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Disorders of the adrenal cortex 

Disorders of the adrenal cortex
Chapter:
Disorders of the adrenal cortex
Author(s):

P.M. Stewart

DOI:
10.1093/med/9780199204854.003.130701_update_001

Update:

Diagnosis of Cushing’s syndrome and primary aldosteronism—minor alterations as recommended by recent Endocrine Society guidelines.

Updated on 30 November 2011. The previous version of this content can be found here.
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Essentials

Three classes of steroid hormone are produced by the adrenal cortex after uptake of precursor cholesterol from the plasma: (1) mineralocorticoids—aldosterone, deoxycorticosterone; secreted in low amounts (100–150 µg aldosterone/day) from the zona glomerulosa, mainly under the control of angiotensin II; enhance uptake of sodium principally in the colon and kidney tubule by binding to receptors whose specificity for mineralocorticoids is established in these tissues by expression of 11 β‎-hydroxysteroid dehydrogenase 2, which converts cortisol to inactive cortisone; (2) glucocorticoids—cortisol, corticosterone; secreted in larger amounts (10–20 mg cortisol/day) from the zona fasciculata in response to stimulation by ACTH; have wide-ranging effects mediated by glucocorticoid receptors; and (3) sex steroids—principally dehydroepiandrosterone (DHEA) and its sulphated derivative (DHAS).

Classical endocrine feedback loops control secretion of these hormones: (1) aldosterone-induced retention of sodium inhibits secretion of renin; (2) cortisol inhibits secretion of both corticotropin-releasing factor (CRF) from the hypothalamus and ACTH from the pituitary.

Adrenocortical diseases are relatively uncommon, but their ease of diagnosis and the availability of effective treatment contribute to their importance in clinical practice. Hormonal deficiency or excess is usually the result of abnormal secretion, but similar functional defects may be caused by deranged metabolism of corticosteroids or by defective receptors. With increasing use of radiological investigations a frequent diagnosis is a patient with an underlying incidental tumour (‘incidentaloma’) of the adrenal: these are usually nonfunctional and benign.

Glucocorticoid excess

Cushing’s syndrome may be (1) ACTH-dependent—usually due to a pituitary adenoma (Cushing’s disease), but sometimes to nonpituitary tumours producing ACTH (most commonly small-cell carcinoma of the bronchus); (2) ACTH-independent—most often adrenal adenoma (rarely carcinoma).

Clinical features—typical presentation is with ‘classical’ manifestations of centripetal obesity, moon face, hirsutism, and plethora, with signs (when present) that best distinguish from simple obesity being bruising and muscle weakness (typically proximal).

Diagnosis of the presence of Cushing’s syndrome—this can be confirmed by finding (1) elevated 24-h urinary free cortisol; and/or (2) raised midnight salivary/plasma cortisol; and/or (3) impaired plasma cortisol suppression (09.00 h sample) in response to a low-dose overnight dexamethasone suppression test.

Diagnosis of the cause of Cushing’s syndrome—ACTH-dependent causes can be distinguished from ACTH-independent causes by measurement of plasma ACTH (09.00 h sample). Determining whether elevated ACTH is coming from the pituitary (Cushing’s disease) or from an ectopic source can be difficult, but may be achieved by consideration of (1) plasma potassium—hypokalaemia is a typical feature of ectopic ACTH but not of Cushing’s disease; (2) high-dose dexamethasone suppression test—which tends to suppress plasma cortisol in Cushing’s disease but not ectopic ACTH; (3) CRF test—producing an exaggerated rise in ACTH and cortisol in Cushing’s disease but not in ectopic ACTH; (4) inferior petrosal sinus sampling/selective venous catheterization—the most robust test to distinguish Cushing’s disease from ectopic ACTH syndrome.

Imaging—pituitary MRI is the investigation of choice if biochemical testing suggests Cushing’s disease, and abdominal CT scanning if biochemical testing suggests ACTH-independent Cushing’s syndrome.

Management—drugs that interfere with cortisol synthesis (e.g. metyrapone, ketoconazole) can lower cortisol levels, but definitive treatment depends on the cause: (1) adrenal adenomas—unilateral adrenalectomy; (2) Cushing’s disease—trans-sphenoidal removal of the pituitary tumour; (3) ectopic ACTH—surgical removal of the tumour is rarely possible but can lead to cure.

Glucocorticoid deficiency

Glucocorticoid deficiency can be due to adrenal disease (primary, in which case mineralocorticoids are also deficient) or because of deficiency of ACTH (secondary, in which case only glucocorticoids are deficient).

Aetiology—primary hypoadrenalism (Addison’s disease) is most commonly caused by autoimmune disease (>70% cases in the Western world, associated with adrenal autoantibodies in many cases, and sometimes with other organ-specific autoimmune diseases) or infection, e.g. tuberculosis (the commonest cause worldwide). The commonest cause of secondary hypoadrenalism is stopping of exogenous glucocorticoid therapy or its inadequacy in stressful situations.

Clinical features—primary adrenal failure may present (1) acutely—with hypotension and acute circulatory failure (Addisonian crisis); or (2) chronically—with vague features of ill health, sometimes including gastrointestinal symptoms, features suggestive of postural hypotension, and salt craving. Skin pigmentation is nearly always present in primary adrenal insufficiency (but not in secondary).

Biochemical diagnosis—this depends on an ACTH stimulation test: plasma cortisol should rise to over 550 nmol/litre in response to injection of tetracosactrin (Synacthen, 250 µg) and failure to do so indicates adrenal insufficiency. In primary adrenal insufficiency the plasma ACTH level is disproportionately elevated in comparison with plasma cortisol.

Management—acute adrenal insufficiency is a medical emergency requiring volume resuscitation and parenteral steroid replacement, e.g. hydrocortisone 100 mg intravenously every 6 h, along with treatment of any precipitating condition, e.g. infection. Long-term treatment requires (1) glucocorticoid replacement—typically hydrocortisone, 20 mg on wakening and 10 mg at 18.00 h, to be doubled in the event of intercurrent stress or illness; (2) mineralocorticoid replacement—fludrocortisone, 0.05 to 0.1 mg/day, is usually required in primary adrenal failure. Every patient should be advised to wear a MedicAlert bracelet or necklace and to carry a ‘steroid card’.

Mineralocorticoid excess

Primary aldosteronism (Conn’s syndrome) is the commonest cause of mineralocorticoid hypertension and may be caused by an aldosterone-producing adenoma of the adrenal gland or by bilateral adrenal hyperplasia. The presence of primary aldosteronism is not easy to diagnose, but in the absence of confounding influences is suggested by a high random plasma aldosterone (PAC)/renin (PRA) ratio if PAC is over 400 pmol/litre (15ng/dl). The cause of primary aldosteronism is also difficult to establish: adrenal MRI/CT scanning may demonstrate an adenoma; adrenal vein cannulation with sampling for estimation of aldosterone/cortisol ratio may be required in difficult cases. Treatment of adrenal adenoma is by surgical excision and of bilateral adrenal hyperplasia is medical, usually with spironolactone.

A number of single-gene defects can cause mineralocorticoid excess, including 17α‎-hydroxylase deficiency, 11β‎-hydroxylase deficiency, glucocorticoid-suppressible hyperaldosteronism (due to formation of a chimeric gene, 11β‎-hydroxylase/aldosterone synthase), and apparent mineralocorticoid excess (mutations in 11β‎-hydroxysteroid dehydrogenase type 2 gene).

Mineralocorticoid deficiency

This is most commonly seen in the context of primary hypoadrenalism (see above) but is also caused (rarely) by conditions including primary defects in aldosterone biosynthesis, defects in aldosterone action, and hyporeninaemic hypoaldosteronism (most commonly in the context of diabetic nephropathy).

Introduction

An initial rate-limiting step in adrenal steroidogenesis is the uptake of cholesterol from circulating cholesterol bound to low-density lipoprotein, by mitochondria in the adrenal cortex. This process is dependent upon steroidogenic acute regulatory protein. Thereafter, the functional zonation of the adrenal cortex is in part achieved through the discrete expression and regulation of the genes for the final steroidogenic enzymes: aldosterone synthase (EC 1.14.15.5) in the zona glomerulosa, and 11β‎-hydroxylase (EC 1.14.15.4) in the zona fasciculata (Fig. 13.7.1.1).

Fig. 13.7.1.1 Pathways of adrenocortical steroid biosynthesis.

Fig. 13.7.1.1
Pathways of adrenocortical steroid biosynthesis.

Aldosterone acts physiologically to stimulate sodium transport across epithelial cells in the distal nephron, colon, and salivary gland. This involves the interaction of aldosterone with the mineralocorticoid receptor, and the induction of the expression of the genes for the basolateral Na+,K+-ATPase pump and the apical sodium channel. This is mediated by the induction of SGK1, the gene for serum/glucocorticoid-regulated kinase 1. The mineralocorticoid receptor, however, is nonselective in vitro; paradoxically, cortisol and aldosterone have the same intrinsic affinity for this receptor, raising the question of why aldosterone is the preferred mineralocorticoid in vivo. This selectivity is achieved at a prereceptor level through the production of an enzyme, 11β‎-hydroxysteroid dehydrogenase type 2 (11β‎-HSD2; HSD11B2; EC 1.1.1.1.46), which efficiently inactivates cortisol to cortisone, allowing aldosterone to occupy the mineralocorticoid receptor. The inhibition of 11β‎-HSD2 results in cortisol, conventionally regarded as a glucocorticoid, acting as a potent mineralocorticoid.

Glucocorticoids have more diverse and extensive roles than mineralocorticoids, regulating sodium and water homeostasis, glucose and carbohydrate metabolism, inflammation, and stress. These effects are mediated by the interaction of cortisol with ubiquitous glucocorticoid receptors, and the induction or repression of target gene transcription.

Adrenocortical diseases are most readily classified by whether they are characterized by hormone excess or deficiency (Table 13.7.1.1).

Table 13.7.1.1 Adrenocortical diseases

Glucocorticoid excess

Cushing’s syndrome

Glucocorticoid deficiency

Primary:

Congenital adrenal hyperplasia (21-hydroxylase, P450 oxido-reductase, 3β‎-hydroxysteroid dehydrogenase, 17-hydroxylase, 11 β‎-hydroxylase, and StAR deficiencies)

Addison’s disease

Hereditary adrenocortical unresponsiveness to ACTH

Secondary:

Post-corticosteroid therapy

Hypothalamic/pituitary disease

Mineralocorticoid excess

Aldosteronism

Other mineralocorticoids—monogenic forms of hypertension

Glucocorticoid resistance

Mineralocorticoid deficiency

Congenital adrenal hyperplasia

Congenital adrenal hypoplasia

Disorders of terminal part of aldosterone biosynthetic pathway

Pseudohypoaldosteronism

Hyporeninaemia

Addison’s disease

Adrenal androgens

Excess:

Congenital adrenal hyperplasia (21-hydroxylase, 11 β‎-hydroxylase deficiency)

Polycystic ovary syndrome (PCOS), tumours

Deficiency:

Congenital adrenal hyperplasia (17-hydroxylase, 3β‎-hydroxysteroid dehydrogenase deficiency)

Adrenal incidentalomas and carcinomas

Glucocorticoid excess: Cushing’s syndrome

Harvey Cushing first described a case of polyglandular syndrome secondary to pituitary basophilia in 1912, and several years later linked this to bilateral adrenal hyperplasia. The first case of an adrenal adenoma was probably reported by H G Turney in 1913 (Fig. 13.7.1.2).

Fig. 13.7.1.2 H G Turney’s case of Cushing’s syndrome before and after developing the condition.

Fig. 13.7.1.2
H G Turney’s case of Cushing’s syndrome before and after developing the condition.

Definition

Cushing’s syndrome comprises the symptoms and signs associated with prolonged exposure to inappropriately elevated levels of free plasma glucocorticoids (Fig. 13.7.1.2). This definition thus takes into account the elevated corticosteroid levels that may be found in severely depressed patients, but which appear to be appropriate to the condition, and also the increased total (but normal free) glucocorticoid levels found when there is an increase in circulating cortisol-binding globulin (e.g. in patients on oestrogen therapy). The use of the term glucocorticoid in the definition covers both endogenous (cortisol) and exogenous steroid excess (e.g. prednisolone, dexamethasone).

The condition is most readily classified into ACTH-dependent and ACTH-independent causes (Table 13.7.1.2). The term ‘Cushing’s syndrome’ is used to describe all causes, whereas ‘Cushing’s disease’ is reserved for cases of pituitary-dependent Cushing’s syndrome.

Table 13.7.1.2 Classification of causes of Cushing’s syndrome

ACTH-dependent

Iatrogenic (treatment with ACTH1–39 or Synacthen®, ACTH1–24)

Cushing’s disease (pituitary-dependent)

Ectopic ACTH syndrome

Ectopic corticotrophin-releasing factor syndrome

ACTH-independent

Iatrogenic (such as pharmacological doses of prednisolone or dexamethasone)

Adrenal adenoma

Adrenal carcinoma

Carney’s syndrome

McCune–Albright syndrome

Aberrant receptor expression (gastric inhibitory polypeptide, interleukin 1β‎).

Alcohol

ACTH, adrenocorticotrophic hormone.

ACTH-dependent causes

Cushing’s disease

When iatrogenic causes are excluded, the most frequent cause of Cushing’s syndrome is Cushing’s disease, which accounts for approximately 70% of cases. The adrenal glands show bilateral adrenocortical hyperplasia, with widening of the zona fasciculata and zona reticularis. Nodules may form within the hyperplastic glands.

