Endocrinology: Disorders of the Adrenal Gland

Steroid physiology and biochemical
19 assessment

Steroid synthesis

The adrenal cortex is functionally divided into three zones which produce aldosterone (zona glomerulosa), cortisol (zona fasciculata) and androgens (zona reticularis). Steroid synthesis proceeds from cholesterol through a series of intermediary steps regulated by enzymes (Figure 19.1).

Glucocorticoids

Cortisol is the major glucocorticoid and has a key role in the regulation of metabolic, cardiovascular and immune responses. Its synthesis is regulated by ACTH; cortisol exerts negative feedback on the hypothalamus, to reduce vasopressin and corticotrophin releasing hormone (CRH) production, and on the anterior pituitary to reduce ACTH (Figure 19.2). Cortisol is secreted in a circadian rhythm, with highest levels on waking at 08.00 falling gradually to very low levels at midnight (Figure 19.3). This has diagnostic relevance with respect to timing of cortisol measurement in the assessment of adrenal insufficiency and Cushing’s syndrome (Chapter 20). Most cortisol circulates bound to CBG (80–90%) and albumin (5–10%), with only a small proportion existing in the free biologically active state. Current cortisol immunoassays measure total (bound and free) cortisol, hence conditions that stimulate CBG levels (e.g. oestrogen therapy) can increase measured cortisol levels without affecting biologically active free levels.

Adrenal androgens

Adrenal androgens are principally controlled by ACTH. They are of minor importance in adult men because testosterone secreted by testicular Leydig cells is the main circulating androgen. They have a more important physiological role in adult women and in both sexes pre-pubertally. The main examples are dehydroepiandrosterone (DHEA and its sulfated form, DHEA-S), and androstenedione. They are converted to the more potent androgens testosterone and, via the enzyme 5α-reductase, dihydrotestosterone in peripheral tissues. Androgens exert their effects on sebaceous glands, hair follicles, the prostate gland and external genitalia.

Mineralocorticoids

Aldosterone is the major mineralocorticoid. In contrast to cortisol and adrenal androgens, its synthesis is mainly regulated by the renin–angiotensin system. In response to low circulating blood volume, hyponatraemia or hyperkalaemia, renin is activated in the juxtaglomerular apparatus of the kidney to catalyse the conversion of angiotensinogen to angiotensin I, which is subsequently converted by angiotensin converting enzyme (ACE) to angiotensin II (Figure 19.4). It stimulates aldosterone release upon binding to the angiotensin receptor.
Aldosterone acts mainly at the renal distal convoluted tubule to cause sodium retention and potassium loss.

Biochemical assessment of the
adrenal axis

An early morning cortisol (08.00–09.00) of <100 nmol/L is strongly suggestive of adrenal insufficiency, whereas a value of >500 nmol/L excludes the diagnosis in virtually all cases, with the caveat that interpretation must take into account the clinical status of the patient because a ‘normal’ level for a healthy individual can be entirely inappropriate for someone who is critically ill. Random cortisol measurements rarely fall into these diagnostic extremes, however, such that a stimulation test is needed to confirm integrity or otherwise of the HPA axis. A short ACTH stimulation test (Synacthen test) is the key investigation. This involves IV (or IM) administration of Synacthen (250 μg), with measurement of cortisol at baseline and 30 minutes after injection. A rise in serum cortisol to 500–550 nmol/L indicates a normal response and excludes the diagnosis. However, interpretation must take into account the local assay used and oestrogen therapy, which can raise total cortisol by CBG stimulation. An additional practice point is that falsely reassuring normal responses can be seen in recent onset secondary adrenal insufficiency (e.g. after pituitary surgery),
where adrenal atrophy has not yet ensued and the cortex consequently retains its ACTH responsiveness. The test can be performed at any time of day because it is the peak value that is relied upon for interpretation.

Adrenal insufficiency

Primary adrenal insufficiency

Primary adrenal failure, or Addison’s disease, arises as a result of a destructive process in the adrenal gland or genetic defects in steroid synthesis. All three zones of the adrenal cortex are typically affected.

Symptoms and signs

The onset is usually gradual. Symptoms may be non-specific, hence it is important to maintain a high index of suspicion for the diagnosis. Most commonly, patients describe fatigue, weakness, anorexia, weight loss, nausea and abdominal pain. Dizziness and postural hypotension occur as a result of mineralocorticoid deficiency whereas glucocorticoid loss leads to hypoglycaemia, and increased pigmentation as a result of ACTH excess (leading to melanocyte stimulation) from reduced cortisol negative feedback. Androgen deficiency in women can lead to reduced libido and loss of axillary and pubic hair.

Causes

There are several causes of primary adrenal failure but autoimmune adrenalitis is by far the most common cause in
Western populations, and is supported by detection of positive adrenal autoantibodies. Other causes are rare but should be considered when antibody testing is negative (Table 20.1).

Investigations

Routine laboratory tests show hyponatraemia (>90%), hyperkalaemia, raised urea, hypoglycaemia and a mild anaemia.
However, specific tests are needed to make the diagnosis. A low 09.00 cortisol and simultaneously raised ACTH concentration is suggestive of the diagnosis, although a Synacthen test is generally needed for confirmation (Table 20.2).

Management

Emergency treatment of adrenal crisis

This is considered in Figure 20.1.

Maintenance treatment

Patients with primary adrenal failure need lifelong glucocorticoid and mineralocorticoid replacement therapy. Hydrocortisone is the glucocorticoid of choice, which is given in total daily doses of 15–30 mg, divided into two (e.g. 10 mg twice daily) or three doses (e.g. 10 mg on waking, 5 mg at lunchtime and 5 mg in the early evening). Mineralocorticoid replacement is given as fludrocortisone 50–200 μg once daily. Patients should be instructed to double the dose of their glucocorticoid at times of illness, and continue on a doubled dose until their illness has resolved. Glucocorticoids need to be administered IV or IM during surgery or in cases of prolonged vomiting or diarrhoea. Patients should be provided with a steroid emergency card (Figure 20.2), encouraged to wear medical alert
jewellery and be provided with emergency contact details for their endocrine team.

Secondary adrenal insufficiency

Secondary hypoadrenalism can arise as a result of any cause of hypopituitarism (Chapter 5). Patients display similar
symptoms and signs to primary adrenal insufficiency, with the exception that pigmentation is absent, as ACTH is not
raised, and mineralocorticoid deficiency is not a feature, because aldosterone secretion is not significantly influenced
by ACTH. As with primary adrenal failure, diagnosis relies upon a failure to demonstrate a rise in cortisol following
Synacthen administration, coupled with demonstration of an inappropriately low/low–normal plasma ACTH level. The
insulin stress test can also be used to diagnose ACTH deficiency (Chapter 2). The principles of hydrocortisone replacement and dose adjustment are the same as for primary adrenal failure but fludrocortisone replacement is not required as mineralocorticoid secretion is intact.

Steroid-induced hypoadrenalism

Corticosteroids are frequently prescribed as anti-inflammatory drugs. An important consequence is suppression of the HPA axis, particularly when prescribed in high doses and/or over a long period of time. Consequently, sudden cessation of longterm therapy can lead to adrenal crisis. Patients taking longterm steroids should thus be instructed not to stop their steroids abruptly, at least until an adequate adrenal reserve has been demonstrated. As with other causes of adrenal insufficiency, patients should carry a steroid card and be educated about steroid supplementation at times of illness.

Adrenocortical tumours

Adrenal Cushing’s syndrome

Adrenal tumours cause Cushing’s syndrome when they secrete glucocorticoids or their metabolites. In this situation, ACTH is suppressed (‘ACTH-independent’ Cushing’s syndrome; Chapter 4) and there may be features of hyperandrogenism with or without virilisation (androgenic alopecia, deepening of the voice, clitoromegaly) if adrenal androgens are co-secreted by an adrenal adenoma or carcinoma (Figure 21.1). Severe hirsutism and virilisation, particularly when associated with a large adrenal tumour (often >10 cm), strongly suggest an adrenal carcinoma.
For adrenal adenomas, adrenalectomy, usually undertaken laparoscopically, is curative. Postoperative hypoadrenalism
can occur because of contralateral adrenal suppression from previously high circulating glucocorticoid levels. This requires steroid cover with hydrocortisone or prednisolone until the HPA axis has recovered, which may take many months. Adrenal carcinoma is very rare, carrying a poor prognosis, with only 30% patients surviving 5 years. Where feasible, open surgery aimed at complete tumour resection should be considered, as this is the only treatment that can offer cure. Patients with metastatic disease can be treated with a combination of radiotherapy, chemotherapy and the adrenal-specific cytotoxic agent mitotane.

Primary hyperaldosteronism

Primary hyperaldosteronism is caused by either an aldosterone-producing adrenal adenoma (Conn’s syndrome)
or the more common bilateral adrenal hyperplasia. Primary hyperaldosteronism is the most common form of endocrine hypertension, whereby aldosterone secretion is inappropriately elevated and independent of the renin–angiotensin system. Classically, patients present with hypertension and a hypokalaemic alkalosis (Figure 21.2). Hypokalaemia is not always present, especially in bilateral hyperplasia. Screening for primary
hyperaldosteronism should be considered in patients with young onset hypertension, refractory hypertension (>3 anti-hypertensive agents), hypertension with hypokalaemia and in hypertensive patients found incidentally to harbour an adrenal adenoma. A random, ambulant aldosterone : renin ratio is the screening method of choice, but drugs that interfere with the renin–angiotensin system, especially beta-blockers, may need to be discontinued for
a few weeks in advance for accurate interpretation. Patients with biochemically confirmed disease require imaging
of the adrenal glands by CT or MRI. Bilateral adrenal hyperplasia is treated with aldosterone receptor antagonists (spironolactone or eplerenone). Patients with unilateral adenomas can benefit from laparoscopic adrenalectomy, which cures hypokalaemia in 100% and hypertension in 70% of patients. Adrenal vein sampling may be required to confirm unilateral aldosterone excess.

