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At the heart of general practice since 1960

July 2007: Detecting patients with adrenal disorders

What are the functions of the adrenal glands?

How does adrenal insufficiency present?

Which investigations in primary care are useful?

What are the functions of the adrenal glands?

How does adrenal insufficiency present?

Which investigations in primary care are useful?

the adrenal glands secrete hormones that regulate metabolism, stress responses and fluid and electrolyte balance. Disorders that interfere with normal adrenal function are often challenging to diagnose, yet if left untreated can be life threatening.

The adrenal gland consists of two distinct types of tissue, the cortex and the medulla. The cortex is the site of synthesis for:

• Aldosterone, a mineralocorticoid regulated by the renin-angiotensin system

• Cortisol, a glucocorticoid regulated by adrenocorticotropic hormone (ACTH)

• Dehydroepiandrostenedione (DHEA), dehydroepiandrostenedione sulphate (DHEAS) and androstenedione, androgens which are also regulated by ACTH.

The adrenal medulla is part of the sympathetic nervous system and produces adrenaline, noradrenaline and dopamine.

Adrenal lesions are categorised as cortical or medullary; and functioning, when secreting hormones give rise to a clinical syndrome, or non-functioning (see table 1, attached). All require endocrine evaluation.

Primary Adrenal Insufficency

Primary adrenal cortical failure (Addison's disease) has an estimated prevalence of 40-60 per million, but a few studies indicate that prevalence may be as high as 120 per million.1 In a GP practice of 2,000 patients there will be 1-3 cases of Addison's disease.

The cause is autoimmune in approximately 70% of cases, in 10-20% it is caused by tuberculosis, with the remainder resulting from a range of other causes (see table 2, attached).

Secondary or tertiary adrenal insufficiency is caused by hypothalamo-pituitary-adrenal axis suppression, which results when high-dose steroids (prednisolone at doses of 7.5mg or more daily) are withdrawn rapidly.

Autoimmune adrenal disease

Adrenal antibodies are detected in 60-75% of patients with Addison's disease. Approximately 50% of patients with Addison's have other autoimmune endocrine disorders, whereas patients with more common autoimmune endocrine disorders, for example type 1 diabetes, hypothyroidism and Graves' disease, rarely develop adrenal insufficiency.

The combination of Addison's disease and other autoimmune endocrine disorders is referred to as polyglandular autoimmune syndromes types 1 and 2. Type 1 is characterised by a combination of mucocutaneous candidiasis, hypoparathyroidism and Addison's disease. It usually presents in childhood. Type 2 is characterised by Addison's disease, thyroid disease and type 1 diabetes.

Menstrual disturbance is common in Addison's disease. Weight loss and chronic illness may be contributory factors in amenorrhoea. Associated autoimmune premature ovarian failure may also occur.

Tuberculous adrenalitis

Tuberculous adrenalitis results from haematogenous spread from infection elsewhere;2 extra-adrenal tuberculosis is usually evident, but may be latent. Anti-tuberculous chemotherapy restores adrenal function in a minority of patients. The majority of patients do not recover adrenal function.3

When to suspect adrenal insufficiency

41140696Most patients with adrenal insufficiency present with fatigue, poor appetite, dizziness, frequent infections, weight loss and nausea, and may have evidence of other autoimmune conditions. Rarely, patients present with adrenal crisis caused by intercurrent infection or stress (see table 3, left).

Physical examination may elicit low blood pressure, postural hypotension, hyperpigmentation of the buccal mucosa or scars caused by the melanocortin action of excess ACTH hormone, and signs of myopathy, systemic tuberculosis and autoimmune disorders such as vitiligo.

Differential diagnosis may include gastroenteritis. Nausea and vomiting are more frequent and diarrhoea less common in Addison's disease. The hyperpigmented skin, mucous membranes and the history of preceding symptoms of fatigue and weight loss should point towards adrenal pathology.

The following tests should be carried out in primary care:

• Urea and electrolytes, for hyponatraemia and hyperkalaemia

• Glucose, for hypoglycaemia

• Calcium, for hypercalcaemia

• Thyroid function tests, to detect thyroid pathology.

These initial tests are only a guide; they are neither sensitive nor specific.

The patient should be referred urgently (within two weeks) for specialist endocrinological assessment to establish the diagnosis of Addison's disease. The tests will include the short synacthen test to measure cortisol and other endocrine tests for ACTH, adrenal antibodies, renin and aldosterone.