Cushing himself raised the question of whether his disease was a primary pituitary condition or secondary to an abnormality of the hypothalamus. There is abundant evidence to indicate that the condition is related to the pituitary rather than the hypothalamus. In over 90% of cases the disease is caused by a pituitary adenoma of monoclonal origin; basophilic hyperplasia is very uncommon, and selective surgical removal of the microadenoma usually results in cure, with a low recurrence rate.

Ectopic production of corticotropin-releasing factor (CRF)

This is a very rare cause of pituitary-dependent Cushing’s disease. However, cases have been described in which a tumour (e.g. medullary thyroid, prostate carcinoma) has been shown to produce CRF, but not ACTH.

Ectopic ACTH syndrome

Cushing’s syndrome may be caused by nonpituitary tumours producing ACTH, most commonly a malignant small-cell carcinoma of the bronchus (Table 13.7.1.3). However, the most challenging diagnostic problems relate to ACTH secretion from more benign and indolent carcinoid tumours, which may present with Cushing’s syndrome many years before the occult tumour manifests. These conditions are described further in Chapter 13.12.

Table 13.7.1.3 Tumours associated with the ectopic ACTH syndrome

Tumour type

Approximate incidence (%)

Small-cell lung carcinoma

50

Non-small-cell lung carcinoma

5

Pancreatic tumours (including carcinoids)

10

Thymic tumours (including carcinoids)

5

Lung carcinoids

10

Other carcinoids

2

Medullary carcinoma of thyroid

5

Phaeochromocytoma and related tumours

3

Rare carcinomas of prostate, breast, ovary, gallbladder, colon

10

ACTH-independent causes

Adrenal adenoma and carcinoma

With the exclusion of iatrogenic Cushing’s syndrome, a solitary cortisol-secreting adrenal adenoma is the cause in about 10% of cases. Carcinomas are rarer, have a poor prognosis, and may be associated with the secretion of other hormones in addition to cortisol (usually adrenal androgens). The aetiology of these tumours is unknown.

Carney’s syndrome (OMIM 160980)

This is an autosomal dominant condition involving mesenchymal tumours (especially atrial myxomas), spotty skin pigmentation, peripheral nerve tumours, and various endocrine tumours, one of which may lead to Cushing’s syndrome. The adrenals then contain multiple small, pigmented nodules. The condition has been described as pigmented multinodular adrenocortical dysplasia, and results from mutations in the regulatory subunit R1A of protein kinase A, causing adrenal hyperfunction.

McCune–Albright syndrome (OMIM 174800)

In this condition, fibrous dysplasia and cutaneous pigmentation may be associated with pituitary, thyroid, adrenal, and gonadal hyperfunction. The adrenal hypersecretion may produce Cushing’s syndrome. The underlying abnormality is a somatic mutation in the α‎ subunit of the stimulatory guanine nucleotide-binding protein (G protein) that is linked to adenylate cyclase. The mutation results in the G protein being constitutively activated, which, in the adrenal gland, mimics constant ACTH stimulation. Adrenal nodular formation may occur.

Aberrant receptor expression (OMIM 219080)

Patients have been described with nodular hyperplasia, ACTH-independent Cushing’s syndrome, and enhanced adrenal responsiveness to gastric inhibitory polypeptide (GIP). The biochemical clues are the presence of subnormal morning levels of plasma cortisol and a rise in cortisol after food. This food-dependent form of Cushing’s syndrome results from the normal increase in GIP after eating. Not surprisingly, the clinical syndrome is related to food intake; fasting can produce adrenal insufficiency. It is now appreciated that a similar form of Cushing’s syndrome can result from the aberrant expression of other receptors, including those for interleukin 1, luteinizing hormone, and serotonin.

Alcohol-associated pseudo-Cushing’s syndrome

In the original description of this syndrome, urinary and plasma cortisol levels were elevated, but were not suppressed with dexamethasone. Plasma ACTH may be normal or suppressed. The frequency and pathogenesis of this condition remain unknown, but a two-hit hypothesis has been put forward to explain its aetiology. Chronic liver disease, irrespective of the cause, is associated with impaired cortisol metabolism, but in alcoholics this is associated with an increase in the cortisol secretion rate, rather than concomitant suppression in the face of impaired metabolism. With abstinence from alcohol the biochemical abnormalities rapidly revert to normal.

Clinical features of Cushing’s syndrome

The classical features of Cushing’s syndrome—centripetal obesity, moon face, hirsutism, and plethora—are well known following Cushing’s initial description in 1912 (Figs. 13.7.1.2 and 13.7.1.3). However, this gross clinical picture is not always present. The signs and symptoms in patients with Cushing’s syndrome are listed in Table 13.7.1.4, together with the most discriminatory features distinguishing Cushing’s syndrome from simple obesity. Weight gain and obesity are the most common symptom and sign, but the distribution of fat is not invariably centripetal—a ‘buffalo hump’ is present in about one-half of patients.

Fig. 13.7.1.3 Typical facies of a patient with Cushing’s syndrome before and after treatment.

Fig. 13.7.1.3
Typical facies of a patient with Cushing’s syndrome before and after treatment.

Table 13.7.1.4 Prevalence of symptoms and signs in Cushing’s syndrome and discriminant index compared with prevalence of features in patients with simple obesity

%

Discriminant index

Symptoms

Weight gain

91

Menstrual irregularity

84

1.6

Hirsutism

81

2.8

Psychiatric

62

Backache

43

Muscle weakness

29

8.0

Fractures

19

Loss of scalp hair

13

Signs

Obesity

97

Truncal

46

1.6

Generalized

55

0.8

Plethora

94

3.0

Moon face

88

Hypertension

74

4.4

Bruising

62

10.3

Red/purple striae

56

2.5

Muscle weakness

56

Ankle oedema

50

Pigmentation

4

Other findings

Hypertension

74

Diabetes

50

Overt

13

Impaired GTT

37

Osteoporosis

50

Renal calculi

15

Data from Ross and Linch (1982).

GTT, glucose tolerance test.

Gonadal dysfunction is very common, with menstrual irregularity in females and loss of libido in males, resulting from a suppressive effect of cortisol on gonadotropin secretion. Hirsutism is frequently found in female patients, as is acne, and reflects ACTH-stimulated hyperandrogenism.

Psychiatric abnormalities have been reported in all series of patients with Cushing’s syndrome, regardless of cause. Depression and lethargy are among the most common problems, but poor concentration, paranoia, and overt psychosis are also well recognized. Lowering of plasma cortisol by medical or surgical therapy usually results in a rapid improvement in the psychiatric state.

Many patients with long-standing Cushing’s syndrome have lost height because of osteoporotic vertebral collapse. Pathological fractures, either spontaneous or after minor trauma, are not uncommon. Rib fractures, by contrast with those of the vertebrae, are often painless. The radiographic appearance is typical, with exuberant callus formation at the site of the healing fracture.

The plethoric appearance of the patient with Cushing’s syndrome results from thinning of the skin, not true polycythaemia. The typical red-purple livid striae of the syndrome are found most frequently on the abdomen, but may also be present on the upper thighs and arms. They are very common in younger patients, and less so in those over 50 years of age.

Myopathy and bruising are two of the most discriminatory features of the syndrome. The myopathy involves the proximal muscles of the lower limbs and the shoulder girdle. Complaints of weakness, such as an inability to climb stairs or get up from a deep chair, are relatively uncommon, but observation of whether the patient can rise from a crouching position often reveals the problem. Bruising of the skin is often extensive and occurs with unknown or trivial trauma.

Hypertension is another prominent feature. Even though epidemiological data show a strong association between blood pressure and obesity, hypertension is much more common in patients with Cushing’s syndrome than in those with simple obesity.

Pigmentation is rare in Cushing’s disease, but common in ectopic ACTH syndrome. However, in some pituitary tumours there is abnormal processing of the pro-opiomelanocortin (POMC) precursor molecule, with resulting pigmentation.

Infections are more common in patients with Cushing’s syndrome than in unaffected individuals. In many instances these are asymptomatic, as the normal inflammatory response may be suppressed. Reactivation of tuberculosis has been reported. Fungal infection of the skin is frequently found. Glucose intolerance may be a predisposing factor, with overt diabetes being present in up to one-third of patients in some series.

Ocular effects may include raised intraocular pressure, chemosis, and exophthalmos (present in up to one-third of patients in Cushing’s original series). Cataracts, a well recognized complication of exogenous corticosteroid therapy, seem to be uncommon, except as a complication of diabetes.

In patients with ectopic ACTH syndrome caused by small-cell lung carcinoma, the clinical presentation more commonly resembles Addison’s disease than Cushing’s syndrome. The patients are very commonly pigmented and have lost weight, but the association of these with hypokalaemic alkalosis and glucose intolerance should alert the clinician to the diagnosis. Patients with more indolent causes, such as bronchial carcinoids, present with the more typical features of Cushing’s syndrome.

Special features of Cushing’s syndrome

Cyclical Cushing’s syndrome

Of particular clinical interest has been a group of patients with cyclical Cushing’s syndrome, characterized by periods of excess cortisol production (e.g. 40 days), followed by intervals of normal cortisol production (e.g. 60–70 days). Some of these patients demonstrate a paradoxical rise in plasma ACTH and cortisol when treated with dexamethasone. Most patients have been thought to have pituitary-dependent disease, and in many of these patients basophil adenomas have been removed, some with long-term cure. However, cortisol secretion may show some evidence of cyclicity in other causes of Cushing’s syndrome, notably ectopic ACTH syndrome.

Children

All the above features occur in children, but growth arrest is almost invariable. The dissociation between height and weight on the growth chart is obvious. If the child is growing along the same centile line then the diagnosis of Cushing’s syndrome is highly unlikely. In addition to glucocorticoid-induced growth arrest, androgen excess may result in precocious puberty.

Pregnancy

Pregnancy is rare in women with Cushing’s syndrome because of associated amenorrhoea resulting from androgen excess or hypercortisolism. However, approximately 100 such cases have been reported, 50% of which resulted from adrenal adenomas.

A few cases of true pregnancy-induced Cushing’s syndrome have been reported, with postpartum regression. In these cases the aetiology is unknown. Establishing a diagnosis and cause can be difficult; normal pregnancy is associated with a threefold increase in plasma cortisol caused by increased production rates and increases in cortisol-binding globulin. Urinary free cortisol also rises, and dexamethasone does not suppress plasma cortisol to the same degree as in the nonpregnant state. Untreated, the condition has high maternal and fetal morbidity and mortality. Adrenal and/or pituitary adenomas should be excised. Metyrapone, which is not teratogenic, has been effective in controlling the hypercortisolism in many cases.

Adrenal carcinomas

In addition to the normal features of glucocorticoid excess the patient may present with other problems relating to: (1), the tumour, e.g. abdominal pain from the primary tumour or secondary deposits, or (2), the secretion of other steroids such as androgens or mineralocorticoids. Thus, in addition to hirsutism, there may be other features of virilization in females, including clitoromegaly, breast atrophy, deepening of the voice, temporal recession, and severe acne.

Investigation of patients with suspected Cushing’s syndrome

Disorders of the adrenal cortexThere are two stages in the investigation of a patient with suspected Cushing’s syndrome: (1), does the patient have Cushing’s syndrome? (2), if the answer to (1) is yes, what is the cause? Unfortunately many investigators fail to make this distinction and ill-advisedly use tests that are relevant to question (2) to try to answer question (1). No single test confers 100% sensitivity and specificity. However, because of the potential seriousness of untreated Cushing’s syndrome, highly sensitive tests are recommended to avoid missing the diagnosis. In all cases this brings with it a high prevalence of false positives, and the pretest likelihood of Cushing’s syndrome, based on clinical symptoms and signs, remains of paramount importance. In particular, it is essential that appropriate radiological investigations are not undertaken until Cushing’s syndrome has been confirmed biochemically. The principal diagnostic tests are listed in Table 13.7.1.5.

Table 13.7.1.5 Tests used in the diagnosis and differential diagnosis of Cushing’s syndrome

Diagnosis

—does the patient have Cushing’s syndrome?

Circadian rhythm of cortisol-late night plasma or salivary* cortisol

Urinary free cortisol excretion*

Low-dose dexamethasone suppression test*

Insulin tolerance test

Differential diagnosis

—what is the cause of the Cushing’s syndrome?

Plasma ACTH

Plasma potassium

High-dose dexamethasone suppression test

Metyrapone test

Corticotrophin-releasing factor

Inferior petrosal sinus ± selective venous sampling for ACTH

MRI/CT scanning of pituitary/adrenals

Scintigraphy

Tumour markers

* Valuable outpatient screening tests (see text).

Diagnostic tests

Practically, three screening tests with high sensitivity should be used to confirm Cushing’s syndrome. Depending on the index of clinical suspicion these can be performed in isolation or combination.

Urinary free cortisol

For many years the diagnosis of Cushing’s syndrome was based on the measurement of urinary metabolites of cortisol (24-h urinary 17-hydroxycorticosteroid or 17-oxogenic steroid excretion, depending on the method used). However, the sensitivity and specificity of these methods is poor and these assays have now been replaced with the much more sensitive measurement of urinary free cortisol excretion. Urinary free cortisol is an integrated measure of plasma free cortisol. As cortisol secretion increases, the binding capacity of cortisol-binding globulin is exceeded, resulting in a disproportionate rise in urinary free cortisol. This is a useful screening test, but even so, it is accepted that urinary free cortisol may be normal in 7 to 10% of patients with Cushing’s syndrome.

