ADRENAL ANATOMY AND FUNCTION
The human adrenals, weighing only 8-10 g together, comprise an outer cortex with three zones (reticularis, fasciculata and glomerulosa) producing steroids and an inner medulla that synthesizes, stores and secretes catecholamines (see Adrenal medulla). The adrenal steroids are grouped into three classes based on their predominant physiological effects:
GLUC0CORTICOIDS. These are named after their effects on carbohydrate metabolism; major actions.
MINERALOCORTICOIDS. Their predominant effect is on the extracellular balance of sodium and potassium in the distal tubule of the kidney: aldosterone is the predominant mineralocorticoid in humans (about 50%);
corticosterone makes a small contribution. The weak mineralocorticoid activity of cortisol is also important since it is present in considerable excess. Aldosterone is produced solely in the zona glomerulosa.
ANDROGENS. Although secreted in considerable quantities, most have only relatively weak intrinsic androgenic activity until metabolized peripherally to testosterone or dihydrotestosterone. The relative potency of common steroids.
Increased or stimulated
Free water clearance
Uric acid production
Decreased or inhibited
Host response to infection
All steroids have the same basic skeleton and the chemical differences between them are slight. The major biosynthetic pathways.
Glucocorticoid production by the adrenal is under hypothalamic- pituitary control. Corticotrophin releasing factor (CRF) is secreted in the hypothalamus in response to circadian rhythm, stress and other stimuli. It travels down the portal system to stimulate ACTH release from the anterior pituitary corticotrophs. Circulating ACTH stimulates cortisol production in the adrenal. The cortisol secreted (or any other synthetic corticosteroid) feeds back on the hypothalamus and pituitary to inhibit further CRF/ ACTH release. The set-point of this system clearly varies through the day according to the circadian rhythm, and is usually overridden by severe stress. Following adrenalectomy or Addison’s disease, cortisol secretion will be absent or reduced; ACTH levels will therefore rise.
Mineralocorticoid secretion is mainly controlled by the renin-angiotensin system.
INVESTIGATION OF GLUCOCORTICOID ABNORMALITIES
ACTH and cortisol are released episodically. The following precautions are therefore necessary when taking a blood sample:
• Sampling time should be accurately recorded.
• Stress should be minimized.
• Sampling should be delayed for 48 hours after admission if Cushing’s syndrome is suspected.
• Appropriate reference ranges (for time and assay method) should be used.
Suppression and stimulation tests are used in instances of excess and deficient cortisol production respectively.
Dexamethasone suppression tests
Administration of synthetic glucocorticoid to a normal subject produces prompt feedback suppression of CRF and ACTH levels and thus of endogenous cortisol secretion (prednisolone and dexamethasone are not measured by most cortisol assays). Three forms of the test, used in the diagnosis and differential diagnosis of Cushing’s syndrome, are available.
ACTH stimulation tests
Synthetic ACTH (tetracosactrin, which consists of the first 24 amino acids of human ACTH) is given to stimulate adrenal cortisol production.
PATHOPHYSIOLOGY AND CAUSES
In this uncommon condition there is destruction of the entire adrenal cortex. Glucocorticoid, mineralocorticoid and sex steroid production are therefore all reduced. This differs from hypothalamic-pituitary disease, in which mineralocorticoid secretion remains largely intact, being predominantly stimulated by angiotensin II. Adrenal sex steroid production is also largely independent of pituitary action. In Addison’s disease reduced cortisol levels lead, through feedback, to increased CRF and ACTH production, the latter being responsible for the hyperpigmentation.
Autoimmune disease (= 80%)
Drugs, e.g. rifampicin
Schilder’s disease (adrenal leucodystrophy)
Primary hypoadrenalism shows a marked female preponderance and is now most often caused by autoimmune disease (=80%) rather than tuberculosis (=20%). All other causes are rare (Table 16.32). Autoimmune adrenalitis results from the destruction of the adrenal cortex by organ-specific autoantibodies. There is an association with other autoimmune conditions, e.g. pernicious anaemia, hypoparathyroidism, thyroiditis, premature ovarian failure, type 1 diabetes mellitus.
