Quick tip; They may not sound exciting on a scan report, but please refer patients with adrenal incidentalomas to endocrinology for work up to exclude subtle hormone excess and even malignancy.
‘Incidentalomas’ in endocrinology are unexpected lesions picked up on a scan done for other reasons and are now very common. It has been estimated that ~5% of people have adrenal nodularity as they age, and whilst this is usually benign and indolent, some can cause long term harm through hormone excess and it is important to identify malignant features.
The European Society for Endocrinology has published guidance on adrenal incidentalomas (AIs) – see link below for more info. Your local departments may have adapted this for their use. It is now generally recommended to only investigate lesions ≥ 1cm, unless there are risk factors for malignancy (inc age under 40 yrs) or relevant symptoms, so clinicians should use their judgement.
ESE guidelines report the following:
~80% of AIs represent benign adrenal adenomas, of which 15-30% may secrete hormones
8% primary adrenal cancer (adrenocortical carcinoma)
5% metastasis from extra-adrenal source
Consider referral to endocrinology for further Ix of incidental adrenal lesions ≥1cm (or if < 1cm with other concerns or in young patients i.e. <40yrs)
Referral may not be appropriate for patients with limited prognosis for other reasons
Refer rapidly (under cancer pathway) if imaging report suggestive of adrenal malignancy (e.g. large size, evidence of local invasion)
Identify features from history/general examination suggestive of adrenal hormone excess
Identify features from history/general examination consistent with malignancy
Hypertension (esp if treatment resistant) – may be in keeping with aldosterone, cortisol or catecholamine excess
Cushingoid features – e.g. diabetes, osteoporosis, myopathy
Adrenal androgen excess – hirsuitism (male distribution of hair in a female), deepening of voice, cliteromegaly, cessation of periods
Catecholamine excess (phaeochromocytoma) – hypertension (may be paroxysmal), headaches, palpitations, anxiety
Malignant features – weight loss, fatigue etc
Tumours that metastasize to adrenals commonly include lung, breast, bowel, pancreas and many other sites.
In patients with bulky bilateral adrenal lesions check for signs/symptoms of adrenal insufficiency which can occur due to malignant (or other) infiltration – e.g. pigmentation, postural hypotension, weight loss, fatigue, hyponatraemia etc.
Please include a detailed drug history with referral – some medications can interfere with interpretation of endocrine tests (esp for measurement of catecholamines and aldosterone).
Endocrine testing is not usually necessary before referral, but U&Es and HbA1c/glucose can be helpful to include.
Patients with AIs will require (usually in secondary care)
Assessment for cortisol excess (overnight 1mg dexamethasone test or 24h urinary cortisol collection plus ACTH assessment)
Assessment for catecholamine excess (plasma or urine metanephrines)
Assessment for androgen excess (plasma androgens – testosterone with sex hormone binding globulin, DHEA-S, androstenedione)
Assessment for aldosterone excess (aldosterone-renin ratio ARR) (if hypertensive)*
Exclusion of malignancy on imaging criteria**
*may require a temporary change to medications as many BP medications can interfere with ARR
** preferred test is a plain (non-contrast) adrenal CT to assess the density of the glands (measured in Hounsfield units – HU). Adrenal glands are usually rich in fat so appear dark (low density, traditionally <10HU) on CT. Malignant lesions have higher density and may be heterogenous in appearance. MRI of adrenals is an alternative test in younger patients.
Further endocrine or imaging tests may then be arranged if hormone hypersecretion or malignancy is suspected.
It is recommended that cases are discussed at a formal adrenal MDT meeting where malignancy or hormone excess is suspected.
NB – adrenal biopsy is rarely carried out and should first be discussed at MDT due to risks of disrupting a phaeochromocytoma, and of seeding malignancy.
European Society of Endocrinology guideline (2016): https://eje.bioscientifica.com/view/journals/eje/175/2/G1.xml
Quick tip; It is vital not to delay initiation of treatment in unwell patients if adrenal insufficiency suspected – the diagnosis can always be established later
The adrenal cortex secretes cortisol and androgens (under control of pituitary ACTH) as well as aldosterone (under control of the renin-angiotensin-aldosterone system).
