Primary and secondary adrenal insufficiency

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Cortisol supports vascular tone, glucose availability and the physiological stress response. Deficiency may develop slowly and become apparent only during infection, trauma, surgery or vomiting. Primary autoimmune Addison's disease is an important cause, but tuberculosis, haemorrhage, infiltration, metastases and genetic conditions also damage the cortex. Central causes include pituitary tumours or treatment, apoplexy, cranial irradiation and exogenous steroid suppression.

The mineralocorticoid distinction is clinically useful. In primary disease, aldosterone deficiency promotes sodium loss, volume depletion, salt craving and potassium retention. In central disease the renin-angiotensin system largely maintains aldosterone, although hyponatraemia can still result from increased vasopressin and impaired free-water excretion.

NICE NG243 places recognition, emergency safety and patient self-management alongside biochemical diagnosis. Assay-specific cortisol cut-offs and dynamic testing pathways differ, so clinicians should use the reporting laboratory and endocrinology service rather than transferring a threshold from another assay.

Key points

Primary adrenal insufficiency is failure of the adrenal cortex: cortisol and often aldosterone are deficient, ACTH rises, and hyperpigmentation, salt craving, postural hypotension, hyponatraemia and hyperkalaemia may occur.
Secondary or tertiary insufficiency reflects pituitary/hypothalamic disease or suppression by exogenous glucocorticoids. ACTH is low or inappropriately normal, aldosterone is usually preserved and hyperkalaemia is not a typical isolated feature.
Symptoms are non-specific: fatigue, weight loss, anorexia, nausea, abdominal discomfort and dizziness. Recurrent unexplained hyponatraemia or deterioration during infection should raise the diagnostic priority.
Ask about every glucocorticoid route, including oral, injected, inhaled, intranasal, topical and rectal preparations, recent repeated courses and CYP3A4 inhibitors that increase systemic exposure.
Use an 08:00 to 09:00 serum cortisol as the initial non-acute test in adults, interpreted with the local assay, sleep pattern and current steroid exposure. Random cortisol is difficult to interpret outside an emergency.
A short Synacthen test assesses adrenal response but does not safely delay treatment in an unwell patient. Early central deficiency can occasionally retain a response before adrenal atrophy develops.
Paired ACTH separates primary from central disease after cortisol deficiency is established. Renin and aldosterone assess mineralocorticoid loss; primary disease usually needs fludrocortisone as well as glucocorticoid.
Patients need more than a prescription: education, NHS Steroid Emergency Card, sick-day rules, extra tablets, emergency injection access and peri-procedure planning are core treatment.
Do not start levothyroxine in a patient with possible untreated adrenal insufficiency without addressing cortisol, because increased cortisol clearance and metabolic demand can precipitate crisis.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Primary adrenal destruction

Autoimmune Addison's disease, tuberculosis, haemorrhage, infiltration, metastasis and genetic disorders can damage adrenal cortex and reduce cortisol and aldosterone production.

Pituitary or hypothalamic disease

Tumours, surgery, radiotherapy, apoplexy and inflammation can reduce ACTH stimulation while the renin-angiotensin system largely preserves aldosterone.

Exogenous glucocorticoid suppression

Systemic exposure from several steroid routes suppresses ACTH and adrenal reserve, particularly after dose reduction, abrupt withdrawal or metabolic interaction.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Cortisol availability declines
Reduced adrenal output or ACTH drive impairs vascular tone, glucose availability and the physiological response to infection, trauma or surgery.
2
Feedback reveals the level
Primary disease raises ACTH through lost cortisol feedback, while central and steroid-induced disease leaves ACTH low or inappropriately normal.
3
Mineralocorticoid loss separates primary disease
Primary cortical damage reduces aldosterone, causing renal sodium loss, volume depletion, salt craving and potassium retention.
4
Stress unmasks limited reserve
A stable person may decompensate during infection, vomiting or surgery when cortisol need rises and oral replacement becomes inadequate or unabsorbed.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Primary adrenal pattern

Hyperpigmentation in creases, scars or oral mucosa, vitiligo, salt craving, postural symptoms, hyponatraemia and hyperkalaemia support primary cortical failure. Pigmentation reflects chronic ACTH excess and may be absent early.

Central adrenal pattern

Pallor, headache, visual-field symptoms, amenorrhoea, reduced libido, loss of body hair or other pituitary deficits point toward secondary disease. Potassium is commonly normal because aldosterone secretion is retained.

Glucocorticoid-induced suppression

Recent prolonged or repeated glucocorticoid exposure, Cushingoid appearance followed by dose reduction, or interacting medicines creates tertiary risk. The underlying inflammatory disease can mask withdrawal and deficiency symptoms.

Evolving adrenal crisisRed flag

Worsening vomiting, diarrhoea, abdominal pain, profound weakness, confusion, hypotension, hypoglycaemia or shock demands emergency hydrocortisone and fluids. A normal potassium does not exclude crisis.

Associated autoimmunity

Autoimmune thyroid disease, type 1 diabetes, pernicious anaemia, coeliac disease or premature ovarian insufficiency increases the likelihood of autoimmune polyglandular disease and should prompt symptom-led screening.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
08:00 to 09:00 serum cortisolFirst step
Why
Screen for impaired morning cortisol production in a stable adult not taking interfering glucocorticoid.
Interpretation and limitations
Use the NICE framework and local assay. A clearly low value requires endocrine assessment and safety planning; an intermediate result commonly leads to repeat or dynamic testing, while acute illness changes expected concentrations.
02
Plasma ACTH paired with cortisol
Why
Localise confirmed cortisol deficiency to adrenal cortex or central control.
Interpretation and limitations
Markedly raised ACTH supports primary disease; low or inappropriately normal ACTH suggests pituitary, hypothalamic or exogenous suppression. Sample handling requirements matter because ACTH is labile.
03
Short Synacthen stimulation test
Why
Measure adrenal cortisol reserve when basal testing is indeterminate and the patient is stable.
Interpretation and limitations
Interpret peak cortisol using the local assay and protocol. Recent-onset central failure may give a misleading preserved response, and exogenous steroids can interfere with measurement.
04
U&E, glucose, FBC and renal profile
Why
Find physiological consequences and competing causes of fatigue or collapse.
Interpretation and limitations
Primary disease may produce low sodium, high potassium, low glucose, eosinophilia and prerenal impairment. Central disease may cause hyponatraemia without hyperkalaemia; none of these patterns is mandatory.
05
Renin and aldosterone
Why
Assess mineralocorticoid failure in suspected or established primary adrenal insufficiency.
Interpretation and limitations
High renin with inappropriately low aldosterone supports deficiency. Interpret posture, sodium intake, kidney function and interfering antihypertensives with endocrine laboratory guidance.
06
Aetiology testing and imaging
Why
Identify autoimmune, structural, infiltrative or pituitary causes after biochemical localisation.
Interpretation and limitations
Consider 21-hydroxylase antibodies for autoimmune primary disease, adrenal CT for non-autoimmune or atypical presentations, and pituitary hormone profile plus MRI for central disease; avoid indiscriminate imaging before localisation.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Gastrointestinal disease

Weight loss, nausea, abdominal pain and diarrhoea overlap, but postural hypotension, steroid history and paired cortisol physiology raise endocrine concern.

Syndrome of inappropriate antidiuresis

Both conditions cause hyponatraemia, but hypotension, hypoglycaemia or hyperkalaemia and cortisol testing support adrenal deficiency when combined with the history and other findings.

Chronic fatigue or depression

Fatigue, poor concentration and weight change are nonspecific; consistent biochemical and haemodynamic findings distinguish impaired adrenal reserve.

Postural autonomic disorder

Orthostatic symptoms with preserved cortisol and no salt-wasting pattern suggest autonomic dysfunction rather than adrenal hormone failure.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Stable suspicionConfirm without creating crisis riskFirst stepChronic compatible symptoms or unexplained hyponatraemia without current haemodynamic instability.

1Review all steroid exposures, timing, shift work and comorbidity; arrange an 08:00 to 09:00 cortisol with electrolytes and glucose using the local testing instructions.
2If cortisol is low or indeterminate, seek endocrinology advice for paired ACTH and dynamic testing, while giving interim emergency precautions when clinical risk is material.
3Once deficiency is confirmed, localise primary versus central disease, establish cause, assess other pituitary or autoimmune deficits and issue safety education before routine discharge.

02Primary diseaseReplace both cortical functionsCortisol deficiency with raised ACTH and evidence supporting adrenal cortical failure.

1Begin physiological glucocorticoid replacement and teach timing that approximates the circadian pattern; address crisis risk immediately rather than waiting for every aetiology test.
2Add fludrocortisone when mineralocorticoid deficient, then individualise using postural symptoms, blood pressure, electrolytes and renin rather than a symptom-free fixed dose.
3Investigate cause, screen clinically for associated autoimmune disease, provide injection training and agree endocrinology follow-up including pregnancy and procedure advice.

03Central diseaseProtect cortisol before other axesLow cortisol with low or inappropriately normal ACTH, steroid suppression or pituitary features.