Management

Adrenal crisis: Adrenal crisis, once suspected, is a life-threatening emergency that requires immediate treatment in a hospital setting. The mainstay of therapy is intravenous hydrocortisone 100mg injections every 8 hours and 4-6 litres of 0.9% intravenous saline daily.

Chronic primary adrenal insufficiency: An important aspect of long-term management will be patient and family education. Education should include:

• The reason for lifelong replacement therapy

• The need to increase the dose of glucocorticoids during minor and major stress

• How to inject hydrocortisone in an emergency

• The importance of wearing a

MedicAlert bracelet and informing medical staff of the patient's condition if undergoing surgery.

Education should be alongside hormone replacement therapy:

• Glucocorticoid replacement: Hydrocortisone 20mg per day, 10mg on waking, 5mg at noon and 5 mg at 5pm, is the preferred regimen.4 Other corticosteroids, for example prednisolone at a dose of 5 to 7.5mg per day can be used.

• Mineralocorticoid replacement: Fludrocortisone, a synthetic mineralocorticoid, at a dose of 0.1 mg to 0.2 mg per day.5

• DHEAS replacement: The adrenal gland is an important source of androgens in women. DHEAS replacement, 25mg once a day, can be used to treat women with adrenal insufficiency; however, its role in routine management is not yet established.6

During minor illnesses or following minor surgical procedures the dose of glucocorticoid should be increased, up to twice or three times the usual maintenance dose for 2 or 3 days, because of the increased cortisol requirements during stress/surgery. Fludrocortisone doses do not need to be increased.

Cushing's syndrome

Cushing's syndrome is characterised by excess adrenocortical hormone production. In approximately 70% of cases of spontaneous overproduction of cortisol the cause is a pituitary tumour secreting ACTH, when it is known as Cushing's disease.

When the source of excess cortisol production is a tumour of the adrenal gland itself, it does not depend on ACTH. Adrenal adenoma and carcinoma account for the majority of cases with an adrenal cause and 10-20% of all cases of Cushing's syndrome.7

Clinical features

41140697The clinical features of this condition are caused by excess adrenal glucocorticoid, mineralocorticoid and androgen secretion. Hypertension, easy bruising and myopathy are found in more than 90% of patients with Cushing's syndrome (see table 4, left).

Evidence of virilisation (baldness and hirsutism) and rapid progression of the condition suggest an adrenocortical carcinoma. The following tests should be undertaken in primary care:

• Urea and electrolytes, for hypernatraemia and hypokalaemia

• Glucose, for hyperglycaemia

• 24-hour urine cortisol repeated on three separate days. The urine samples will be stable enough to send to the laboratory on the next available transport (urgent transfer is not needed).

Cushing's syndrome is a complex disease, which demands a high degree of clinical suspicion and referral to a specialist for further tests. These will include 24-hour urine cortisol, diurnal serum cortisol and dexamethasone suppression tests, both low and high dose, measurement of ACTH levels and CT or MRI imaging.

Management

The goals of therapy for Cushing's syndrome are resection of the tumour and a reduction in hypercortisolaemia.

The definitive management of adrenal Cushing's is by adrenalectomy, carried out as a laparoscopic procedure. Adenoma is almost always treated by unilateral adrenalectomy.9 Bilateral adrenalectomy is effective in bilateral micronodular adrenal hyperplasia and macronodular adrenal hyperplasia. In comparison, adrenal carcinomas are metastatic at presentation, almost invariably recur, and usually do not respond to either irradiation or chemotherapy.10 Adrenal carcinomas are diagnosed by imaging and histology.

Medical management involves blocking adrenal cortisol synthesis by use of adrenal enzyme inhibitors, such as metyrapone 250 to 500mg three times a day. In patients with adrenal carcinoma, an adrenolytic, mitotane, is used to control symptoms of excess cortisol.10

Primary Hyperaldosteronism

Primary hyperaldosteronism results from hypersecretion of aldosterone from one or both adrenal glands. This is characterised by increased aldosterone levels, low plasma renin and an elevated plasma aldosterone:plasma renin (PA:PRA) ratio.11

The most common cause of primary hyperaldosteronism is adrenal adenoma (Conn's adenoma), which accounts for nearly 70% of cases. Other causes include micronodular or macronodular adrenal hyperplasia, glucocorticoid suppressible hyperaldosteronism and aldosterone producing adrenocortical carcinoma.