Measurement of the cortisol:creatinine ratio in the first urine specimen passed on waking obviates the need for a timed collection, and has been used by some as a sensitive screening test, particularly if cyclical Cushing’s syndrome is suspected. Urine aliquots are stable at room temperature for up to 7 days, and can then be sent by post to the local endocrine laboratory.

Late night plasma/salivary cortisol

In normal subjects, plasma cortisol concentrations are at their highest first thing in the morning and reach a nadir at around midnight (up to100 nmol/litre in the morning and <50 nmol/litre at midnight effectively excluding Cushing’s syndrome). This circadian rhythm is lost in patients with Cushing’s syndrome, such that in most patients the 09.00 level of plasma cortisol is normal, but nocturnal levels are raised. Random morning levels of plasma cortisol are therefore of little value in making the diagnosis. In addition, various factors, such as the stress of venepuncture, intercurrent illness, and admission to hospital, may result in normal subjects losing their circadian rhythm. It is therefore good practice not to measure plasma cortisol until the patient has been in hospital for 48 h. For this reason midnight plasma cortisol is not routinely used as a first-line screening test.

By contrast, midnight salivary cortisol can be collected at home and offers greater accuracy. A salivary cortisol value of more than 5.5 nmol/litre (2.0 ng/ml) has 100% sensitivity and 95% specificity in diagnosing Cushing’s syndrome. Other screening and confirmatory tests may be required to evaluate false positive results.

Low-dose/overnight dexamethasone suppression tests

In normal subjects, administration of a supraphysiological dose of a glucocorticoid results in suppression of ACTH and hence cortisol secretion. In Cushing’s syndrome of whatever cause there is failure of this suppression when low doses of the synthetic glucocorticoid dexamethasone are given. The overnight test is often used as an outpatient screening test. Various doses of dexamethasone have been used, usually given at midnight, but most experience is with a dose of 1 mg. A plasma cortisol of less than 50 nmol/litre between 08.00 and 09.00 the following morning has a sensitivity of 95% and specificity of 80% in excluding Cushing’s syndrome. Thus the outpatient overnight test has high sensitivity but low specificity, and further investigation is often required.

The conventional low-dose 48-h test is more accurate, but usually requires inpatient admission. Here, plasma cortisol is measured at 09.00 on day 0 and 48 h later, following dexamethasone given at a dose of 0.5 mg every 6 h for 48 h. This test is reported as having a 97 to 100% true positive rate and a false positive rate of less than 1%. Certain drugs (phenytoin, rifampicin) may increase the metabolic clearance rate of dexamethasone, thereby giving false positive results. If pseudo-Cushing’s syndrome is suspected, physicians in North America have modified this test slightly by administering CRF at the end of the dexamethasone suppression; ….

Differential diagnostic tests

Once the biochemical diagnosis has been made, other investigations are required to determine the cause of the Cushing’s syndrome.

Plasma ACTH at 09.00

This will differentiate ACTH-dependent from ACTH-independent causes. ACTH is either within the normal reference range (50% of cases) or elevated in patients with Cushing’s disease. ACTH levels in ectopic ACTH syndrome are high, but overlap the values seen in Cushing’s disease in 30% of cases and cannot therefore be used to differentiate these two conditions (Fig. 13.7.1.4). The measurement of ACTH precursors (pro-ACTH, POMC) is not routinely available, but may be more useful in detecting an ectopic source of ACTH.

Fig. 13.7.1.4 Immunoreactive N-terminal ACTH levels in plasma samples taken between 08.00 and 10.00 in normal subjects (hatched area), and patients with Cushing’s disease (either untreated or postadrenalectomy), adrenal tumours, or ectopic ACTH syndrome.

Fig. 13.7.1.4
Immunoreactive N-terminal ACTH levels in plasma samples taken between 08.00 and 10.00 in normal subjects (hatched area), and patients with Cushing’s disease (either untreated or postadrenalectomy), adrenal tumours, or ectopic ACTH syndrome.

(Courtesy of Professor L H Rees.)

In patients with autonomous adrenal tumours, plasma ACTH is invariably undetectable. This can also occur with degradation of ACTH; consequently, nonhaemolysed blood samples should be taken on ice and immediately separated.

Diagnosis is a problem in those patients whose plasma ACTH levels are in the low normal range or intermittently detectable. This may occur in macronodular hyperplasia. The danger is that in some patients the asymmetry of the nodular hyperplasia may lead to a diagnosis of adrenal adenoma, the plasma ACTH is ignored, and an inappropriate adrenalectomy is performed. Conversely, in some patients with this syndrome an autonomous adrenal tumour develops and, despite detectable ACTH, unilateral adrenalectomy is required.

Plasma potassium

Hypokalaemic alkalosis is present in more than 95% of patients with ectopic ACTH syndrome, but in fewer than 10% of patients with Cushing’s disease. Patients with the ectopic syndrome usually have higher cortisol secretion rates that saturate the renal protective 11β‎-HSD2 enzyme, resulting in cortisol-induced mineralocorticoid hypertension (see ‘Apparent mineralocorticoid excess syndrome’ below). In addition, these patients have higher levels of the ACTH-dependent mineralocorticoid deoxycorticosterone. See also Chapter 21.2.2.

High-dose dexamethasone suppression test

The rationale for this test is that in Cushing’s disease there is negative feedback control of ACTH, but set at a higher level than normal. Thus, in this disease, cortisol levels are not suppressed with a low dose of dexamethasone, but are suppressed with a higher dose. The original test introduced by Liddle was based on giving dexamethasone at a dose of 2 mg every 6 h for 48 h and measuring urinary 17-oxogenic steroids. Suppression was defined as a greater than 50% fall in 24-h urinary 17-oxogenic steroids. In the modern test, plasma cortisol is measured at 0 and 48 h or, less commonly, plasma cortisol is measured at 08.00 (basal sample), 8 mg dexamethasone is given orally at 23.00 on the same day, and plasma cortisol is measured again at 08.00 on the following morning. In both these tests, greater than 50% suppression of plasma cortisol in comparison with the basal sample has been used to define a positive response. In Cushing’s disease about 90% of patients have a positive 48-h test, compared with 10% with ectopic ACTH syndrome. With overnight high-dose testing, 89% sensitivity and 100% specificity has been reported for Cushing’s disease.

Metyrapone test

Metyrapone is an 11β‎-hydroxylase inhibitor that blocks the conversion of 11-deoxycortisol to cortisol, and deoxycorticosterone to corticosterone (Fig. 13.7.1.1). This lowers plasma cortisol and, via negative feedback control, increases plasma ACTH. This in turn stimulates an increase in the secretion of adrenal steroids proximal to the block. When metyrapone is given in doses of 750 mg every 4 h for 24 h, patients with Cushing’s disease exhibit an exaggerated rise in plasma ACTH, with 11-deoxycortisol levels at 24 h exceeding 1000 nmol/litre. In most patients with ectopic ACTH syndrome there is little or no response.

The metyrapone test was originally used to distinguish patients with Cushing’s disease from those with a primary adrenal cause. However, these can be more reliably distinguished by measuring plasma ACTH and CT scanning of the adrenal glands. As indicated, the test does not reliably distinguish between Cushing’s disease and ectopic ACTH syndrome and is now rarely used.

CRF test

CRF is a peptide of 41 amino acids, identified by Vale in 1981 from ovine hypothalami. The ovine sequence differs by seven amino acid residues from that of the human peptide, but despite this stimulates the release of ACTH in humans. The test involves the intravenous injection of either ovine or human CRF at a dose of 1 µg/kg body weight or a single dose of 100 µg. The test can be performed in the morning or afternoon, and after basal sampling, blood samples for ACTH and cortisol are taken every 15 min for 1 to 2 h after administering CRF.

In normal subjects CRF elicits a rise in ACTH and cortisol, and this response is exaggerated in Cushing’s disease. It is typically absent in ectopic ACTH syndrome and patients with adrenal tumours. In distinguishing pituitary-dependent Cushing’s disease from ectopic ACTH syndrome, the response of ACTH to CRF has a specificity of 90%, and with cortisol as the endpoint, 95%. Using as an endpoint an ACTH increase of 100% over basal, or a cortisol rise of 50%, this positive response eliminates a possible diagnosis of ectopic ACTH syndrome.

Inferior petrosal sinus sampling/selective venous catheterization

This is the most robust test for distinguishing Cushing’s disease from ectopic ACTH syndrome, but also the most costly and technically demanding. As blood from each half of the pituitary drains into the ipsilateral inferior petrosal sinus, catheterization of both sinuses with simultaneous sampling of venous blood can distinguish a pituitary from an ectopic source, and aid in the lateralization of a pituitary microadenoma (Fig. 13.7.1.5). In patients with ectopic ACTH syndrome there is no ACTH gradient between the inferior petrosal sinus samples and simultaneously drawn peripheral venous levels. In Cushing’s disease the ipsilateral:contralateral ACTH ratio is usually greater than 1.4. However, because of the problem of intermittent ACTH secretion, it is useful to make measurements before and at intervals (e.g. 2, 5, and 15 min) after intravenous injection of 100 µg of synthetic ovine CRF. Using this approach, patients with Cushing’s disease and bilateral inferior petrosal sinus ratios of less than 1.4 can readily be distinguished from those with the ectopic syndrome. The precise ratio that distinguishes Cushing’s disease from the ectopic syndrome has been debated. Some authors use 2 rather than 1.4.

Fig. 13.7.1.5 Positions of bilateral catheters in inferior petrosal sinus sampling.

Fig. 13.7.1.5
Positions of bilateral catheters in inferior petrosal sinus sampling.

In our hands, petrosal sinus sampling is reserved for those cases where the differential diagnosis is still in doubt after high-dose dexamethasone, pituitary imaging, and peripheral CRF testing.

Rarely, selective catheterization of vascular beds may be required to identify the source of ectopic ACTH secretion, e.g. from a small pulmonary carcinoid or thymic tumour.

Tumour markers

Many tumours responsible for ectopic ACTH syndrome also produce peptide hormones other than ACTH or its precursors. Calcitonin, chromogranin A, and gut hormones such as gastrin and vasoactive intestinal polypeptide should be measured.

Imaging

There is no doubt that high-resolution contrast-enhanced imaging of thin sections of the pituitary and adrenals by either CT or MRI has revolutionized the investigation of Cushing’s syndrome. However, if mistakes are to be avoided it is essential that the results of any imaging technique always be interpreted in the light of the biochemical results. In imaging the adrenals, asymmetrical nodular hyperplasia may lead to a false diagnosis of adrenal adenoma (Fig. 13.7.1.6). Owing to the presence of pituitary incidentalomas, pituitary MRI/CT scanning may produce false-positive results, particularly for lesions of less than 5 mm diameter (see ‘Adrenal incidentalomas’ below).

Fig. 13.7.1.6 CT scan of adrenals in patient with asymmetrical nodular hyperplasia. The macronodule on the left was initially thought to be an adrenal tumour. The biochemistry indicating ACTH-dependent Cushing’s syndrome was ignored, and a unilateral adrenalectomy performed without cure of the hypercortisolism. Further investigation confirmed Cushing’s disease, and a selective pituitary microadenomectomy resulted in cure.

Fig. 13.7.1.6
CT scan of adrenals in patient with asymmetrical nodular hyperplasia. The macronodule on the left was initially thought to be an adrenal tumour. The biochemistry indicating ACTH-dependent Cushing’s syndrome was ignored, and a unilateral adrenalectomy performed without cure of the hypercortisolism. Further investigation confirmed Cushing’s disease, and a selective pituitary microadenomectomy resulted in cure.

Pituitary MRI is the investigation of choice if the biochemical tests suggest Cushing’s disease, and has a sensitivity of 70% and specificity of 87% (Figs. 13.7.1.7 and 13.7.1.8). About 90% of ACTH-secreting pituitary tumours are microadenomas, i.e. less than 10 mm in diameter. The classical features of a pituitary microadenoma are a hypodense lesion after contrast, associated with deviation of the pituitary stalk and a convex upper surface of the pituitary gland (Fig. 13.7.1.7). With such small tumours it is not surprising that the sensitivity of CT scanning is relatively low (20–60%), with a similar specificity.

Fig. 13.7.1.7 MRI scan of pituitary demonstrating the typical appearance of a pituitary microadenoma. A hypodense lesion is seen in the left side of the gland, with deviation of the pituitary stalk away from the lesion. Following a biochemical diagnosis of Cushing’s disease, this patient was cured following transsphenoidal hypophysectomy.

Fig. 13.7.1.7
MRI scan of pituitary demonstrating the typical appearance of a pituitary microadenoma. A hypodense lesion is seen in the left side of the gland, with deviation of the pituitary stalk away from the lesion. Following a biochemical diagnosis of Cushing’s disease, this patient was cured following transsphenoidal hypophysectomy.

Fig. 13.7.1.8 MRI scan of the pituitary gland, demonstrating a large macroadenoma in a patient with Cushing’s disease. By contrast with smaller tumours, these tumours are invariably invasive and recur following surgery.

Fig. 13.7.1.8
MRI scan of the pituitary gland, demonstrating a large macroadenoma in a patient with Cushing’s disease. By contrast with smaller tumours, these tumours are invariably invasive and recur following surgery.

By contrast, CT scanning rather than MRI is the investigation of choice for adrenal imaging, offering better spatial resolution (Fig. 13.7.1.9). Once again it is stressed that adrenal incidentalomas are present in up to 5% of normal subjects, and thus adrenal imaging should not be performed unless biochemical investigation suggests a primary adrenal cause. Adrenal carcinomas are large and often associated with metastatic spread at presentation (Fig. 13.7.1.10).