Primary hypoadrenalism shows a marked female preponderance and is now most often caused by autoimmune disease (=80%) rather than tuberculosis (=20%). All other causes are rare. Autoimmune adrenalitis results from the destruction of the adrenal cortex by organ-specific autoantibodies. There is an association with other autoimmune conditions, e.g. pernicious anaemia, hypoparathyroidism, thyroiditis, premature ovarian failure, type 1 diabetes mellitus.
The symptomatology of Addison’s disease is often vague-non-specific complaints of weakness, tiredness, weight loss and anorexia
Important features are:
PIGMENTATION (dull, slaty, grey-brown) in the mouth (opposite the molars), hand and all flexural regions is the predominant sign. It is particularly significant if it occurs in a recent scar. It is caused by the direct action of ACTH on melanocytes.
POSTURAL SYSTOLIC HYPOTENSION, due to hypovolaemia and sodium loss, is usually present even if supine blood pressure is normal.
Once Addison’s disease is suspected, investigation is urgent. If the patient is seriously ill or very hypotensive, hydrocortisone 100 mg should be given intramuscularly, ideally after a blood sample is taken for later measurement of plasma cortisol, or an ACTH stimulation test can be performed immediately. Full investigation should be delayed until emergency treatment has improved the patient’s condition. Otherwise, tests are as follows:
SINGLE CORTISOL MEASUREMENTS are of virtually no value.
THE SHORT ACTH STIMULATION TEST should be performed (see Table 16.31). An absent or impaired cortisol response is seen, confirmed if necessary by a long ACTH stimulation test to exclude adrenal suppression by steroids.
A 0900 PLASMA ACTH LEVEL – a high level (>80 ng litre-I) with low or low-normal cortisol confirms primary hypoadrenalism.
ELECTROLYTES AND UREA: these classically show hyponatraemia, hyperkalaemia and a high urea but can be normal.
BLOOD GLUCOSE may be low, with symptomatic hypoglycaemia.
ADRENAL ANTIBODIES are present in many cases of autoimmune adrenalitis.
CHEST AND ABDOMINAL X-RA YS may show evidence of tuberculosis and/or calcified adrenals.
SERUM ALDOSTERONE is reduced with high plasma renin activity.
HYPERCALCAEMIA AND ANAEMIA (after rehydration) are sometimes seen. They resolve on treatment.
Long-term treatment is with replacement glucocorticoid and mineralocorticoid; tuberculosis must be treated if present or suspected. Replacement dosage details.
Adequacy of glucocorticoid dose is judged by:
• Clinical well-being and restoration of normal, but not excessive, weight
• Normal cortisol levels during the day while on replacement hydrocortisone (this cannot be used for synthetic steroids)
Fludrocortisone replacement is assessed by:
• Restoration of serum electrolytes to normal
• Blood pressure response to posture (it should not fall >10 mmHg systolic after 2 min standing)
• Suppression of plasma renin activity to normal
All patients requiring replacement steroids should:
CARRY A STEROID CARD.
WEAR A MEDIc-ALERT BRACELET; this gives details of their condition so that emergency replacement therapy can be given if found unconscious.
KEEP AN (UP-TO-DATE) AMPOULE OF HYDROCORTISONE at home in case oral therapy is impossible, and the general practitioner has to be called.
The major deficiencies are of salt, steroid and glucose. ASSUMING NORMAL CARDIOVASCULAR FUNCTION, 1 litre of normal saline should be given over 30-60 min with 100 mg of intravenous hydrocortisone.
DEXTROSE should be infused if there is hypoglycaemia. SUBSEQUENT SALINE REQUIREMENTS may be for several litres within 24 hours (assessing with central venous pressure line if necessary) plus hydrocortisone, 100 mg i.m. 6-hourly, until the patient is clinically stable.
ORAL REPLACEMENT MEDICATION is then started, initially hydrocortisone about 20 mg 8-hourly or equivalent, reducing to 20 mg + 10 mg or equivalent over a few days.
FLUD~OCORTISONE is unnecessary acutely as the high cortisol doses provide sufficient mineralocorticoid activity-it should be introduced later.