1EscalationReplace glucocorticoid when indicated and do not commence or escalate levothyroxine until cortisol safety has been secured.
2Assess other pituitary axes, visual fields and MRI as appropriate; acute headache or visual deficit raises concern for pituitary apoplexy and requires emergency specialist care.
3Fludrocortisone is generally unnecessary because aldosterone is preserved. Review whether the hypothalamic-pituitary-adrenal axis may recover after exogenous steroid taper and plan testing rather than assuming lifelong disease.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Preferred glucocorticoid replacement because its shorter action permits a larger morning dose and lower late-day exposure.

Hydrocortisone physiological replacement

NICE adult total 15 to 25 mg daily by mouth in two to four divided doses, individualised by endocrinology and clinical response.

Both under- and over-replacement cause harm. Assess weight, postural symptoms, blood pressure, glucose, bone risk and sleep; never omit sick-day education or stop abruptly.

Provides physiological glucocorticoid effect with simpler dosing for selected patients under specialist supervision.

Prednisolone replacement alternative

NICE lists 3 to 5 mg orally daily in one or two doses for adults when hydrocortisone is unsuitable or adherence favours longer action.

Longer exposure may increase metabolic and bone effects and makes clinical titration important. It still requires stress dosing, an emergency card and peri-operative cover.

Replaces aldosterone effect in primary adrenal insufficiency and supports sodium retention, potassium excretion and circulating volume.

Fludrocortisone

Specialist dose titrated to symptoms, lying and standing blood pressure, electrolytes and renin; use current BNF and local endocrine targets.

Excess causes hypertension, oedema and hypokalaemia; deficiency causes salt craving, postural hypotension and raised renin. Requirements may change with climate, activity and pregnancy.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Adrenal crisis

Acute cortisol deficiency causes vomiting, shock, hypoglycaemia and hyponatraemia, with hyperkalaemia more likely when primary aldosterone loss coexists.

Recurrent hospital admission

Inadequate sick-day knowledge, inaccessible injection supplies or poor cross-service communication allows ordinary illness to trigger repeated decompensation.

Replacement overexposure

Chronic excessive glucocorticoid replacement causes weight gain, hypertension, diabetes, infection and osteoporosis, so the lowest effective physiological regimen is sought.

Associated autoimmune disease

Autoimmune primary disease can coexist with thyroid, gonadal or other autoimmune conditions that add symptoms and alter replacement needs.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Review energy, nausea, postural symptoms, weight, blood pressure and features of glucocorticoid excess; there is no single routine serum cortisol target for replacement adequacy.
In primary disease, follow sodium, potassium, seated and standing blood pressure and renin where the specialist service uses it to adjust fludrocortisone.
For central disease, monitor other pituitary axes and structural pathology; ensure thyroid replacement changes are coordinated with cortisol coverage.
At every transition of care, verify Steroid Emergency Card, spare oral supply, injection kit availability, expiry dates and that the patient or carer can use it.
After intercurrent illness, crisis or procedure, document the return from stress dosing to maintenance and review whether the precipitant revealed an education or access gap.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Potassium localises imperfectly

Hyperkalaemia supports aldosterone loss in primary disease, but a normal result does not exclude Addison's disease or crisis. Central deficiency commonly leaves potassium unchanged.

Pigmentation needs chronic ACTH

Hyperpigmentation is a clue to primary disease, not an entry requirement. Rapid adrenal destruction or lighter baseline skin assessment can make it subtle.

Synacthen has a timing blind spot

Soon after pituitary injury the adrenal cortex may still respond to synthetic ACTH. Clinical context and basal ACTH/cortisol can outweigh a superficially reassuring early dynamic test.

Steroid history is multisurface

Potent topical preparations, joint injections and inhaled treatment can suppress the axis, especially in combination or with CYP3A4 inhibition. Asking only about tablets misses preventable risk.

Cortisol precedes thyroxine

Replacing thyroid hormone increases metabolic demand and cortisol clearance. When both axes may have failed, glucocorticoid safety is established first.

11Common pitfallsFrequent interpretation and management errors.

01
Using a random afternoon cortisol to rule out adrenal insufficiency in a stable patient.
02
Waiting for a short Synacthen test before treating hypotension and vomiting as possible crisis.
03
Assuming normal potassium excludes primary adrenal disease or an acute crisis.
04
Prescribing hydrocortisone without a Steroid Emergency Card, sick-day supplies and injection education.
05
Giving fludrocortisone routinely for secondary adrenal insufficiency despite preserved aldosterone.
06
Starting levothyroxine first when combined pituitary or autoimmune endocrine failure is plausible.