Adrenal incidentalomas

The term adrenal incidentaloma applies to an adrenal mass 1 cm in size which is discovered unintentionally in the work-up of clinical disorders unrelated to adrenal disease. Such adrenal nodules are common, with a discovery rate of >4% in patients over the age of 50 years using CT or MRI (Figure 21.3). Most tumours are benign and hormonally inactive, but all require work-up to exclude malignancy and hormone excess (Table 21.1). The likelihood of hormonal hypersecretion is greater with increasing size of the tumour, with the exception of aldosterone producing adenomas, which tend to be small (<1 cm). The risk of malignancy also increases with size, such that adrenalectomy is indicated when tumours are >4 cm regardless of hormonal status. Adrenalectomy is also indicated for tumours showing hormone excess, although there is some uncertainty surrounding the merits of surgery in those with low grade cortisol secretion (subclinical Cushing’s syndrome).
The diagnostic work-up of these tumours should include an unenhanced CT scan: low density lesions, often expressed in Hounsfield units, support a benign, lipid-rich adenoma whereas those with higher density are indeterminate and require further characterisation. Tumours that are vascular, calcified and heterogeneous are unlikely to be benign incidentalomas. The biochemical work-up should include measurement of plasma or urinary metanephrines (Chapter 22), plasma aldosterone : renin ratio and a 1 mg overnight DST (Chapter 4) to test for phaeochromocytoma, primary hyperaldosteronism and Cushing’s syndrome, respectively.

Disorders of the adrenal medulla

Phaeochromocytoma and paraganglioma

Definition

Phaeochromocytomas are catecholamine-secreting tumours which occur in about 0.1% of patients with hypertension. In about 90% of cases they arise from the adrenal medulla. The remaining 10%, which arise from extra-adrenal chromaffin tissue, are termed paragangliomas (Figure 22.1). Most phaeochromocytomas are sporadic but a genetic basis is recognised in up to 30% of patients (Table 22.1), especially in bilateral, extra-adrenal or malignant tumours (<10%).

Symptoms and signs

Common presenting symptoms include one or more of headache, sweating, pallor and palpitations. Less commonly, patients describe anxiety, panic attacks and pyrexia. Hypertension, whether sustained or episodic, is present in at least 90% of patients. Left untreated, phaeochromocytomas can occasionally lead to hypertensive crisis, encephalopathy, hyperglycaemia, pulmonary oedema, cardiac arrhythmias or even death. Patients with undiagnosed phaeochromocytomas having routine surgery can develop severe hypertension or sudden death.

Investigations

Diagnosis relies on the biochemical confirmation of elevated catecholamines or their metabolites (metanephrines), followed by radiological localisation of the tumour.

Biochemistry

The biochemical screening investigation of choice is usually 24-hour urinary fractionated metanephrines with or without free catecholamines. Two or more collections may be needed if the index of suspicion is high because of the episodic nature of tumour secretion. Measurement of plasma metanephrines has replaced urine collection in many centres, and is especially useful if measured during symptoms or crisis. Serum chromogranin A levels, a marker of neuro-endocrine hypersecretion, can be elevated in phaeochromocytoma or paraganglioma.

Radiology

CT (Figure 22.2) or MRI of the abdomen are the initial imaging modalities of choice, followed by whole-body MRI if the tumour is not localised. 123I-meta-iodobenzylguanidine (MIBG) can locate tumours not seen on MRI and is useful pre-operatively to exclude multiple tumours (Figure 22.3).

Genetic testing

Genetic testing is indicated in patients with syndromic presentations but also in many apparently sporadic tumours,
because up to 30% harbour germline mutations in susceptibility genes. Mutations are more likely in patients presenting at a young age, or in those with multifocal, malignant or extra-adrenal disease. Identification of a predisposing mutation should lead to annual screening for new or recurrent disease in index cases, and cascade genetic testing of first degree relatives.

Management

The definitive treatment is surgical excision, which is performed laparoscopically or through an open procedure. In advance of surgery, it is mandatory that all patients are protected from the effects of catecholamine excess by pharmacological alpha with or without beta-blockade. Alpha-blockade, conventionally administered as oral phenoxybenzamine, should be commenced before beta-blockade in order to avoid unopposed alpha-adrenergic
stimulation and the risk of hypertensive crisis. Beta-blockers can be introduced subsequently to control reflex
tachycardia.

Prognosis

Five-year survival for apparently benign tumours is 96% and the recurrence rate is less than 10%. Successful surgical removal leads to cure of hypertension in most patients. Malignant disease can be treated with 131-I MIBG therapy or chemotherapy. There is increasing interest in the use of newer radionuclides in both the diagnosis and treatment of metastatic disease.