Fig. 13.7.1.9 Typical solitary left-sided adrenal adenoma on adrenal CT scanning.

Fig. 13.7.1.9
Typical solitary left-sided adrenal adenoma on adrenal CT scanning.

Fig. 13.7.1.10 CT scan of a patient with rapidly progressing Cushing’s syndrome as a result of a right-sided adrenal carcinoma. An irregular right adrenal mass is shown (a) with a large liver metastasis (b).

Fig. 13.7.1.10
CT scan of a patient with rapidly progressing Cushing’s syndrome as a result of a right-sided adrenal carcinoma. An irregular right adrenal mass is shown (a) with a large liver metastasis (b).

In patients with occult ectopic ACTH syndrome, high-definition MRI/CT scanning of the neck, thorax, and abdomen/pelvis, with images every 0.5 cm, may be required to detect small ACTH-secreting carcinoid tumours.

Adrenal scintigraphy is of value in certain patients with primary adrenal pathology. The most commonly used agent is [131I]-6β‎-iodomethyl-19-norcholesterol, a marker of adrenocortical cholesterol uptake. In patients with adrenal adenomas the isotope is taken up by the adenoma, but not by the contralateral suppressed adrenal. Adrenal scintigraphy is useful in patients with suspected adrenocortical macronodular hyperplasia, in which CT scanning may mislead by suggesting unilateral pathology, whereas with isotope scanning the bilateral adrenal involvement is identified (Fig. 13.7.1.11).

Fig. 13.7.1.11 Adrenal scintigraphy in a patient with Cushing’s syndrome and macronodular hyperplasia. Note asymmetrical uptake in the adrenals, with 1.6% uptake on the left and 0.4% on the right.

Fig. 13.7.1.11
Adrenal scintigraphy in a patient with Cushing’s syndrome and macronodular hyperplasia. Note asymmetrical uptake in the adrenals, with 1.6% uptake on the left and 0.4% on the right.

Treatment of Cushing’s syndrome

Prognosis

Studies carried out before the introduction of effective therapy suggested that 50% of patients with untreated Cushing’s syndrome died within 5 years, causing some physicians to label this the ‘killing disease’. Even with modern management, an increased prevalence of cardiovascular risk factors persists for many years after an apparent cure. Close follow-up of all patients is recommended.

Adrenal causes

Adrenal adenomas should be removed by unilateral adrenalectomy, which has a 100% cure rate. With the increasing experience of laparoscopic adrenalectomy in most tertiary centres, this has now become the surgical treatment of choice for unilateral tumours, reducing surgical morbidity and postoperative hospital stay compared with traditional open approaches. After surgery it may take many months or even years for the suppressed adrenal to recover. It is wise therefore to give slightly suboptimal replacement therapy (<25–30 mg hydrocortisone/day or equivalent), with intermittent measurement of the 08.00 level of plasma cortisol after having omitted therapy for 24 h. When the morning plasma cortisol is above 180 nmol/litre a stimulation test such as an insulin tolerance test may then demonstrate whether or not the hypothalamic–pituitary–adrenal axis has recovered.

Adrenal carcinomas have a very poor prognosis and most patients are dead within 2 years. It is usual practice to try to remove the primary tumour, even though metastases may be present, so as to enhance the response to the adrenolytic agent mitotane (see ‘Medical treatment of Cushing’s syndrome’ below). Radiotherapy to the tumour bed and to some metastases, such as those in the spine, may be of limited value.

Pituitary-dependent Cushing’s disease

The treatment of Cushing’s disease has been improved by trans-sphenoidal surgery conducted by an experienced surgeon. Before the selective removal of a pituitary microadenoma the treatment of choice was bilateral adrenalectomy. This had an appreciable mortality, even in the best centres (c.4%), as well as morbidity. The main risk was the subsequent development of Nelson’s syndrome (postadrenalectomy hyperpigmentation with locally aggressive pituitary tumour) (Fig. 13.7.1.12). To avoid this, pituitary irradiation was often carried out following bilateral adrenalectomy. These patients required lifelong replacement therapy with hydrocortisone and fludrocortisone. Today, bilateral adrenalectomy is reserved for the occasional patient with Cushing’s disease in whom no pituitary tumour can be found, or when pituitary surgery has failed or the condition has recurred.

Fig. 13.7.1.12 A young woman with Cushing’s disease, photographed initially alongside her identical twin sister (a). In this case treatment with bilateral adrenalectomy was undertaken and several years later the patient re-presented with Nelson’s syndrome and right third cranial nerve palsy following cavernous sinus infiltration from a locally invasive corticotropinoma.

Fig. 13.7.1.12
A young woman with Cushing’s disease, photographed initially alongside her identical twin sister (a). In this case treatment with bilateral adrenalectomy was undertaken and several years later the patient re-presented with Nelson’s syndrome and right third cranial nerve palsy following cavernous sinus infiltration from a locally invasive corticotropinoma.

After selective removal of a microadenoma, the surrounding corticotrophs are normally suppressed (Fig. 13.7.1.13). In these cases plasma cortisol concentrations are also suppressed postoperatively, and glucocorticoid replacement therapy is required, but gradual recovery of the hypothalamic–pituitary–adrenal axis can be anticipated (Fig. 13.7.1.14), particularly in patients with normal pituitary function as it relates to other endocrine axes. A nonsuppressed postoperative plasma cortisol suggests that the patient is not cured, even though cortisol secretion may have fallen to normal or subnormal values. Close follow-up of such individuals is required.

Fig. 13.7.1.13 Selective removal of a microadenoma and its effect on the hypothalamic–pituitary–adrenal axis. Because the surrounding normal pituitary corticotrophs are suppressed in a patient with an ACTH-secreting pituitary adenoma, successful removal of the tumour results in ACTH and hence adrenocortical deficiency with an undetectable (<50 nmol/litre) level of plasma cortisol. A plasma cortisol of more than 50 nmol/litre postoperatively implies that the patient is not cured.

Fig. 13.7.1.13
Selective removal of a microadenoma and its effect on the hypothalamic–pituitary–adrenal axis. Because the surrounding normal pituitary corticotrophs are suppressed in a patient with an ACTH-secreting pituitary adenoma, successful removal of the tumour results in ACTH and hence adrenocortical deficiency with an undetectable (<50 nmol/litre) level of plasma cortisol. A plasma cortisol of more than 50 nmol/litre postoperatively implies that the patient is not cured.

(Courtesy of Professor P Trainer.)

Fig. 13.7.1.14 Gradual recovery of function of the hypothalamic–pituitary–adrenal axis after removal of a pituitary ACTH-secreting microadenoma. The insulin hypoglycaemia test eventually demonstrated the return of a normal stress response.

Fig. 13.7.1.14
Gradual recovery of function of the hypothalamic–pituitary–adrenal axis after removal of a pituitary ACTH-secreting microadenoma. The insulin hypoglycaemia test eventually demonstrated the return of a normal stress response.

In the past, pituitary irradiation was often used in the treatment of Cushing’s disease. However, improvements in pituitary surgery have resulted in far fewer patients being so treated. In children, pituitary irradiation appears to be effective. Radiotherapy is not recommended as a primary treatment, but is reserved for patients not responding to pituitary microsurgery, when bilateral adrenalectomy has been performed, or in those with established Nelson’s syndrome.

Ectopic ACTH syndrome

Treatment of ectopic ACTH syndrome depends on the cause. If the tumour can be found and has not spread, then its removal can lead to cure (e.g. bronchial carcinoid tumours, or thymomas). However, the prognosis for small-cell lung cancer associated with ectopic ACTH syndrome is poor. The cortisol excess and associated hypokalaemic alkalosis and diabetes mellitus can be ameliorated by medical therapy (see below). Treatment of the small-cell tumour itself will also, at least initially, produce improvement (see Chapter 18.19.3). Sometimes, if the ectopic source of ACTH cannot be found, it may be necessary to perform bilateral adrenalectomy and then follow the patient carefully (sometimes for several years) to find the primary tumour.

Medical treatment of Cushing’s syndrome

Several drugs have been used in the treatment of Cushing’s syndrome. Their site of action is shown in Fig. 13.7.1.15. Most commonly, metyrapone in Europe or ketoconazole in the United States of America has been given, often to lower cortisol concentrations before definitive therapy, or while awaiting benefit from pituitary irradiation. The daily dose has to be determined by measuring either plasma or urinary free cortisol. The aim should be to achieve a mean plasma cortisol of about 300 nmol/litre during the day, or a normal urinary free cortisol. Metyrapone is usually given in doses ranging from 250 mg twice daily to 1.5 g every 6 h. Nausea may be produced and can be alleviated (if not caused by adrenal insufficiency) by giving the drug with milk. Ketoconazole is an imidazole that has been widely used as an antifungal agent; it produces abnormal liver function tests signifying hepatitis in about 14% of patients. Ketoconazole blocks a variety of steroidogenic cytochrome P450-dependent enzymes and thus lowers plasma cortisol levels. For effective control of Cushing’s syndrome, 400 to 800 mg ketoconazole daily is required, but liver function tests must be monitored closely since hepatic failure is a potentially serious complication.

Fig. 13.7.1.15 Medical treatment of Cushing’s syndrome: site of action of various drugs.

Fig. 13.7.1.15
Medical treatment of Cushing’s syndrome: site of action of various drugs.

Aminoglutethimide is a more toxic drug that in high doses blocks the initial steps in the biosynthetic pathway, and thus affects the secretion of steroids other than cortisol. In doses of 1.5 to 3 g daily (starting with 250 mg every 8 h) it commonly produces nausea, marked lethargy, and a skin rash. Trilostane, a 3β‎-hydroxysteroid dehydrogenase inhibitor, is ineffective in Cushing’s disease since the block in steroidogenesis is overcome by the rise in ACTH. However, it can be effective in patients with adrenal adenomas.

Mitotane is an adrenolytic drug that is taken up by both normal and malignant adrenal tissue, causing adrenal atrophy and necrosis. Because of its toxicity, mitotane has been used mainly in the management of adrenal carcinoma. Doses of up to 8 g/day are required to control glucocorticoid excess, although evidence that it causes tumour shrinkage or improves long-term survival is scant. The drug will also produce mineralocorticoid deficiency, and both glucocorticoid and mineralocorticoid replacement therapy may be required. Side effects are common and include fatigue, skin rashes, and gastrointestinal disturbance.

Glucocorticoid deficiency: primary and secondary hypoadrenalism

Primary hypoadrenalism refers to glucocorticoid deficiency occurring in the setting of adrenal disease, whereas secondary hypoadrenalism arises from a deficiency of ACTH, the major trophic hormone controlling cortisol secretion. The principal distinction between these two conditions is that mineralocorticoid deficiency invariably accompanies primary hypoadrenalism, but this does not occur in secondary hypoadrenalism because only ACTH is deficient; the renin–angiotensin–aldosterone axis is intact.

Primary hypoadrenalism

Congenital adrenal hyperplasia

Various inherited enzyme defects have been identified in the synthetic pathway of adrenocortical hormones, which cause a spectrum of glucocorticoid and/or mineralocorticoid deficiency. Adrenal androgens may be increased or decreased, depending upon the underlying enzyme block. This group of conditions is addressed in Chapter 13.7.2.

Addison’s disease

Thomas Addison described this condition in his classic monograph published in 1855. Addison worked with Bateman, a dermatologist who produced one of the first classifications of skin disease. It seems likely that this stimulated Addison’s interest in the skin pigmentation that is so characteristic of this disease.

Aetiology

This is a rare condition, with an estimated incidence in the developed world of 0.8 cases per 100 000 population. The causes of Addison’s disease are listed in Table 13.7.1.6.

Table 13.7.1.6 Aetiology of adrenocortical insufficiency

Primary: Addison’s disease

Tuberculosis

Autoimmune:

Sporadic

Polyglandular deficiency type I (Addison’s disease, chronic mucocutaneous candidiasis hypoparathyroidism, dental enamel hypoplasia, alopecia, primary gonadal failure)

Polyglandular deficiency type II (Schmidt’s syndrome) (Addison’s disease, primary hypothyroidism, primary hypogonadism, insulin-dependent diabetes, pernicious anaemia, vitiligo)

Metastatic tumour

Lymphoma

Amyloid

Intra-adrenal haemorrhage (Waterhouse–Friderichsen syndrome) following meningococcal septicaemia

Haemochromatosis

Adrenal infarction or infection other than tuberculosis (especially AIDS)

Adrenoleucodystrophies

Congenital adrenal hypoplasia (DAX-1 mutations)

Hereditary adrenocortical unresponsiveness to ACTH

Bilateral adrenalectomy

Secondary

Exogenous glucocorticoid therapy

Hypopituitarism:

Selective removal of ACTH-secreting pituitary adenoma

Pituitary tumours and pituitary surgery, craniopharyngiomas

Pituitary apoplexy

Granulomatous disease (tuberculosis, sarcoid, eosinophilic granuloma)

Secondary tumour deposits (breast, bronchus)

Postpartum pituitary infarction (Sheehan’s syndrome)

Pituitary irradiation (effect usually delayed for several years)

Isolated ACTH deficiency

Worldwide, infectious diseases are the most common cause of primary adrenal insufficiency. Leading causes include tuberculosis, fungal infections (histoplasmosis, cryptococcosis), and cytomegalovirus. Adrenal failure may occur in AIDS. In tuberculous Addison’s disease the adrenals are initially enlarged, with extensive epithelioid granulomas and caseation. Calcification eventually ensues in most cases (Fig. 13.7.1.16). Both the cortex and the medulla are affected.

Fig. 13.7.1.16 Plain radiograph of the abdomen showing adrenal calcification in a patient with tuberculous Addison’s disease.

Fig. 13.7.1.16
Plain radiograph of the abdomen showing adrenal calcification in a patient with tuberculous Addison’s disease.

In the Western world, autoimmune adrenalitis accounts for over 70% of all cases of Addison’s disease. Pathologically, the adrenal glands are atrophic, with loss of most of the cortical cells, but the medulla is usually intact. Adrenal autoantibodies can be detected in up to 75% of newly diagnosed cases, and have helped elucidate the cause of the disease. Fifty per cent of patients with Addison’s disease have an associated autoimmune disease, and these polyglandular autoimmune syndromes have been classified into two distinct variants:

  • Type I (OMIM 240300) is inherited as an autosomal recessive condition and comprises Addison’s disease, chronic mucocutaneous candidiasis, and hypoparathyroidism. The condition is rare and usually presents in childhood with either candidiasis or hypoparathyroidism. Other autoimmune conditions, such as pernicious anaemia, thyroid disease, chronic active hepatitis, and gondal failure may occur, but are rare. Autoantibodies to the cholesterol side-chain cleavage enzyme and 17α‎-hydroxylase may be detected, but not to 21-hydroxylase. The condition occurs because of mutations in the autoimmune regulator gene, AIRE.

  • Type II polyglandular autoimmune syndrome (OMIM 269200) is more common, comprising Addison’s disease, autoimmune thyroid disease, diabetes mellitus, and hypogonadism. The condition has an inherited basis, with linkage to the HLA major histocompatibility complex, notably HLA DR3 and DR4. Autoantibodies to 21-hydroxylase are usually present, and are predictive for the development of adrenal destruction.

With the exception of tuberculosis and autoimmune adrenal failure, other causes of Addison’s disease are rare (Table 13.7.1.6). Adrenal metastases (most commonly from primary lung and breast tumours) are often found at postmortem examinations, but adrenal insufficiency from these is uncommon. Necrosis of the adrenals following intra-adrenal haemorrhage should be considered in any severely ill patient, and may result from infection, trauma, or hypercoagulability. Intra-adrenal bleeding may be found in severe septicaemia of any cause, particularly in children. When this is caused by meningococci, the association with adrenal insufficiency is known as Waterhouse–Friderichsen syndrome. Adrenal replacement leading to glandular failure may also occur with amyloidosis and haemochromatosis. Congenital adrenal hypoplasia (OMIM 300200) is an X-linked disorder comprising congenital adrenal insufficiency and hypogonadotropic hypogonadism. The condition is caused by mutations in the DAX1 (NR0B1) gene, a known member of the nuclear receptor family that is expressed in the adrenal cortex, gonads, and hypothalamus.

X-linked adrenoleukodystrophy causes adrenal insufficiency in association with demyelination within the nervous system, and results from a failure of β‎-oxidation of fatty acids within peroxisomes. Increased accumulation of very long-chain fatty acids (VLCFA) occurs in many tissues, and serum assays can be used diagnostically. Only male patients have the fully expressed condition, and female carriers are usually normal. Two forms are recognized, adrenoleukodystrophy and adrenomyeloneuropathy. Adrenoleukodystrophy (OMIM 300371) presents at 5 to 10 years of age, with progression eventually to a blind, mute, and severely spastic tetraplegic state. Adrenal insufficiency is usually present, but does not appear to correlate with the neurological deficit. X-linked adrenoleucodystrophy accounts for about 10% of cases of adrenocortical failure in boys and men. Adrenomyeloneuropathy by contrast presents later in life, with the gradual development of spastic paresis and peripheral neuropathy. Both the childhood and adult conditions result from mutations in the ABCD1 gene on chromosome Xq28, which encodes an ATP-binding cassette peroxisomal membrane protein involved in the import of VLCFA into the peroxisome. Monounsaturated fatty acids that block the synthesis of saturated VLCFA have been used for treatment. A combination of erucic acid and oleic acid (Lorenzo’s oil) has led to normal levels of VLCFA, but this has not altered the rate of neurological deterioration. Bone marrow transplantation appears to be more effective if undertaken in the early stages of the disease.

Familial glucocorticoid deficiency is a rare autosomal recessive cause of hypoadrenalism that usually presents in childhood. The renin–angiotensin–aldosterone axis is intact, and children usually present either with neonatal hypoglycaemia, or later with increasing pigmentation, often with enhanced growth velocity. Patients have glucocorticoid deficiency with very high plasma ACTH levels; this occurs because of mutations in the melanocortin 2 receptor (MC2R; ACTH receptor; OMIM 607397) or an accessory protein involved in the cellular trafficking of MC2R (OMIM 60916).

A variant syndrome is called the triple A or Allgrove’s syndrome (OMIM 231550), and refers to a triad of adrenal insufficiency, namely ACTH resistance, achalasia, and alacrima. Mutations have not been found in the ACTH receptor and the molecular basis for this inherited syndrome is unknown.

Secondary hypoadrenalism (ACTH deficiency)

This is a common clinical problem and most often results from a sudden cessation of exogenous glucocorticoid therapy, or a failure to give glucocorticoid cover for intercurrent stress in a patient who has been on long-term glucocorticoid therapy. Such therapy suppresses the hypothalamic–pituitary–adrenal axis, with consequent adrenal atrophy that may last for months after stopping glucocorticoid treatment. Adrenal atrophy and subsequent deficiency should be anticipated in any subject who has taken more than the equivalent of 30 mg of oral hydrocortisone per day (approximately 7.5 mg/day prednisolone or 0.75 mg/day dexamethasone) for longer than 1 month. In addition to the magnitude of the dose of glucocorticoid, the timing of administration may affect the degree of adrenal suppression. Thus prednisolone in a dose of 5 mg at night and 2.5 mg in the morning will produce more marked suppression of the hypothalamic–pituitary–adrenal axis than 2.5 mg at night and 5 mg in the morning because the larger evening dose blocks the early morning surge of ACTH.

Other causes of secondary adrenal insufficiency are rare (Table 13.7.1.6), and reflect inadequate ACTH production from the anterior pituitary gland. In many of these, other pituitary hormones are deficient in addition to ACTH, so that the patient presents with partial or complete hypopituitarism. The clinical features of hypopituitarism make this a relatively easy diagnosis to make (see Chapter 13.4). However, if there is isolated ACTH deficiency this diagnosis may be readily missed. Lymphocytic hypophysitis and mutations in a transcription factor gene, Tpit (TBX19), involved in dictating the corticotroph lineage within the anterior pituitary, are rare diseases that may cause isolated ACTH deficiency (OMIM 604614).

Hypoadrenalism may also complicate critical illness, even in individuals with a previously intact hypothalamic–pituitary–adrenal axis. This functional adrenal insufficiency is usually transient and not caused by a structural lesion. Debate continues regarding its diagnosis and aetiology, but an inability to mount an adequate cortisol response to overwhelming stress and/or sepsis encountered in intensive care units substantially increases the risk of death during acute illness. This can be reversed with supplementary corticosteroids.

Clinical features of adrenal insufficiency

The most obvious feature differentiating primary from secondary hypoadrenalism is skin pigmentation (Fig. 13.7.1.17), which is nearly always present in primary adrenal insufficiency (unless of short duration) and absent in secondary. The pigmentation is seen in sun-exposed areas, recent rather than old scars, axillae, nipples, palmar creases, pressure points, and in mucous membranes (buccal, vaginal, vulval, anal). The pigmentation reflects increased melanocyte activity induced by POMC-related peptides acting via the melanocortin 1 receptor (MC1R). In autoimmune Addison’s disease there may be associated vitiligo (Fig. 13.7.1.17).

Fig. 13.7.1.17 Pigmentation in a patient with Addison’s disease before and after treatment with hydrocortisone and fludrocortisone.

Fig. 13.7.1.17
Pigmentation in a patient with Addison’s disease before and after treatment with hydrocortisone and fludrocortisone.

(Courtesy of Professor C R W Edwards.)

Patients with primary adrenal failure usually have both glucocorticoid and mineralocorticoid deficiency. By contrast, those with secondary adrenal insufficiency have an intact renin–angiotensin–aldosterone system. This accounts for differences in salt and water balance in the two groups of patients, which in turn result in different clinical presentations.

Primary adrenal failure may present with hypotension and acute circulatory failure (addisonian crisis). Anorexia may be an early feature that progresses to nausea, vomiting, diarrhoea, and sometimes, abdominal pain. These crises may be precipitated by intercurrent infection or by stress, such as surgery. Alternatively, the patient may present with vague features of chronic adrenal insufficiency—weakness, tiredness, weight loss, nausea, intermittent vomiting, abdominal pain, diarrhoea or constipation, general malaise, muscle cramps, and symptoms suggestive of postural hypotension. Salt craving may be a feature, and there may be a low-grade fever. The lying blood pressure is usually normal, but almost invariably there is a fall in blood pressure on standing.

In adrenal insufficiency secondary to hypopituitarism, the presentation may relate to deficiency of hormones other than ACTH, notably luteinizing hormone/follicle-stimulating hormone (infertility, oligo-/amenorrhoea, poor libido), thyroid-stimulating hormone (weight gain, cold intolerance), and growth hormone (hypoglycaemia). Patients with isolated ACTH deficiency present with malaise, weight loss, and other features of chronic adrenal insufficiency. By contrast with primary adrenal failure, patients are usually pale.

Laboratory investigation of hypoadrenalism

Routine biochemical profile

In established primary adrenal insufficiency, hyponatraemia is present in about 90% of cases and hyperkalaemia in 65%. The blood urea concentration is usually elevated. In secondary adrenal failure there may be dilutional hyponatraemia, with normal or low blood urea, because glucocorticoids are required to maintain the glomerular filtration rate and excrete a water load. Hypoglycaemia has been found in up to 50% of patients with chronic adrenal insufficiency.

Plasma cortisol/ACTH

Clinical suspicion of the diagnosis should be confirmed with definitive diagnostic tests. Basal plasma cortisol and urinary free cortisol levels are often in the low normal range and cannot be used to exclude the diagnosis. In primary adrenal insufficiency the simultaneous measurement of plasma cortisol and plasma ACTH reveals an ACTH level that is disproportionately elevated in comparison with plasma cortisol (Fig. 13.7.1.18).

Fig. 13.7.1.18 Morning immunoreactive ACTH values in patients with hypoadrenalism. The reference range is indicated by the horizontal lines.

Fig. 13.7.1.18
Morning immunoreactive ACTH values in patients with hypoadrenalism. The reference range is indicated by the horizontal lines.

(Courtesy of Professor L H Rees.)

Mineralocorticoid status

In primary hypoadrenalism there is usually mineralocorticoid deficiency, with elevated plasma renin activity and either low or low-normal plasma aldosterone. This aspect of investigation is all too frequently ignored in patients with Addison’s disease. By contrast, in secondary adrenal failure, only ACTH drive to the adrenal cortex is lacking; the renin–angiotensin–aldosterone axis is intact.

Stimulation tests

In practice, all patients suspected of having adrenal insufficiency should have an ACTH stimulation test. This involves the intramuscular or intravenous administration of 250 µg of tetracosactrin (Synacthen), a peptide comprising the first 24 amino acids of normally secreted 1–39 ACTH. Plasma cortisol levels are measured at 0 and 30 min after tetracosactrin administration, and a normal response is defined by a peak plasma cortisol of more than 550 nmol/litre. Levels of less than 550 nmol/litre in response to tetracosactrin are found in both primary and secondary adrenal insufficiency, although false-positive results have occasionally been reported, particularly in cases of sudden-onset secondary hypoadrenalism. A low-dose ACTH stimulation test giving only 1 µg ACTH has been proposed to screen for adequate function of the hypothalamo–pituitary–adrenal axis, with the suggestion that it may be more sensitive than the conventional 250 µg test. At present there are insufficient data to support such a concept.

A prolonged ACTH stimulation test, involving the administration of depot tetracosactrin in a dose of 1 mg by intramuscular injection, with measurement of plasma cortisol at 0, 4, and 24 h will differentiate primary from secondary hypoadrenalism. However, the test is now rarely required if plasma ACTH has been appropriately measured at baseline.

The insulin-induced hypoglycaemia or insulin tolerance test remains one of the most useful in assessing ACTH and growth hormone reserves. It should not be performed in patients with ischaemic heart disease (check ECG before test), epilepsy, or severe hypopituitarism (i.e. plasma cortisol at 09.00 <180 nmol/litre). The test involves the intravenous administration of soluble insulin in a dose of 0.1 to 0.15 U/kg body weight, with measurement of plasma cortisol at 0, 30, 45, 60, 90, and 120 min. Adequate hypoglycaemia (blood glucose <2.2 mmol/litre, with signs of neuroglycopenia—sweating and tachycardia) is essential. In normal subjects the peak plasma cortisol exceeds 500 nmol/litre. However, the response to hypoglycaemia can be reliably predicted by the response to acute ACTH stimulation (see above); a safer, cheaper, and quicker test. If the ACTH test is normal, insulin-induced hypoglycaemia testing is not necessary in the vast majority of cases, unless there is a need to document endogenous growth hormone reserve in a patient with pituitary disease.

Other tests

Radioimmunoassays to detect autoantibodies, such as those against the 21-hydroxylase antigen, are available and should be undertaken in patients with primary adrenal failure. In autoimmune Addison’s disease it is also important to look for evidence of other organ-specific autoimmune disease. In long-standing tuberculous adrenal disease there may be adrenal atrophy with calcification on plain radiographs or CT scanning. Early morning urine samples should be cultured for mycobacteria if tuberculosis is suspected.