Adrenal insufficiency may be primary (due to destruction/dysfunction of the adrenal gland itself), secondary (due to inadequate ACTH from the pituitary) or tertiary (due to pituitary suppression from exogenous steroids).
Primary adrenal insufficiency causes deficiency of cortisol, androgens and aldosterone; secondary and tertiary insufficiency cause deficiency of cortisol and androgens alone.
Causes of adrenal insufficiency
Symptoms of adrenal insufficiency are non-specific include
Adrenal crisis is a life-threatening manifestation of adrenal insufficiency characterised by shock.
Management of adrenal crisis
Prevention of adrenal crisis
SOCIETY FOR ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency management of acute adrenal insufficiency (adrenal crisis) in adult patients (2016) URL: https://ec.bioscientifica.com/view/journals/ec/5/5/G1.xml
Guidelines for the management of glucocorticoids during the peri‐operative period for patients with adrenal insufficiency
Guidelines from the Association of Anaesthetists, the Royal College of Physicians and the Society for Endocrinology UK (2020) URL: https://onlinelibrary.wiley.com/doi/full/10.1111/anae.14963
Quick tip; never hold back hydrocortisone treatment in an emergency in order to secure a diagnosis of adrenal insufficiency. That can always be done later. A blood sample taken before hydrocortisone can be analysed afterwards for cortisol (and ideally ACTH).
Cortisol is the main glucocorticoid hormone. It circulates >95% bound to CBG (cortisol binding globulin), however it is the free unbound hormone that is active.
We measure total serum cortisol levels rather than the free active component as this is very difficult to do outside the research setting.
There are many caveats with measuring plasma cortisol levels and a single random cortisol measurement may not be helpful in proving sufficiency or insufficiency. Patients with cortisol deficiency or excess may have a cortisol level within the “normal range” at certain times of the day. It is for these reasons that we usually investigate suspected cortisol disorders with dynamic function testing (e.g. synacthen test, dexamethasone suppression test) to determine if cortisol levels are appropriate to the circumstance (section on DFTs to follow).
The main usefulness of a plasma cortisol measurement in the hospital setting is in excluding adrenal insufficiency. We might think about this in the investigation of unexplained hyponatraemia or weight loss, for instance, or in a hypotensive patient in a sample taken before we administer empirical hydrocortisone.
Random plasma levels of cortisol have no real use if cortisol excess is suspected (including patients with features of glucocorticoid excess such as obesity and diabetes, or in patients with adrenal or pituitary masses).
Factors influencing cortisol levels:
Timing – cortisol exhibits circadian (24h) and ultradian (hourly) variation. In normal individuals, morning cortisol levels range roughly from 275-555 nmol/L; in late afternoon may be 85-275 nmol/L; and may be <140 nmol/L at midnight but there is great inter-individual variation and no absolute cut-offs.
Cortisol insufficiency suspected – a morning level is most helpful
Cortisol excess suspected – a midnight level is most helpful
Type of assay –measured by immunoassay (antibodies). There may be overlap in reactivity for other steroids (endogenous and exogenous). Different assays have different specificities for cortisol so you should consult local reference ranges as they may differ significantly. There is no cross-reactivity with dexamethasone (hence why we use it for suppression tests), but there is with hydrocortisone and potentially with prednisolone.
Cortisol binding globulin – since 95% of the cortisol measured is bound to CBG, variations in CBG levels may have dramatic effects on total cortisol but free cortisol levels remain normal.
High CBG = high total cortisol – usually due to oestrogens, e.g. pregnancy, OCP, HRT use therefore a “normal” cortisol may be inappropriately low
Low CBG = low total cortisol e.g. nephrotic syndrome, liver failure or sepsis therefore a “low”(ish) cortisol may actually be normal
If cortisol insufficiency suspected:
If cortisol insufficiency confirmed:
Cortisol excess suspected: