Adrenal incidentalomas

The diagnosis of adrenal masses during abdominal imaging performed for an alternative reason, not associated with clinical hyperfunction.

Baseline investigations - all patients

Full blood count

Useful indicator of general health and screen for malignancy.

Urea and electrolytes

Hypokalaemia may occur in both Cushing's and Conn's syndromes. It is important to document the severity of hypokalaemia when patients are off all treatments. If not possible, it is crucial to document all medications being taken at the time of any biochemical assessments.

Liver function tests

Fatty liver is common in obesity, diabetes and Cushing's.

Abnormal results may also occur with liver metastases.

Bone profile

Hypercalcaemia commonly occurs with malignancy. It may also indicate an underlying multiple endocrine neoplasia.

Fasting lipids, glucose, glycosylated haemoglobin (HbA1c)

Essential to stratify cardiovascular risk in all patients with hypertension.

Random recumbent renin and aldosterone

Recent guidelines suggest taking a baseline random renin and aldosterone to calculate ratio is a worthwhile initial screen even in the presence of interfering medications.

Assay methods, and units of measurement vary, but ratios above 800 using the units below, should prompt medication review and formal evaluation.

Aldosterone/renin ratio: 

>2000 Almost certainly Conn's
800-2,000 Possibly Conn's, investigate further
<800 Excludes Conn's

Plasma renin: 

Typically <0.5pmol/ml/hr (normal range 0.5-3.1)

Aldosterone

Typically >250pmol/l (normal range 100-800)

9am cortisol, testosterone, androstenedione, dehydroepiandrosterone, sex hormone binding globulin

Adrenal steroid hormones should be checked in all patients with an adrenal mass. This should ideally be performed on waking, in the early follicular phase, and always off the contraceptive pill. 

SHBG is typically low in polycystic ovarian syndrome and Cushing’s. Adrenal androgens are typically minimally elevated in polycystic ovarian syndrome and higher in Cushing's and adrenocortical tumours.

2x24hr collections for urinary free cortisol

Together with a dexamethasone suppression test, urinary free cortisols are a sensitive but not specific initial screen for Cushing’s syndrome.

Two normal results are reassuring if taken in conjunction with low probability of Cushing’s on thorough clinical assessment. Also useful as this can be performed and interpreted in patients taking oestrogen containing medication such as the oral contraceptive pill.

However, this should never be considered as a screening test alone - multiple conditions lead to false positive results, for example obesity, depression, alcohol excess, and false negative results occur with cyclical and biochemically mild disease.

Low dose dexamethasone suppression test

Dexamethasone suppression testing is the second screen for Cushing’s syndrome should also be performed in all patiens with an adrenal mass.

If both are normal, then a glucocorticoid secreting tumour is highly unlikely and no further investigations are needed to rule out Cushing’s in the absence of clinical signs.

2x24hr urinary metanephrines

Urinary metanephrines are the most sensitive and specific, widely available screen for phaeochromocytoma.

All patients with strongly positive results (>3x upper limit of normal) should be considered as having a phaeochromocytoma requiring immediate treatment and investigation.

Patients with results between 1-3x the upper limit of normal require further assessment with a serum metanephrine in the first instance. False positives may be found within this range, for example from interfering medication or obstructive sleep apnoea. 

Electrocardiogram

ECG should be taken to assess cardiovascular status and seek end organ damage.

Chest radiograph

Chest XR should be taken to assess cardiovascular status and seek end organ damage.

Prostate specific antigen

PSA should also be tested in male patients as a simple screen for prostate cancer.

Adrenal venous sampling

In patients over 50, non functioning adrenal adenomas are particularly common, so lesions must be confirmed as functioning prior to considering surgery.

In patients under 50, if a unilateral adenoma is visualised and the contralateral adrenal is clearly normal, sampling may not be necessary prior to surgery.

Unilateral disease is typified by the aldosterone:cortisol ratio in the affected gland being at least four times higher than the ratio in the contralateral adrenal; and greater than the ratio in the inferior vena cava. All other results are ambiguous and consistent with bilateral disease, thus are not likely to be cured by surgery.

Further investigations - selected cases only

9am ACTH

This test is usually performed after the biochemical diagnosis of Cushing’s has been made and should be low or undetectable in adrenal Cushing’s.

High levels should prompt re-evaluation of the imaging and further investigation as they suggest ACTH dependent Cushing’s syndrome in which bilateral adrenal hyperplasia with, or without, obvious nodules is usually present.

Midnight cortisol

This is a highly specific test for Cushing’s syndrome and is usefully performed after an initial positive dexamethasone suppression screening test.

The test is most reliable with the patient asleep at the start of venepuncture. Practical difficulties performing this test have led to the development of salivary cortisol assays which are currently under review and not in wide usage. 

Plasma metanephrines

This test is usually performed to confirm the diagnosis of phaeochromocytoma after a positive or borderline urinary collection.

Repeat renin and aldosterone, off all interfering medications

If the initial ratio is suggestive, Conn's syndrome should be confirmed by removing interfering medications under close supervision to repeat the test and recalculate the ratio.

Ratios above 800 should prompt medication review and formal evaluation.

Aldosterone/renin ratio: 

>2000 Almost certainly Conn's
800-2,000 Possibly Conn's, investigate further
<800 Excludes Conn's

Plasma renin: 

Typically <0.5pmol/ml/hr (normal range 0.5-3.1)

Aldosterone: 

Typically >250pmol/l (normal range 100-800)

CT chest, abdomen and pelvis

An apparently isolated adrenal mass should be further investigated by imaging the rest of the body to detect widespread metastatic disease if this has not already been performed.

Adrenal magnetic resonance imaging

Depending on the features of the CT scan, some radiologists and surgeons may request an MRI to further delineate the characteristics and anatomy of an adrenal lesion.

Meta-iodo benzylguianidine scan

Phaeochromocytomas typically take up MIBG, and this scan is usually performed after biochemical diagnosis, but prior to surgery.

Adrenal biopsy

This must never be performed unless a phaeochromocytoma has first been ruled out.

A biopsy is frequently performed when an adrenal mass is noted in a patient with distant malignancy. In this case, it is useful to differentiate adrenal metastases from primary adrenal lesions as this will dictate the staging and hence management of the malignancy.

Baseline pituitary function

Prolactin, IGF-1, growth hormone, thyroid stimulating hormone, thyroxine, luteinising hormone and follicle stimulating hormone should also be assessed if a functioning adrenal tumour has been diagnosed.

Adrenocortical adenomas are associated with pituitary tumours within the context of multiple endocrine neoplasia type 1.

Parathyroid hormone

This should be assessed at baseline in patients with a confirmed phaeochromocytoma, and in those with documented hypercalcaemia, due to the association of adrenal disease with multiple endocrine neoplasia types 1 and 2.