Treatment of acute adrenal insufficiency

This is an emergency, and treatment should not be delayed while waiting for definitive proof of diagnosis. However, in addition to the measurement of plasma electrolytes and blood glucose, appropriate samples for ACTH and cortisol determination should be taken before giving corticosteroid therapy. If the patient is not critically ill, an acute ACTH stimulation test can be performed. However, if necessary, this can be delayed and carried out with the patient on corticosteroid therapy; provided the drug used does not interfere with the plasma cortisol assay (e.g. change from hydrocortisone to dexamethasone).

Intravenous hydrocortisone should be given at a dose of 100 mg every 6 h. If this is not possible then the intramuscular route should be used. In the patient with shock, 1 litre of normal saline should be given intravenously over the first hour. Because of possible hypoglycaemia, it is usual to give 5% dextrose saline. Subsequent intravenous fluid replacement will depend on biochemical monitoring and the patient’s condition. Clinical improvement, especially in blood pressure, should be seen within 4 to 6 h if the diagnosis is correct. It is important to recognize and treat any associated condition, such as an infection, that may have precipitated the acute adrenal crisis.

After the first 24 h the dose of hydrocortisone can be reduced, usually to 50 mg intramuscularly every 6 h for the second 24 h and then, if the patient can take by mouth, to oral hydrocortisone, 40 mg in the morning and 20 mg at 18.00. This can then be rapidly reduced to the normal replacement dose of 20 mg on waking and 10 mg at 18.00. Some patients will require more than 30 mg/day, but most patients can cope with less than this (usually 15–25 mg/day in divided doses). In primary adrenal failure, cortisol day curves with simultaneous ACTH measurements may provide some insight into the adequacy of replacement therapy, but unfortunately there are no good objective tests in secondary adrenal failure. Nevertheless, crude objectives such as weight and body mass index, well-being, and blood pressure are important in this regard.

In primary adrenal failure, mineralocorticoid replacement is usually also required in the form of fludrocortisone at a dose of 0.05 to 0.1 mg/day. This has mineralocorticoid activity about 125 times that of hydrocortisone. After the acute phase has passed, the adequacy of mineralocorticoid replacement can be assessed by measuring electrolytes, supine and erect blood pressure, and plasma renin activity; too little fludrocortisone may cause postural hypotension with elevated plasma renin activity, and too much causes the converse.

Patients receiving glucocorticoid replacement therapy should be advised to double the dose in the event of an intercurrent febrile illness, accident, or mental stress such as an important examination. If the patient is vomiting and cannot take by mouth, parenteral hydrocortisone must be given urgently, as indicated above. For minor surgery, 50 to 100 mg of hydrocortisone hemisuccinate is given with the premedication. For major procedures this is then followed by the same regimen as for acute adrenal insufficiency.

Disorders of the adrenal cortexEvery patient on glucocorticoid therapy should be advised to register for a MedicAlert bracelet or necklace and must carry a steroid card giving information on the treatment being given. Many patients also carry hydrocortisone emergency kits for self-injection in case immediate access to medical care is not possible.

For patients with both primary and secondary adrenal failure, beneficial effects have been reported for adrenal androgen replacement therapy with 25 to 50 mg/day DHEA. Benefit is principally confined to female patients and includes improvement in sexual function and well-being.

Mineralocorticoid excess

Blood pressure is a quantitative trait that significantly affects cardiovascular and cerebrovascular risk and mortality. Based on this, arbitrary cut-offs define a hypertensive population that, depending on age, constitutes 10 to 25% of the population. In most cases, no underlying cause for the patient’s raised blood pressure can be found, and they are given a diagnosis of essential hypertension. Mineralocorticoid-based hypertension may account for secondary causes of hypertension, and classically refers to hypertension caused by increased sodium and water retention by the kidney, and expansion of the extracellular fluid compartment, resulting in suppression of endogenous plasma renin activity. The implicated mineralocorticoid is usually aldosterone.

Unlike most cases of secondary aldosteronism, which arise either in the setting of reduced oncotic pressure (nephrosis, cirrhosis) or in patients with cardiac failure, oedema is not a feature of primary aldosteronism, probably because of the aldosterone escape phenomenon. Nevertheless, in the short term, intravascular volume is reset to a higher level, and this leads to increased cardiac output and blood pressure. In the chronic state, hypervolaemia cannot be consistently demonstrated, and other mechanisms may be equally important in raising blood pressure. Mineralocorticoid receptors have been characterized in the vasculature and heart, and depending upon the activity of local 11β‎-HSD, either glucocorticoids or mineralocorticoids may increase vascular tone by potentiating catecholamine and angiotensin II-induced vasoconstriction, or by inhibiting endothelial relaxation. Mineralocorticoids can also modulate blood pressure centrally, independent of changes in renal electrolyte transport or vascular reactivity.

Mineralocorticoid hypertension: differential diagnosis

A comprehensive list of the causes of mineralocorticoid hypertension is given in Table 13.7.1.7.

Table 13.7.1.7 Differential diagnosis of mineralocorticoid excess

Cause

Offending mineralocorticoid

Primary aldosteronism

Aldosterone

Congenital adrenal hyperplasia

Deoxycorticosterone

11β‎-Hydroxylase deficiency

17α‎-Hydroxylase deficiency

Glucocorticoid receptor resistance

Deoxycorticosterone

Glucocorticoid receptor mutations

Metyrapone, RU486 ingestion

Deoxycorticosterone-secreting adrenal tumour

Deoxycorticosterone

Liddle’s syndrome

None

11 β‎-Hydroxysteroid dehydrogenase deficiency

Cortisol

Apparent mineralocorticoid excess

Liquorice and carbenoxolone ingestion

Ectopic ACTH syndrome

Primary aldosteronism

First described by Conn in 1955, this is the most common cause of mineralocorticoid hypertension. Prevalence rates of 0.5 to 2% were widely reported in the literature, but an exciting development in recent years has been the realization that this might form a much more common cause of hypertension, with prevalence rates of 10%. This increased prevalence is due in part to the widespread implementation of the plasma aldosterone:renin ratio (ARR) as a screening tool.

Symptoms are often absent or nonspecific, but include tiredness, muscle weakness, thirst, polyuria, and nocturia resulting from hypokalaemia. Spontaneous hypokalaemia (<3.5 mmol/litre) is rare in untreated hypertension; when it is found in a patient on diuretics these should be withdrawn, and potassium stores replenished and remeasured 2 weeks later. Despite this, it is now accepted that most patients with confirmed primary aldosteronism will have normal serum potassium concentrations.

In approximately one-third of patients, primary aldosteronism results from a small (0.5–2 cm), solitary, aldosterone-producing adenoma of the adrenal, which is commoner in women than men (male:female ratio 1:3). Two-thirds of cases are caused by bilateral adrenal hyperplasia, and the remaining few (<2%) by glucocorticoid-suppressible hyperaldosteronism or adrenal carcinomas. The aetiology of aldosterone-producing adenomas is unknown, although rarely they may have a genetic basis and can occur as a component of multiple endocrine neoplasia type 1.

Diagnosis of primary aldosteronism

As with the diagnosis of Cushing’s syndrome, this should be split into confirming the diagnosis, followed by establishing the differential diagnosis; again, inappropriate radiology before the diagnosis is biochemically confirmed can be misleading. The initial screening test should be the ARR (ratio of plasma aldosterone concentration (PAC) to plasma renin activity (PRA)). This can be performed in an outpatient setting with the patient in the sitting position. Primary aldosteronism is suspected by demonstrating a high ratio (see Table 13.7.1.8 for laboratory cut-off values). However, virtually all patients with suppressed plasma renin activity will have a high ratio; it is important to look also at the absolute aldosterone value, with an absolute aldosterone concentration of more than 400 pmol/litre (15 ng/dl) being highly suggestive in the face of a high ratio.

Table 13.7.1.8 Measurement of the plasma aldosterone:renin ratio (ARR), with suggested cut-off values indicative of primary aldosteronism, depending on whether renin is measured as plasma renin activity (PRA) or direct immunoreactivity (IrR), and the units used

Aldosterone

PRA

IrR

ng/ml per h

pmol/min

µU/ml

ng/litre

ng/dl

27

2.1

3.3

5.4

pmol/litre

750

59

90

150

There are also important confounders: β‎-blockers, by suppressing PRA, increase the ARR, whereas ACE inhibitors and diuretics do the converse. α‎-Blockers, such as prazosin or doxazosin, interfere least with the renin–angiotensin–aldosterone axis and can be used as alternatives. Prevailing sodium intake and assay performance are vitally important issues that must be discussed with the local biochemist in establishing a normal reference range.

In each case a high ARR is insufficient to make the diagnosis. A confirmatory test must be performed to demonstrate autonomous aldosterone secretion, usually in the form of sodium loading; 30–50% of patients with a high ARR will suppress aldosterone secretion normally. Primary aldosteronism is confirmed if plasma aldosterone fails to be suppressed to below 140 pmol/litre (<5 ng/dl) following 2 litres of intravenous saline given over 4 h, or oral sodium supplementation (300 mmol/day) over 3 days. An alternative is to give fludrocortisone 0.1 mg four times daily for 4 days with a high salt diet.

Who should be screened? At present the recommendations are to screen any hypertensive with unexplained hypokalaemia, young patients with a family history of hypertension or stroke, patients with ongoing hypertension despite triple therapy, and patients referred with an adrenal incidentaloma (see ‘Adrenal incidentalomas’ below). However, it is now appreciated that elevated aldosterone is an important cardiovascular risk factor in its own right, independent of its effects upon blood pressure, mediating extrarenal effects including vascular inflammation and cardiac fibrosis. It seems likely therefore that the use of the ARR will increase.

Differential diagnosis of primary aldosteronism

The use of the ARR has seen a change in the breakdown of cases of primary aldosteronism, with an increased diagnosis of the ill-understood condition, bilateral adrenal hyperplasia. Unlike an autonomous adrenal adenoma, where aldosterone regulation by the normal secretagogue angiotensin II is lost, patients with hyperplasia show an exaggerated PAC response to any given level of angiotensin II.

Adrenal MRI/CT scanning should only be performed after a biochemical diagnosis has been made, because of the high incidence of nonfunctioning adrenal incidentalomas. CT has a better spatial resolution and may be more sensitive in detecting smaller aldosterone-producing adenomas (Fig. 13.7.1.19). Adopting the approach outlined in Fig. 13.7.1.20, few patients need selective adrenal vein sampling, although this may be required in an older patient if surgery is planned. Although technically difficult and not without risk, the demonstration of an aldosterone ratio of greater than 10:1 in one adrenal vein compared with the other remains the most sensitive diagnostic test. Simultaneous cortisol measurements ensure adrenal vein cannulation and, when expressed as an aldosterone:cortisol ratio, improve diagnostic accuracy.

Fig. 13.7.1.19 (a) Adrenal CT scan demonstrating a solitary adrenal adenoma in a patients with Conn’s syndrome and (b) the characteristic yellow appearance of the cut surface of the excised tumour reflecting the high cholesterol content of these tumours.

Fig. 13.7.1.19
(a) Adrenal CT scan demonstrating a solitary adrenal adenoma in a patients with Conn’s syndrome and (b) the characteristic yellow appearance of the cut surface of the excised tumour reflecting the high cholesterol content of these tumours.

Fig. 13.7.1.20 Suggested algorithm for a patient suspected of having primary aldosteronism. PAC, plasma aldosterone concentration; PRA, plasma renin activity.

Fig. 13.7.1.20
Suggested algorithm for a patient suspected of having primary aldosteronism. PAC, plasma aldosterone concentration; PRA, plasma renin activity.

In patients with a strong family history, glucocorticoid-suppressible hyperaldosteronism can be diagnosed by PCR sequencing of the cytochrome P450 11β‎-hydroxylase genes (see ‘Glucocorticoid-suppressible hyperaldosteronism’ below).

One reason for establishing a definitive diagnosis is that treatment is usually surgical excision in the case of an aldosterone-producing adenoma, but strictly medical for bilateral adrenal hyperplasia and glucocorticoid-suppressible hyperaldosteronism. The latter responds well to dexamethasone at 0.25 to 0.5 mg/day. Patients with an aldosterone-producing adenoma who are not suitable for surgery (or decline operation) and patients with bilateral adrenal hyperplasia should be treated with the mineralocorticoid receptor antagonist spironolactone at doses of 25 to 200 mg/day. Side effects are common and include painful gynaecomastia in men and menstrual irregularity in premenopausal women. Eplerenone is a more selective mineralocorticoid receptor antagonist and an effective alternative in such cases, but needs to be given twice daily.

To reduce surgical morbidity to a minimum, a laparascopic approach should be used for adrenalectomy wherever possible. Pre- and perioperative treatment should involve the coordinated management of surgeon and endocrinologist. Aldosterone secretion from the contralateral normal adrenal gland may be suppressed, and postoperative hypoaldosteronism should be anticipated and treated appropriately, by increasing sodium intake and/or giving transient fludrocortisone therapy. Overall, in patients treated surgically or effectively with specific medical therapy, normokalaemia is restored in 100% of patients postoperatively, and blood pressure falls to normal values in 70%.

