fat mobilisation, redistribution and deposition, increase blood pressure and stress responses, increase sodium retention and potassium loss, and affect immune function, including lymphocyte inhibition.
  • Mineralocorticoids The main mineralocorticoid is aldosterone, which acts on the kidney at the distal convoluted tubule via an intracellular receptor to increase sodium resorption from the urine, and decrease potassium resorption.
  • Androgens, secreted in a weak form until metabolised in peripheral tissues to testosterone or dihydrotestosterone.

 

The Adrenal Gland

Adrenal gland

Aetiology and Pathophysiology

 

Autoimmune pathology is the main cause of adrenal insufficiency in developed countries. It involves atrophy of the entire adrenal cortex. Atrophy is due to tissue destruction from autoimmune adrenalitis, thought to be caused by abnormalities in circulating cytotoxic T lymphocytes, though anti-adrenal antibodies are commonly present. Adrenal atrophy may also be present in secondary hypoadrenalism, as pituitary failure and reduced ACTH will fail to stimulate and maintain adrenal tissues.

In TB related hypoadrenalism, the whole gland is involved (both cortex and medulla). Calcium deposits may be detected on radiograph or CT. The incidence of TB adrenalitis is highly correlated with the prevalence of tuberculosis infections in the community.

Approximately 80-90% of adrenal tissue in both glands must be affected to destroy adrenal reserve.

 

Rarer causes of hypoadrenalism include:

  • Enzyme deficiencies (e.g. congenital adrenal hyperplasia, adrenoleucodystrophy)
  • AIDS related illnesses (CMV, histoplasmosis)
  • Sarcoidosis
  • Amyloidosis
  • Haemochromotosis
  • Neoplastic infiltration
  • Iatrogenic e.g. adrenalectomy for Cushing's disease.
  • Drugs e.g. Ketoconazole inhibits the adrenal cytochrome P450 steroidogenic enzymes.
  • Adrenal haemorrhage, e.g. in those on anticoagulants
  • Adrenal infarcts e.g. in septicaemia (Waterhouse-Friedrichsen syndrome)

 

 

Symptoms and Signs

Investigations

 

Full blood count: Anaemia may be present.

Serum cortisol: Single cortisol measurements are of little value.  A 9am cortisol is more useful than a random sample. In a normal subject cortisol levels are usually > 500nmol/L. In severe hypoadrenalism they are < 200 nmol/L in . Low baseline cortisol (<100 nmol/L) is strongly suggestive of adrenal insufficieny. Further investigation is needed to confirm the diagnosis.

U&Es: These may show hyponatraemia and hyperkalaemia due to lack of aldosterone action in the distal convoluted tubules and collecting ducts of the kidney. Hypercalcaemia occurs in less than 10% of cases.

Glucose: Hypoglycaemia may be present and symptomatic

Serum aldosterone is low.

If Tuberculosis supected: Chest and abdominal x-rays to show evidence of TB or calcified adrenal glands.

 

Synacthen tests:  This test is based on adminstration of synthetic ACTH, and monitoring cortisol response. The short synacthen is the most commonly conducted, but, unlike the long synacthen test, does not differentiate primary from secondary hypoadrenalism.

  • 0 min. - baseline blood for cortisol; follow by 250 micrograms synacthen® IV/IM
  • 30 and 60 minutes: measure cortisol level
  • Cortisol levels > 550nmol/L indicates a normal response.
  • Peak cortisol levels < 550nmol/L indicate hypoadrenalism (primary or secondary)

 

 

Differentiating primary from secondary hypoadrenalism:

      ACTH: Usually >50ng/L. Sample is sensitive to environment - centrifuge and freeze immediately. If the level is rasied, this indicates PRIMARY hypoadrenalism, if it is reduced, SECONDARY hypoadrenalism is likely.

      Aldosterone level: is usually low, with high renin activity. If taken 30 minutes in to short synacthen test: secondary hypoadrenalism will show a rise in aldosterone, primary will not.

      Long synacthen test: not often done. Involves measuring of cortisol at 0, 30, 60, 90 and 120 minutes and 4, 6, 8, 12, 24, 48 and 72 hours after administration of synacthen.  In secondary hypoadrenalism, the cortisol starts to rise by 24 hours, with a cortisol >580nmol/L by 72 hours. In primary hypoadrenalism, no rise occurs.

       

       

      Management

      Treatment is for life.

      Replacement is with hydrocortisone (synthetic cortisol) and fludrocortisone (synthetic aldosterone). The morning tablets should be taken on waking, before breakfast, to mimic the normal circadian pattern of cortisol levels.

      Adequacy of glucocorticoid replacement is judged by the clinical wellbeing and restoration of normal, (not excessive) weight.

      Adequacy of fludrocortisone replacement is assessed by the restoration of serum electrolytes, postural blood pressure (should not fall more than 10mmHg systolic after 2 minutes standing) and normal suppression of plasma renin activity.

       

        Immediate management of adrenal crisis

        If patient is acutely sick or hypotensive:

        • Take bloods for cortisol, glucose, U&Es
        • Give hydrocortisone 100mg IV bolus
        • Give 0.9% saline infusion (several litres may be required in the first 24-48 hrs)
        • Correct hypoglycaemia with IV boluses of 20% glucose

        Continue with hydrocortisone 100mg IM 6 hourly until the patient has clinically improved.

        Long-term management

        • Referral to endocrine unit
        • Hydrocortisone orally 10mg on waking, 5mg at lunch and evening.
        • Fludrocortisone 0.1-0.2mg  per day orally.
        • Supply a  STEROID WARNING CARD, a Medicalet bracelet and 'emergency pack' (containing hydrocortisone ampoule with saline, 21G needle and syringe).
        • Educate patient and partner how to give IM injection
        • Educate patient about need for extra hydrocortisone in case of illness (e.g. gastroenteritis) or physical stress.

        Complications and Prognosis

         

        The biggest risk to patients is adrenal crisis. Adrenal crisis occurs when the physiological demand for adrenal hormones exceeds the ability of the adrenal glands to produce them. This could occur if the patient forgets or does not take their medication. It could also happen if the patient undergoes any physiological stress, such as:

        • Infections,
        • Trauma, eg. injury, surgery
        • Pregnancy
        • General anaesthesia.

         

        Adrenal crisis is a life threatening emergency. Death can occur due to circulatory collapse, arrhythmias and hypoglycaemia.

        Ensure patients are educted in doubling medication when suffering with intercurrent illness. If the patient is so unwell that they are unable to take the medication orally, then they will need to take it parenterally - they will need to be given IM hydrocortisone and be taught how to administer it.

        In the majority of Addison's patients, replacement therapy should result in a return to health with a normal life expectancy.

         

        References and Further reading

        Kumar, P., and Clark, M., Clinical Medicine, Sixth Edition, 2005, Elsevier Saunders, p1082-1084

        Chew, S., and Leslie, D., Clinical Endocrinology and Diabetes - an Illustrated Colour Text, 2006. Churchill Livingstone Elsevier.

        Bentley, P., Memorizing Medicine: A Revision Guide, 2007. The Royal Society of Medicine Press.

        Stevens, A., Lowe, J., and Scott, I., Core Pathology, 3rd Edition, 2009. Mosby Elsevier.

        Boron, W., Boulpaep, E., Medical Physiological, Updated Edition, 2005. Elsevier Saunders.

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