Conn's syndrome is caused by a benign adrenal adenoma and occurs most commonly in women. Although there is autonomous secretion of aldosterone, these tumours are responsive to ACTH, whereas adrenal hyperplasia is responsive to angiotensin.

Secondary hyperaldosteronism is characterised by high aldosterone and high renin levels and the most common cause is renovascular hypertension.

Red flags

Primary hyperaldosteronism should be suspected in patients with:

• Hypertension that is resistant to conventional therapy12

• Spontaneous hypokalaemia with hypertension

• Hypokalemia (including patients treated with low-dose diuretics)

• An adrenal incidentaloma and hypertension.

Hypertensive patients with hypokalaemia should be referred to an endocrinologist for measurement of renin and aldosterone levels, adrenal venous sampling and imaging.

Management

In patients with unilateral aldosterone hypersecreting tumours, for example adrenal adenoma or unilateral adrenal hyperplasia, laparoscopic unilateral adrenalectomy is the treatment of choice.13 Hypokalaemia should be corrected with spironolactone preoperatively.

Treatment of idiopathic adrenal hyperplasia consists of mineralocorticoid receptor blockade with spironolactone, or eplerenone, a highly selective mineralocorticoid receptor antagonist.

Phaeochromocytoma


Catecholamine secreting tumours that arise from the adrenal medulla and the sympathetic ganglia are referred to as phaeochromocytomas.

Catecholamine secreting tumours are rare neoplasms, probably occurring in less than 0.2% of patients with hypertension.

The classic triad of symptoms in patients with a phaeochromocytoma are episodic headache, sweating and tachycardia. On clinical examination findings include hypertension, pallor and orthostatic hypotension indicating a low plasma volume.14

Symptoms and signs

Patients with phaeochromocytoma may present with:

• Hyperadrenergic spells (palpitations, sweating, headache, tremor and pallor)

• Resistant hypertension

• Familial syndromes that predispose to catecholamine secreting tumours, for example multiple endocrine neoplasia type 2, neurofibromatosis type 1 and von Hippel-Lindau syndrome

• Onset of hypertension at a young age (under 20 years).

Patients should be tested in primary care for calcium, as hypercalcaemia is present in multiple endocrine neoplasia type 2, and undergo 24-hour urine catecholamine testing repeated on two separate days. These samples are collected in acid-containing bottles and do not require urgent transfer to the laboratory.

Positive signs and raised urine catecholamine levels should prompt referral for management by an endocrinologist.

CT imaging of the abdomen and 123I-metaiodobenzylguanidine (MIBG) scintigraphy are both helpful in evaluating phaeochromocytoma.

Management

The goals of therapy are pre-operative preparation with the alpha adrenergic blocker phenoxybenzamine at a dose of 10mg to 40mg twice daily, and beta blockade with propranolol 20mg to 40mg three times a day. The definitive treatment is surgical removal of the adrenal tumour and the entire unilateral adrenal gland by laparoscopy.15

Adrenal incidentalomas

Incidentally discovered adrenal masses greater than 1cm on radiological imaging must be investigated to detect malignancy and subtle hormonal overproduction. Patients should therefore be referred promptly to a specialist. The incidence of adrenal incidentaloma may be as high as 10% of the ‘normal' population. Most of the adrenocortical carcinomas in a case series were greater than 7cm in diameter. For prophylactic purposes, adrenal incidentalomas greater than 4cm should be treated by surgery, and for those smaller than that, close radiological monitoring is appropriate as follow up.16

Adrenal disorders as a group are complex clinical conditions. The majority of patients present to their GP and diagnosing a specific adrenal disorder requires a high degree of clinical suspicion, prompting appropriate investigations and a detailed management plan.

Useful information

MedicAlert, a registered charity, provides identification bracelets for patients with serious conditions bearing their personal ID number, medical details and the organisation's 24-hour emergency phone number.
www.medicalert.org.uk

authors Authors

Dr Jaidev Sudagani
MB BS MRCP
specialist registrar in endocrinology, Hope Hospital, Salford

Dr Tara Kearney
BSc MB BS MD FRCP
consultant endocrinologist, Hope Hospital, Salford

key points adrenal Key points adrenal table 1 Table 1: Causes of adrenal disorders table 2 adrenal Table 2: Causes of primary adrenal insufficiency in Western countries Table 3: adrenal adrenal table 4

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