Single gene defects resulting in mineralocorticoid excess

Hypertension is known to be a phenotype of some well-documented gene mutations; 17α‎-hydroxylase deficiency and 11β‎-hydroxylase deficiency cause forms of congenital adrenal hyperplasia in which mineralocorticoid excess occurs because of ACTH-driven deoxycorticosterone excess. A similar process is thought to explain the hypertension seen in patients with glucocorticoid resistance resulting from mutations in the glucocorticoid receptor gene (Table 13.7.1.1). More recently, a significant advance in our understanding of the molecular basis of cardiovascular disease has been the elucidation of other single gene defects causing mineralocorticoid hypertension (Fig. 13.7.1.21).

Fig. 13.7.1.21 A schematic diagram representing an epithelial cell in the distal colon or distal nephron. In normal physiology, aldosterone interacts with the mineralocorticoid receptor (MR) to stimulate sodium reabsorption via induction of the apical sodium channel and serosal Na+,K+-ATPase pump. GSH (glucocorticoid-suppressible hyperaldosteronism) is a cause of aldosterone excess that results from the production of a chimaeric gene, 11β‎-hydroxylase/aldosterone synthase, within the adrenal cortex. Apparent mineralocorticoid excess results because cortisol cannot be inactivated to cortisone by the type 2 isoform of 11β‎-hydroxysteroid dehydrogenase (11β‎-HSD2); cortisol can then act as a potent mineralocorticoid. Liddle’s syndrome occurs because of constitutively active mutations in the β‎- or γ‎-subunits of the apical sodium channel. Activating mutations in the MR can also lead to inappropriate sodium retention.

Fig. 13.7.1.21
A schematic diagram representing an epithelial cell in the distal colon or distal nephron. In normal physiology, aldosterone interacts with the mineralocorticoid receptor (MR) to stimulate sodium reabsorption via induction of the apical sodium channel and serosal Na+,K+-ATPase pump. GSH (glucocorticoid-suppressible hyperaldosteronism) is a cause of aldosterone excess that results from the production of a chimaeric gene, 11β‎-hydroxylase/aldosterone synthase, within the adrenal cortex. Apparent mineralocorticoid excess results because cortisol cannot be inactivated to cortisone by the type 2 isoform of 11β‎-hydroxysteroid dehydrogenase (11β‎-HSD2); cortisol can then act as a potent mineralocorticoid. Liddle’s syndrome occurs because of constitutively active mutations in the β‎- or γ‎-subunits of the apical sodium channel. Activating mutations in the MR can also lead to inappropriate sodium retention.

Glucocorticoid-suppressible hyperaldosteronism (OMIM 103900)

Glucocorticoid-suppressible hyperaldosteronism was first reported in 1966, and is an autosomal dominant form of low-renin hypertension characterized by aldosterone excess under the control of ACTH, rather than the normal principal secretogogue angiotensin II. There are two important consequences of this: first, there is dysregulation of aldosterone secretion because of the loss of the negative feedback loop (aldosterone does not suppress ACTH secretion), and second, the exogenous administration of a glucocorticoid such as dexamethasone, by decreasing ACTH secretion, results in the suppression of aldosterone secretion and can be used therapeutically. Long-term glucocorticoid therapy leads to reactivation and normal regulation of the renin–angiotensin–aldosterone axis. A further characteristic of glucocorticoid-suppressible hyperaldosteronism is the secretion of large quantities of 18-hydroxy- and 18-oxo-corticosterone/cortisol metabolites, again under the control of ACTH, and while there is some overlap with levels seen in aldosterone-producing adenoma, these provide a diagnostic marker for the condition.

The molecular basis for glucocorticoid-suppressible hyperaldosteronism was described by Lifton and colleagues following the cloning and characterization of the final two enzymes in the cortisol and aldosterone synthetic pathways, 11β‎-hydroxylase and aldosterone synthase, respectively. 11β‎-Hydroxylase converts 11-deoxycortisol to cortisol in the zona fasciculata, and aldosterone synthase converts corticosterone to aldosterone through an enzymatic step involving 11β‎-hydroxylation and 18-hydroxylation and oxidation. These enzymes are encoded by two genes, CYP11B1 and CYP11B2, lying in tandem on chromosome 8. Despite the similarity in the coding sequences of 11β‎-hydroxylase and aldosterone synthase (>95%), their 5′‎ sequences differ, permitting the regulation of 11β‎-hydroxylase by ACTH through cAMP, and aldosterone synthase by angiotensin II through intracellular calcium ions, thereby establishing functional zonation of the adrenal cortex. In glucocorticoid-suppressible hyperaldosteronism a hybrid gene is formed at meiosis from unequal crossover of the CYP11B1 and CYP11B2 genes; this contains proximal components of CYP11B1 and distal components of CYP11B2. As long as the breakpoint of the hybrid gene is in or 5′‎ to exon 4 of the CYP11B1 gene, the product of this gene can synthesize aldosterone, but is now under the control of ACTH (Fig. 13.7.1.22). The chimaeric gene can be detected by Southern blotting or long polymerase chain reaction, providing a screening test for glucocorticoid-suppressible hyperaldosteronism and the facility for prenatal diagnosis.

Fig. 13.7.1.22 (a) The chimaeric gene responsible for glucocorticoid-remediable hyperaldosteronism and its impact upon adrenal steroid secretion, and (b) the chimaeric gene is expressed in the zona fasciculata (boxed area) and can synthesize aldosterone, but is under the regulatory control of ACTH.

Fig. 13.7.1.22
(a) The chimaeric gene responsible for glucocorticoid-remediable hyperaldosteronism and its impact upon adrenal steroid secretion, and (b) the chimaeric gene is expressed in the zona fasciculata (boxed area) and can synthesize aldosterone, but is under the regulatory control of ACTH.

Numerous kindreds with glucocorticoid-suppressible hyperaldosteronism have been reported, and an international register for such cases has been established (http://www.brighamandwomens.org/gra/). Interesting observations to come from these larger cohorts are that potassium may be normal in up to 50% of cases and there is poor correlation between genotype and phenotype (potassium, blood pressure), both between and within families. Severe mineralocorticoid excess has been reported in some individuals with this gene defect, but in other members of the same family the gene defect has not caused an abnormal phenotype. Patients with glucocorticoid-suppressible hyperaldosteronism are more susceptible to cerebrovascular haemorrhage.

Liddle’s syndrome (OMIM 177200)

In 1963, Grant Liddle described a family with several siblings affected by early-onset hypertension and hypokalaemia associated with low renin and low aldosterone levels. The condition responded well to inhibitors of epithelial sodium transport such as triamterene, but not to mineralocorticoid receptor antagonists such as spironolactone, and studies on erythrocytes suggested a generalized defect in sodium transport. Furthermore, in the proband of one of Liddle’s original patients, renal transplantation resulted in blood pressure and potassium returning to normal levels, arguing against a circulating mineralocorticoid.

Mineralocorticoid-dependent epithelial sodium transport requires the activation of the apical sodium channel. Three subunits of this channel (α‎, β‎, and γ‎) have been cloned and characterized. Full sodium conductance requires the concerted action of α‎/β‎ or α‎/γ‎ subunits and cannot be sustained by any subunit in isolation. The β‎ and γ‎ subunits lie in close proximity on chromosome 16, and mutations in these subunits have been described in kindreds with Liddle’s syndrome. In each case these cause deletions of the C-terminal part of the protein (45–75 amino acids), producing a sodium channel which is constitutively active. Liddle’s syndrome is inherited as an autosomal dominant trait, and several other kindreds have been reported following the description of the genetic basis for the condition. As is the case with glucocorticoid-suppressible hyperaldosteronism, potassium has been reported to be normal in several patients.

Apparent mineralocorticoid excess and abnormalities of 11β‎-hydroxysteroid dehydrogenase type 2

Apparent mineralocorticoid excess (OMIM 218030) was first described in detail by Ulick and New in the late 1970s. This is an autosomal recessive form of low renin, low aldosterone hypertension, in which cortisol, conventionally regarded as a glucocorticoid, is able to act as a potent mineralocorticoid. The condition can be diagnosed by gas chromatography for cortisol metabolites in a 24-h urine collection. Affected individuals have a characteristic increase in urinary cortisol compared with cortisone metabolites (tetrahydrocortisol:tetrahydrocortisone ratio or urinary free cortisol:urinary free cortisone ratio). Serum cortisol levels are unhelpful because although patients with apparent mineralocorticoid excess have a prolonged plasma cortisol half-life, a reduction in the cortisol secretion rate mediated by the negative feedback mechanism ensures normal circulating concentrations. This defect in cortisol metabolism occurs because of the loss of 11β‎-HSD activity.

Two isozymes of 11β‎-HSD catalyse the interconversion of hormonally active cortisol (F) to inactive cortisone (E). 11β‎-HSD1 is predominantly found in the liver, adipose tissue, and gonads and acts principally as an oxoreductase generating F from E, but it is the 11β‎-HSD2 isoform, acting as an efficient dehydrogenase inactivating F to E, that is expressed in the mineralocorticoid target tissues kidney, colon, and salivary gland that is more important in modulating corticosteroid control of blood pressure. Aldosterone gains access to the mineralocorticoid receptor in vivo only when 11β‎-HSD2 activity is intact and F can be inactivated to E at a prereceptor level (Fig. 13.7.1.23). Homozygous inactivating mutations and/or compound heterozygous mutations in the human HSD11B2 gene have been identified in approximately 100 patients with apparent mineralocorticoid excess and result in cortisol-mediated mineralocorticoid hypertension. The condition is inherited as an autosomal recessive trait, and most heterozygotes, with a few notable exceptions, have a normal phenotype. Milder forms of apparent mineralocorticoid excess have been described, and there appears to be a close correlation between genotype and phenotype. Spironolactone or amiloride (often in higher doses than those used to treat primary aldosteronism) can be used therapeutically, as can dexamethasone, which suppresses endogenous cortisol secretion, but itself is not a good substrate for 11β‎-HSD2.

Fig. 13.7.1.23 (a) The role of 11β‎-hydroxysteroid dehydrogenase (11β‎-HSD2) in protecting the nonspecific mineralocorticoid receptor from cortisol, and (b) with congenital or acquired deficiency of the enzyme, F (cortisol) cannot be inactivated to E (cortisone) and acts as a potent mineralocorticoid.

Fig. 13.7.1.23
(a) The role of 11β‎-hydroxysteroid dehydrogenase (11β‎-HSD2) in protecting the nonspecific mineralocorticoid receptor from cortisol, and (b) with congenital or acquired deficiency of the enzyme, F (cortisol) cannot be inactivated to E (cortisone) and acts as a potent mineralocorticoid.

Liquorice has been associated with a mineralocorticoid excess state since the late 1940s, when Reevers, a Dutch physician, used a liquorice preparation, succus liquoritiae, to treat patients with dyspepsia. This was the origin of the antiulcer drug, carbenoxolone, which also results in mineralocorticoid side effects in up to 50% of patients. The active ‘mineralocorticoids’ in both cases are glycyrrhizic acid and its hydrolytic product, glycyrrhetinic acid, which themselves have little inherent mineralocorticoid activity, but cause hypertension and hypokalaemia by inhibiting 11β‎-HSD2. Such patients will also have an increase in the urinary ratio of cortisol to cortisone metabolites (THF+allo-THF/THE), although not to the same extent as patients with apparent mineralocorticoid excess.

Cortisol is also the offending mineralocorticoid in patients with some forms of Cushing’s syndrome. In ectopic ACTH syndrome, for example, the high cortisol secretion rate overwhelms renal 11β‎-HSD2, resulting in spillover to the mineralocorticoid receptor. A high THF+allo-THF/THE ratio is also observed in some patients with pituitary-dependent Cushing’s syndrome, and this may explain the hypertension in these cases.

Activating mutations in the mineralocorticoid receptor

One kindred has been reported with a homozygous point mutation in the mineralocorticoid receptor that results in a serine to leucine change at amino acid 810. The phenotype is severe hypertension at a young age; an interesting facet of this mutation is that the mutated receptor is induced by progesterone and some of its hydroxylated derivatives, thereby explaining pregnancy-induced hypertension in affected female members of the kindred.

These unusual causes of mineralocorticoid hypertension have significantly enhanced our understanding of corticosteroid biosynthesis and hormone action. In addition they raise new questions as to the role of adrenal steroids in wider populations of patients with hypertension. Defects in the activity of 11β‎-HSD2, the epithelial sodium channel (ENaC), and CYP11β‎-hydroxylases have been reported in patients with essential hypertension, but have not consistently been associated with mineralocorticoid excess.

Glucocorticoid resistance

A small number of patients have been described who have increased cortisol secretion, but none of the stigmas of Cushing’s syndrome. These patients are resistant to the suppression of cortisol with low-dose dexamethasone, but respond to high doses. ACTH levels are elevated and lead to increased adrenal production of androgens and deoxycorticosterone. Thus the patients may present with the features of androgen and/or mineralocorticoid excess. Treatment with a dose of dexamethasone adequate to suppress ACTH (usually 3 mg/day) results in a fall in adrenal androgens and often the return of plasma potassium and blood pressure to normal levels. Many of these patients have been found to have point mutations in the steroid-binding domain of the glucocorticoid receptor, with consequent reduction of glucocorticoid-binding affinity.

Mineralocorticoid deficiency

These syndromes are listed in Table 13.7.1.9. They can be divided into those that are congenital and others that are acquired.

Table 13.7.1.9 Causes of mineralocorticoid deficiency

Addison’s disease

Adrenal hypoplasia

Congenital adrenal hyperplasia:

17-hydroxylase

3β‎-hydroxysteroid dehydrogenase deficiencies

Pseudohypoaldosteronism types I and II

Hyporeninaemic hypoaldosteronism

Aldosterone biosynthetic defects

Drug induced

Adrenal insufficiency

Mineralocorticoid deficiency may occur in some forms of congenital adrenal hyperplasia and these are discussed elsewhere (see Chapter 13.7.2). Similarly, other causes of adrenal insufficiency (e.g. Addison’s disease and congenital adrenal hypoplasia) are discussed above.

