Adrenal insufficiency

Adrenal insufficiency

The adrenal glands
The adrenal glands are located at the superior poles of the two kidneys and are made up of two distinct parts, the adrenal medulla and adrenal cortex. The medulla acts with the central nervous system to secrete the hormones epinephrine and A norepinephrine in response to sympathetic stimulation. The adrenal cortex is anatomically separated into three zones: zona glome A rulosa, zona fasciculata, and zona reticularis. The outer zona A glomerulosa is responsible for secreting the aldosterone (a A mineralo?corticoid) and the inner zonae fasciculate and reticularis, responsible for secreting glucocorticoids (e.g. cortisol) and androgens. An adrenocorticotropic hormone (ACTH), stimulates the adrenal cortex to synthesize and secrete cortisol, which regulates carbohydrate, protein and lipid metabolism, and aldosterone, which regulates fluid and electrolyte balance through sodium and potassium homeostasis. The adrenal cortex also secretes other steroids with glucocorticoid, mineralo?corticoid, or both activities, but in much smaller quantities.

Pathophysiology
When there is a reduction in the output of adrenal hormones, for example glucocorticoids and/or mineralo?corticoids, this is termed as adrenal insufficiency. There are two kinds of adrenal insufficiency. Primary insufficiency is an inability of the adrenal glands to produce sufficient steroid hormones to meet physiological needs, despite release of ACTH from the pituitary (Addison’s disease is the name given to the autoimmune cause of this insufficiency). Glucocorticoid and often mineralo?corticoid hormones are lost. Secondary insufficiency is inadequate A pituitary or hypothalamic stimulation of the adrenal glands.
Secondary adrenocortical insufficiency happens when exogenous steroids have suppressed the hypothalamic?pituitary?A adrenal (HPA) axis. Too rapid withdrawal of exogenous steroid may precipitate adrenal crisis, or sudden stress may induce A cortisol requirements in excess of the adrenal glands’ ability to respond immediately.

Signs and symptoms
The signs and symptoms of adrenal insufficiency often develop gradually and these can include:
•a•? Severe fatigue and weakness
•a•? Increased pigmentation of the skin
•a•? Syncope and hypotension, with orthostatic hypostension
•a•? Anorexia, nausea, vomiting, diarrhoea
•a•? Salt craving (hyponatraemia)
•a•? Myalgia and arthralgia
•a•? Depression
•a•? Altered menstrual cycles
As a result of the sometimes non?specific nature of symptoms and their gradual progression, they are often missed or ignored until a relatively minor infection results in an abnormally long recovery, prompting an investigation. Often, it is not until a crisis is triggered that attention is turned to the adrenal glands.




Investigations
A detailed history and physical examination are needed. The signs and symptoms associated with adrenal insufficiency, for example exhaustion, fatigue, muscle weakness and weight loss, are often unclear. Adrenal insufficiency can cause changes in the serum sodium (hyponatraemia) and high serum potassium (hyperkalaemia). There may also be anaemia. These findings are somewhat general and can be found in the context of a number of conditions other than adrenal insufficiency.
To establish a diagnosis, a short synacthen test (SST) has to be performed. This test is also called ACTH stimulation test or a cosyntropin test. The SST determines the ability of the adrenal glands to produce cortisol in response to ACTH (the pituitary hormone regulating adrenal cortisol production). When the test is undertaken a baseline blood sample is drawn prior to injecting a dose of ACTH, followed by drawing of a second sample of blood 30–60 minutes after the ACTH injection. If the adrenal glands are functioning, cortisol production in the second sample exceeds a particular level, (usually 500–550a•›nmol/L). Adrenal glands that are poorly functioning will not be able to produce this amount of cortisol. Other investigations may include electrocardiograph, abdominal
X?ray, CT scan or MRI of adrenals, and 24?hour urine test to assess alterations in the biosynthesis of adrenal cortical hormones.

Management
Adrenal crisis can occur after physical or mental stress. This could be life threatening and is characterized by volume depletion, hypotension and vascular collapse. When a patient is suspected of suffering from adrenal insufficiency and concurrently shows signs of possible adrenal crisis (persistent vomiting with profound muscle weakness, hypotension or even shock, extreme sleepiness or even coma), admission to hospital as an emergency is needed. Emergency treatment should be initiated without delay as the diagnosis can still be formally confirmed later by the short synacthen test once the patient is stable again. Only those who have been conclusively diagnosed with adrenal insufficiency should receive adrenal hormone replacement therapy as advised by an endocrinologist. A normal adrenal gland does not need supplements to function effectively, either the adrenal is working effectively and requires no treatment or there is insufficiency due to adrenal or pituitary failure, as measured by an endocrinologist. The person should be provided with information about the condition, advised to wear a medical alert type bracelet and should carry a steroid card. During intercurrent illness, if the patient is tolerating oral medication, the dose should be doubled until recovered. If the patient is unwell and unable to take oral medication then it should be given parenterally; they will need to be given intramuscular hydrocortisone and be taught how to administer it. For glucocorticoid replacement, hydrocortisone is the mainstay of treatment. Secondary adrenocortical insufficiency may involve multiple deficiencies, that is, panhypopituitarism. Other causes include ACTH suppression by sodium valporate, metastases, craniopharyngioma, tuberculosis, postpartum pituitary necrosis, trauma and following radiotherapy or surgery. Hormone replacement therapy may be required with more definitive treatment, for example surgical removal of a pituitary tumour.






Cushing’s syndrome
Excessive levels of glucocorticoid in the body cause Cushing’s syndrome. There are a number of reasons why the body may produce too much of the glucocorticoid cortisol; a variety of tests and investigations may be required to determine the root cause of the excess cortisol.

Cushing’s syndrome

Glucocorticoids
Glucocorticoids are a class of steroid hormones (others include mineralo?corticoids and sex hormones). Glucocorticoids are steroids that reduce inflammation throughout the body. Cortisol is a naturally occurring glucocorticoid produced by the adrenal glands, working to regulate inflammation and other processes. Synthetic glucocorticoids are drugs including prednisone, dexamethasone and hydrocortisone. They function in a similar way to stop inflammation and may be even more potent than naturally occurring glucocorticoids.
Glucocorticoids work in interrupting inflammation by moving into cells and suppressing the proteins that cause the inflammation; they also affect the metabolism.

Pathophysiology
The condition is more common in women than in men. The normal feedback mechanisms that control adrenocortical function are ineffective; this results in the secretion of adrenal cortical hormones regardless of the amounts of these hormones in the circulation. Cushing’s syndrome is caused by prolonged exposure to elevated levels of endogenous glucocorticoids or exogenous glucocorticoids.
Excess levels of either exogenously administered glucocorticoids (this may include therapeutic administration) or endogenous overproduction of cortisol causes Cushing’s syndrome. Endogenous glucocorticoid overproduction that is independent of adenocorticotropic hormone (ACTH) is frequently due to a primary adrenocortical neoplasm (usually an adenoma). Causes of Cushing’s syndrome can be allocated to two groups. ACTH?dependent disease: excessive ACTH from the pituitary (Cushing’s disease), ectopic ACTH?producing tumours or excess ACTH administration. Non?ACTH?dependent: adrenal adenomas, adrenal carcinomas, excess glucocorticoid administration. ACTH?secreting neoplasms cause ACTH?dependent Cushing’s syndrome. They often are due to an anterior pituitary tumour – classic Cushing’s disease. Non?pituitary ectopic sources of ACTH, such as an oat cell carcinoma, small?cell lung carcinoma or carcinoid tumour, cause the balance of ACTH?dependent disease. Ectopic corticotropin?releasing hormone secretion leading to increased ACTH secretion makes up a very rare group of cases of Cushing’s syndrome. There can be an excess of all the hormones or just one; the hormone predominantly secreted is the glucocorticoid and this determines the predominant symptoms.

Signs and symptoms
The manifestations of Cushing’s syndrome are the result of excessive glucocorticoids. A detailed history and physical examination is required.
There may be menstrual irregularities, amenorrhoea, infertility and decreased sex drive in women; in the man, there could be decreased libido and erectile dysfunction.
Psychological problems, for example depression, cognitive dysfunction and emotional lability can develop. Those with an ACTH?producing pituitary tumour (Cushing’s disease) may develop headaches, polyuria and nocturia, visual problems or galactorrhoea. If sufficient mass effect from the tumour is present on the anterior pituitary, hyposomatotropism, hypothyroidism, hyperprolactinaemia or hypoprolactinaemia and hypogonadism may develop.
Rapid onset of symptoms of glucocorticoid excess in conjunction with virilization in women or feminization in men can suggest an adrenal carcinoma as the primary cause of the Cushing’s syndrome. Because of the significant morbidity and mortality of Cushing’s syndrome, early diagnosis and prompt treatment are essential.

Investigations
Several different types of investigations and tests are needed to make a diagnosis, no one single test is perfect. Diagnostic tests for the presence of Cushing’s syndrome are 24?hour urinary free cortisol, 1â•›mg overnight low dose dexamethasone suppression test and late?night salivary cortisol. A full blood count is required, as well as assessment of electrolytes (there may be hypokalaemia) and acid base balance (there may be metabolic alkalosis). Investigations to identify the cause of Cushing’s syndrome include an assessment of plasma ACTH, high?dose dexamethasone suppression test, inferior petrosal sinus sampling, MRI of the pituitary, chest and abdominal CT scans.

Management
Treatment of Cushing’s syndrome is directed by the primary cause of the syndrome. Therapy generally aims to reduce the cortisol secretion to normal, reducing the risk of comorbidities. Definitive therapy of endogenous Cushing’s syndrome involves tumour resection. Indications for medical therapy include acutely ill patients in preparation for surgery, patients with unknown tumour location or un?resectable lesions, those who are unfit for surgery and those with persistent raised glucocorticoid levels postoperatively. The treatment of choice in most patients is surgical, but the metabolic consequences, including increased tissue fragility, poor wound healing, hypertension and diabetes mellitus, increase the risks of surgery. Drug therapy has an important role to play and remains very important for normalizing cortisol levels. Metyrapone, ketoconazole and mitotane are drugs that can be used to lower cortisol by inhibiting synthesis and secretion in the adrenal gland. Medical treatment can also be used in patients who do not want surgery or who are unfit for surgery. Surgical treatment is the treatment of choice for pituitary tumours (trans?sphenoidal microsurgery). Radiation therapy may be used as an adjunct for patients who are not cured. Bilateral adrenalectomy may be needed to control toxic cortisol levels. Adrenocortical tumours require surgical removal. Pituitary radiotherapy can be used for persisting hypercortisolaemia after trans?sphenoidal surgery.