Primary defects in aldosterone biosynthesis

Before the characterization of the CYP11B2 gene, the disease was termed corticosterone methyl oxidase type I (CMO I) deficiency (OMIM 203400) and corticosterone methyl oxidase type II (CMO II) deficiency (OMIM 124080). Subsequently, both variants were shown to be secondary to mutations in aldosterone synthase, and are now termed type I and type II aldosterone synthase deficiency. Both variants are rare and inherited as autosomal recessive traits. The type II deficiency is found most frequently among Jews of Iranian origin. Presentation is usually in neonatal life as a salt-wasting crisis with severe dehydration, vomiting, and failure to grow and thrive. Hyperkalaemia, metabolic acidosis, dehydration, and hyponatraemia are found. Plasma renin activity is elevated, and plasma aldosterone levels are low. Plasma 18-hydroxycorticosterone levels and the ratio of plasma 18-hydroxycorticosterone to aldosterone and their urinary metabolites are used to differentiate the type I and II variants. In most infants the disorders become less severe as the child ages; in older children, adolescents, and adults, the abnormal steroid pattern described may be present and may persist throughout life without clinical manifestations. Mineralocorticoids (fludrocortisone) are given during infancy and early childhood, but this therapy can be discontinued in most adults. Spontaneous normalization of growth can occur in untreated patients. Rarely, presentation can be in adulthood.

Defects in aldosterone action: pseudohypoaldosteronism

Pseudohypoaldosteronism (PHA) is a rare, inherited salt-wasting disorder characterized by a defective renal tubular response to mineralocorticoids. Patients present in the neonatal period with dehydration, hyponatraemia, hypokalaemia, metabolic acidosis, and failure to thrive, despite normal glomerular filtration and normal renal and adrenal function. Renin levels and plasma aldosterone are grossly elevated and patients fail to respond to mineralocorticoid therapy.

PHA type I can be divided into two distinct disorders. The first is an autosomal dominant form (OMIM 177735) that is usually less severe, with the patient’s condition often improving spontaneously within the first several years of life, allowing discontinuation of treatment. This is explained on the basis of inactivating mutations in the mineralocorticoid receptor. By contrast, the second form (OMIM 264350) is a multiorgan disorder, with mineralocorticoid resistance seen in the kidney, sweat, and salivary glands, and the colonic mucosa. The condition does not spontaneously improve with age and is generally more severe. This arises because of inactivating mutations in the α‎, and to a lesser extent the β‎ and γ‎ subunits of ENaC (in effect this represents the opposite of Liddle’s syndrome described above).

Two other variants of PHA have been described: types II and III. Type II PHA, or Gordon’s syndrome (OMIM 145260), is in retrospect a misnomer. Patients with Gordon’s syndrome share some of the features of patients with PHA type I, notably hyperkalaemia and metabolic acidosis, but exhibit salt retention (with mild hypertension and suppressed plasma renin activity) rather than salt wasting. The condition is explained by mutations in a serine threonine kinase family, WNK1 and WNK4, resulting in increased expression of these proteins, with activation of the thiazide-sensitive Na+,Cl cotransporter in the cortical and medullary collecting ducts. Type III PHA is an acquired and usually transient form of mineralocorticoid resistance seen in patients with underlying renal pathologies, including obstruction and infection, and in patients with excessive loss of salt through the gut or skin.

Hyporeninaemic hypoaldosteronism

Angiotensin II is a key stimulus for aldosterone secretion, and damage or blockade of the renin–angiotensin system may result in mineralocorticoid deficiency. Various renal diseases have been associated with damage to the juxtaglomerular apparatus and hence renin deficiency. These include systemic lupus erythematosus, myeloma, amyloidosis, AIDS, and the use of nonsteroidal anti-inflammatory drugs, but the most common (>75% of cases) is diabetic nephropathy.

The usual picture is of an older patient with hyperkalaemia, acidosis, and mild to moderate impairment of renal function. Plasma renin activity and aldosterone are low and fail to respond to sodium depletion, erect posture, or furosemide administration. By contrast with adrenal insufficiency, patients have normal or elevated blood pressure and no postural hypotension. Muscle weakness and cardiac arrhythmias may also occur. Other factors may contribute to the hyperkalaemia, including the use of potassium-sparing diuretics, potassium supplementation, insulin deficiency, and β‎-adrenoceptor blockers and prostaglandin synthase inhibitors that inhibit renin release.

The treatment of primary renin deficiency is with fludrocortisone in the first instance, together with dietary potassium restriction. However, these patients are not salt depleted and may become hypertensive with fludrocortisone. In such a scenario the addition of a loop-acting diuretic such as furosemide is appropriate. This will increase acid excretion and improve the metabolic acidosis.

Adrenal incidentalomas

With the more widespread use of high-resolution imaging procedures (CT, MRI), incidentally discovered adrenal masses have become a common problem. An adrenal mass will be uncovered in up to 4% of patients imaged for nonadrenal pathology. Over 80% of cases are nonfunctioning, with phaeochromocytomas and cortisol- or aldosterone-secreting adenomas making up the remainder. In addition, it is established that some incidentalomas may cause abnormal hormone secretion without obvious clinical manifestations of a hormone excess state; the best example of this relates to preclinical Cushing’s syndrome, which may occur in up to 10% of all cases. This may explain why incidentalomas appear to be more common in patients with obesity and diabetes mellitus. As a result, all patients with incidentally discovered adrenal masses should undergo appropriate endocrine screening tests (24-h urinary catecholamines, urinary free cortisol, overnight dexamethasone suppression tests, plasma aldosterone:renin ratio, adrenal androgens) to exclude a functional lesion.

The possibility of malignancy should be considered in each case. In patients with a known extra-adrenal primary, the incidence of malignancy is obviously much higher (e.g. up to 20% of patients with lung cancer have adrenal metastases on CT scanning). Primary adrenal carcinoma is rare; in one study only 26 of 630 incidentalomas were found to be adrenal carcinomas. In true incidentalomas, size appears to be predictive of malignancy—a lesion of less than 5 cm diameter is most unlikely to be malignant. Nonfunctioning lesions of less than 5 cm can therefore be treated conservatively, and patients followed with annual imaging. Functional lesions, or tumours larger than 5 cm in diameter, should be removed by laparascopic adrenalectomy.

Further reading

Cushing’s syndrome

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Atkinson AB, et al. (1985). Five cases of cyclical Cushing’s syndrome. Br Med J, 291, 1453–7.Find this resource:

Findling JW, Raff H (2005). Screening and diagnosis of Cushing’s syndrome. Endocrinol Metab Clin North Am, 34, 385–402.Find this resource:

Kirschner LS, et al. (2000). Mutations of the gene encoding the protein kinase A type I-alpha regulatory subunit in patients with the Carney complex. Nat Genet, 26, 89–92.Find this resource:

Lacroix A, et al. (1992). Gastric-inhibitory polypeptide-dependent cortisol hypersecretion—a new cause of Cushing’s syndrome. N Engl J Med, 327, 974–80.Find this resource:

Mampalam TJ, Tyrell B, Wilson CB (1988). Transsphenoidal microsurgery for Cushing’s disease. A report of 216 cases. Ann Intern Med, 109, 487–93.Find this resource:

Newell-Price J, et al. (1998). The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states. Endocr Rev, 19, 647–72.Find this resource:

Nieman LK, et al. (2008). The diagnosis of Cushing’s syndrome: An Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab, 93, 1526–40.Find this resource:

Oldfield EH, et al. (1991). Petrosal sinus sampling with and without corticotropin releasing hormone for the differential diagnosis of Cushing’s syndrome. N Engl J Med, 325, 897–905.Find this resource:

Plotz CM, Knowlton AI, Ragan C (1952). The natural history of Cushing’s syndrome. Am J Med, 13, 597–614.Find this resource:

Ross EJ, Linch DC (1982). Cushing’s syndrome—killing disease: discriminatory value of signs and symptoms aiding early diagnosis. Lancet, 2, 646–9.Find this resource:

Wallace C, et al. (1996). Pregnancy-induced Cushing’s syndrome in multiple pregnancies. J Clin Endocrinol Metab, 81, 15–21.Find this resource:

Mineralocorticoids

Botero-Valez M, Curtis JJ, Warnock DG (1994). Brief report: Liddle’s syndrome revisited—a disorder of sodium reabsorption in the distal tubule. N Engl J Med, 330, 178–81.Find this resource:

Conn JW (1955). Primary aldosteronism: a new clinical syndrome. J Lab Clin Med, 45, 6–17.Find this resource:

Edwards CRW, et al. (1988). Tissue localisation of 11β‎-hydroxysteroid dehydrogenase-tissue specific protector of the mineralocorticoid receptor. Lancet, ii, 986–9.Find this resource:

Fraser R, Davies DL, Connell JMC (1989). Hormones and hypertension. Clin Endocrinol, 31, 701–46.Find this resource:

Funder JW, et al. (2008). Case detection, diagnosis and treatment of patients with primary aldosteronism: an Endocrine Society Clinical Practice guideline. J Clin Endocrinol Metab, 93, 3266–81.Find this resource:

Gagner M, et al. (1997). Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg, 226, 238–46.Find this resource:

Gittler RD, Fajans SS (1995). Primary aldosteronism (Conn’s syndrome). J Clin Endocrinol Metab, 80, 3438–41.Find this resource:

Gordon RD, et al. (1992). Primary aldosteronism: hypertension with a genetic basis. Lancet, 340, 159–61.Find this resource:

Hansson JH, et al. (1995). Hypertension caused by a truncated epithelial sodium channel γ‎ subunit: genetic heterogeneity of Liddle syndrome. Nat Genet, 11, 76–82.Find this resource:

Lamberts SWJ, et al. (1992). Cortisol receptor resistance. The variability of its clinical presentation and response to treatment. J Clin Endocrinol Metab, 74, 313–21.Find this resource:

Lifton RP, et al. (1992). A chimaeric 11β‎-hydroxylase/aldosterone synthase gene causes glucocorticoid remediable aldosteronism and human hypertension. Nature, 355, 262–5.Find this resource:

Mulatero P, et al. (2005). Diagnosis of primary aldosteronism: from screening to subtype differentiation. Trends Endocrinol Metab, 16, 114–19.Find this resource:

Pascoe L, et al. (1992). Glucocorticoid-suppressible hyperaldosteronism results from hybrid genes created by unequal crossovers between CYP11B1 and CYP11B2. Proc Natl Acad Sci USA, 89, 8327–31.Find this resource:

Rich GM, et al. (1992). Glucocorticoid-remediable aldosteronism in a large kindred: Clinical spectrum and diagnosis using a characteristic biochemical phenotype. Ann Intern Med, 116, 813–20.Find this resource:

Shimkets RA, et al. (1994). Liddle’s syndrome: heritable human hypertension caused by mutations in the α‎-subunit of the epithelial sodium channel. Cell, 79, 407–14.Find this resource:

Stewart PM, et al. (1987). Mineralocorticoid activity of liquorice: 11β‎-hydroxysteroid dehydrogenase deficiency comes of age. Lancet, 2, 821–4.Find this resource:

Stewart PM, et al. (1995). 11β‎-Hydroxysteroid dehydrogenase activity in Cushing’s syndrome: Explaining the mineralocorticoid excess state of the ectopic ACTH syndrome. J Clin Endocrinol Metab, 80, 3617–20.Find this resource:

White PC (2004). Aldosterone synthase deficiency and related disorders. Mol Cell Endocrinol, 217, 81–7.Find this resource:

White PC, Mune T, Agarwal AK (1997). 11β‎-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr Rev, 18, 135–56.Find this resource:

Wilson FH, et al. (2001). Human hypertension caused by mutations in WNK kinases. Science, 293, 1030.Find this resource:

Young WF (2007). Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol, 66, 607–18.Find this resource:

Zennaro MC, et al. (2004). Mineralcorticoid resistance. Trends Endocrinol Metab, 15, 264–70.Find this resource:

Addison’s disease

Arlt W, Allolio B (2003). Adrenal insufficiency. Lancet, 361, 1881–93.Find this resource:

Arlt W, et al. (1999). Dehydroepiandrosterone replacement in women with adrenal insufficiency. N Engl J Med, 341, 1013–20.Find this resource:

Betterle C, Greggio NA, Volpato M (1998). Clinical review 93: Autoimmune polyglandular syndrome type 1. J Clin Endocrinol Metab, 83, 1049–55.Find this resource:

Cooper MS, Stewart PM (2003). Corticosteroid insufficiency in acutely ill patients. N Engl J Med, 348, 727–34.Find this resource:

Erturk E, Jaffe CA, Barkan AL (1998). Evaluation of the integrity of the hypothalamo-pituitary adrenal axis by insulin hypoglycaemia test. J Clin Endocrinol Metab, 83, 2350–4.Find this resource:

Oelkers W (1996). Adrenal insufficiency. N Engl J Med, 335, 1206–12.Find this resource:

Stewart PM, et al. (1988). A rational approach for assessing the hypothalamo-pituitary adrenal axis. Lancet, 1, 1208–10.Find this resource:

Miscellaneous

Kloos RT, et al. (1995). Incidentally discovered adrenal masses. Endocr Rev, 16, 460–84.Find this resource:

Young WF (2007). Clinical practice: the incidentally discovered adrenal mass. N Engl J Med, 356, 601–10.Find this resource: