Addison's Disease (Primary Adrenal Insufficiency)

Primary adrenal insufficiency (Addison's disease) is failure of the adrenal cortex itself, causing deficiency of both cortisol (glucocorticoid) and aldosterone (mineralocorticoid) — this combined deficiency, plus compensatory elevation of ACTH from an intact pituitary, is what distinguishes it from secondary adrenal insufficiency (pituitary ACTH deficiency) and tertiary adrenal insufficiency (hypothalamic CRH deficiency, most often from prolonged exogenous glucocorticoid use), in which the renin-angiotensin-aldosterone axis is intact and mineralocorticoid production is preserved.^[1] It is an uncommon but genuinely life-threatening condition to miss: symptoms develop gradually and are frequently nonspecific enough that the diagnosis is often delayed for months to years, yet an unrecognized or undertreated patient can decompensate into adrenal crisis — refractory hypotension and shock — with any intercurrent illness, injury, or surgical stress.^[2] Lifelong glucocorticoid and mineralocorticoid replacement, dosed to mimic normal physiology as closely as possible, is disease-modifying rather than curative, and every patient needs durable, repeated education on two skills that determine whether they live an ordinary life or end up in an emergency department: adjusting the glucocorticoid dose for illness ("sick-day rules"), and recognizing and self-treating an evolving adrenal crisis with an emergency injection before it becomes irreversible.

• Autoimmune adrenalitis — the leading cause in Canada and other iodine-sufficient countries, often in the context of autoimmune polyendocrine syndrome (coexisting autoimmune thyroid disease, type 1 diabetes, premature ovarian insufficiency, celiac disease, pernicious anemia, or vitiligo).^[1]
• Infectious adrenalitis — tuberculosis remains a leading global cause where endemic; HIV/CMV adrenalitis and other opportunistic infection in advanced immunosuppression.
• Adrenal hemorrhage or infarction — meningococcemia (Waterhouse-Friderichsen syndrome), antiphospholipid syndrome, or therapeutic anticoagulation, particularly with a preceding critical illness.
• Metastatic malignancy or infiltrative disease involving both adrenal glands (lymphoma, amyloidosis, hemochromatosis).
• Bilateral adrenalectomy, or a genetic cause such as congenital adrenal hyperplasia or adrenoleukodystrophy.
• Drug-induced — immune checkpoint inhibitors can trigger autoimmune primary adrenalitis; ketoconazole, etomidate, and mitotane directly inhibit adrenal steroidogenesis.
• A first-degree relative with autoimmune Addison's disease or another organ-specific autoimmune condition.

Also refer to or consult endocrinology for: any newly suspected diagnosis (confirmatory ACTH stimulation testing and etiology workup should not be managed outside specialist care); pregnancy in a patient with known adrenal insufficiency; recurrent adrenal crises despite apparently adequate sick-day education; persistent hypertension or edema on fludrocortisone; or any patient/caregiver who cannot demonstrate correct emergency-injection technique.

History and examination

Ask specifically about the symptom cluster above, the pace of onset, salt craving, postural symptoms, and — critically — look for hyperpigmentation in sun-exposed skin, the buccal mucosa, gums, palmar creases, scars, and pressure points, since its presence versus absence is the single most useful bedside clue distinguishing primary from secondary/tertiary adrenal insufficiency.

Confirming the diagnosis

In an acutely unwell patient with a clinical picture suggestive of adrenal crisis, draw blood for a random cortisol and ACTH and then treat immediately with hydrocortisone — do not wait for the results before treating.^[4] In a stable outpatient:

• A morning (8-9 AM) serum cortisol below 140 nmol/L (about 5 mcg/dL), combined with an ACTH more than twice the upper reference limit, strongly suggests primary adrenal insufficiency and may be sufficient when urgent confirmation is needed.
• The 250 mcg ACTH (cosyntropin/tetracosactide) stimulation test is the standard confirmatory test: measure cortisol at baseline and 30-60 minutes after IM or IV cosyntropin. A peak cortisol below 500 nmol/L (about 18 mcg/dL) confirms adrenal insufficiency.^[4]
• Once biochemically confirmed, measure plasma ACTH to localize the defect — markedly elevated in primary adrenal insufficiency (the pituitary is trying to compensate), low or inappropriately normal in secondary/tertiary disease — and measure plasma renin and aldosterone to confirm mineralocorticoid deficiency (elevated renin with low aldosterone in primary disease).
• Screen for 21-hydroxylase autoantibodies to identify an autoimmune cause; when negative, adrenal CT is used to look for hemorrhage, infiltrative disease, metastases, or tuberculosis (adrenal enlargement or calcification).

A normal or borderline stimulation test does not always fully exclude very early autoimmune adrenalitis in a patient with strong clinical suspicion and positive 21-hydroxylase antibodies — because primary adrenal insufficiency is rare and its presentation nonspecific, maintaining a low threshold to test (rather than the stimulation test itself being technically difficult) is what actually catches most patients before a first crisis.^[2]

Testing caveats: do not test cortisol in a patient already taking exogenous glucocorticoids at a physiologic-or-higher dose — the result will be uninterpretable; if testing cannot be deferred, bridge temporarily to dexamethasone, which does not cross-react on most cortisol assays. Discontinue oral estrogen for about 6 weeks before testing where possible, since it raises cortisol-binding globulin and can falsely elevate total cortisol. Biotin supplements can interfere with the same immunoassay platforms affected in thyroid testing — ask about biotin use if a result is clinically discordant.

• Replace glucocorticoid and mineralocorticoid to as close to normal physiology as achievable — avoiding both under-replacement (fatigue, risk of crisis) and over-replacement (Cushingoid effects, bone loss, cardiometabolic harm).
• Prevent adrenal crisis, and ensure the patient and their household can recognize and self-treat one immediately if it begins.
• Build durable competence in sick-day dose adjustment as a routine self-management skill, not a one-time instruction.
• Screen for and manage associated autoimmune conditions when the cause is autoimmune.
• Support normal quality of life, fertility, and pregnancy outcomes.

• Steroid emergency card and medical alert identification (bracelet or necklace stating "adrenal insufficiency — requires hydrocortisone") — every patient should carry or wear this at all times, since it is often what prompts correct emergency treatment before the patient can speak for themselves.^[5]
• Emergency glucocorticoid injection kit — every patient with primary adrenal insufficiency should be issued one and trained (along with a household member or caregiver) to reconstitute and inject it; check the expiry date on the hydrocortisone, needles, and syringes at every refill and replace before they lapse.^[5]
• Do not restrict dietary salt intake; encourage a liberal, not reduced, salt intake to support mineralocorticoid replacement.
• Never stop glucocorticoid replacement abruptly for any reason, including running out of medication — build in a buffer supply and refill before running low.
• Carry extra oral hydrocortisone (and the injection kit) when travelling, and know how to access emergency care while away from home.
• Inform every treating clinician — including dentists and any clinician performing even a minor procedure with sedation — of the diagnosis before the appointment, not on arrival.
• Provide a written, individualized sick-day action plan the patient keeps and can reference under stress, rather than relying on memory alone in the moment.

Breastfeeding

Hydrocortisone and prednisone are both compatible with breastfeeding at usual replacement doses.

Pediatrics

Hydrocortisone is dosed at approximately 8 mg/m²/day divided into 3-4 doses, with the largest dose on waking; avoid long-acting synthetic glucocorticoids (dexamethasone, and generally prednisone) in growing children given the added growth-suppression risk. Infants often need a relatively higher fludrocortisone dose than older children, plus oral sodium chloride supplementation, since breast milk and standard infant formula are both low in sodium.^[5]

Older adults

Watch particularly closely for over-replacement — bone loss and fracture risk, new or worsening hyperglycemia, and hypertension — since this age group tolerates supraphysiologic dosing poorly, while comorbid illness can also make an evolving crisis harder to recognize early. Maintain a low threshold to treat when in doubt rather than waiting to confirm.

Coexisting autoimmune hypothyroidism

When both primary adrenal insufficiency and hypothyroidism are present (a recognized autoimmune polyendocrine combination), always start or optimize glucocorticoid replacement before starting or increasing levothyroxine — thyroid hormone replacement accelerates cortisol clearance and can precipitate an adrenal crisis if the adrenal insufficiency is not yet adequately treated.

Drug interactions affecting glucocorticoid requirement

Strong hepatic enzyme inducers — rifampin, phenytoin, carbamazepine, and mitotane — accelerate hydrocortisone metabolism and can necessitate a higher maintenance dose; strong CYP3A4 inhibitors (ritonavir, itraconazole) can have the opposite effect. Reassess clinically, and consider a dose adjustment, whenever one of these is started or stopped.

There is no laboratory test that reliably titrates the glucocorticoid replacement dose — hydrocortisone and prednisone doses are adjusted on clinical grounds: body weight, blood pressure, energy level, and symptoms of over- or under-replacement, reviewed at every visit and at least annually once the patient is stable.^[4] Watch specifically for signs of over-replacement (weight gain, skin thinning/easy bruising, new hyperglycemia, new or worsening hypertension, insomnia) and under-replacement (persistent fatigue significantly limiting activity, weight loss, nausea, or hyperpigmentation that fails to fade).

Assess mineralocorticoid adequacy separately: supine and standing blood pressure at every visit, serum electrolytes, and clinical signs of excess (edema, hypertension) or deficiency (postural hypotension, salt craving); plasma renin trending toward the upper end of the normal reference range supports an appropriate fludrocortisone dose.^[4]

Annually: screen for other autoimmune conditions when the cause is autoimmune (thyroid function, B12, and consider celiac serology if symptomatic), obtain a baseline bone density measurement within a few years of diagnosis with periodic follow-up given lifelong glucocorticoid exposure, and check a lipid profile and glucose/HbA1c.^[5] Ask specifically and directly, at every visit, how many sick-day dose increases and emergency injections the patient has needed since the last visit, and confirm the emergency kit has not expired — this single question is one of the highest-yield things a pharmacist can do at a routine refill.

For persistent fatigue or impaired well-being despite otherwise optimized glucocorticoid and mineralocorticoid replacement, adjunctive DHEA can be considered in women, per specialist direction, once other explanations (undertreated dose, coexisting autoimmune thyroid or celiac disease, depression) have been reasonably excluded.

1. Confirm adherence, dose timing, and administration technique before assuming the dose itself is wrong — a missed or mistimed dose is the most common reason for apparently poor control.
2. Review the medication list for a new interacting drug that increases hydrocortisone clearance (rifampin, phenytoin, carbamazepine, mitotane); increase the glucocorticoid dose if one cannot be avoided.
3. Reassess the glucocorticoid and mineralocorticoid components separately — persistent postural hypotension, salt craving, or hyperkalemia despite fludrocortisone points to an inadequate mineralocorticoid dose even if the glucocorticoid dose looks adequate, and vice versa for persistent fatigue with normal blood pressure and electrolytes.
4. For persistent fatigue or reduced well-being despite an apparently adequate standard regimen, screen for a coexisting undertreated autoimmune condition (thyroid disease, celiac disease) before assuming the cortisol dose alone needs to increase, and consider adjunctive DHEA in women per specialist direction.
5. For recurrent adrenal crises despite a written sick-day plan, directly re-observe the patient's or caregiver's actual injection technique and sick-day decision-making rather than assuming the written plan alone was sufficient, and lower the threshold for escalating to the emergency injection next time.
6. If control remains difficult after working through the steps above, refer to or consult endocrinology rather than continuing to adjust the dose empirically.

• Withholding the emergency hydrocortisone injection to wait for a confirmatory cortisol/ACTH result in a patient who looks like they may be in crisis — treat immediately; draw blood first only if it does not delay the dose.^[3]
• Increasing the fludrocortisone dose during sick days — unnecessary and not part of the sick-day rule, since the increased hydrocortisone dose itself provides adequate mineralocorticoid activity.
• Stopping glucocorticoid replacement abruptly for any reason, including simply running out of medication between refills.
• Using dexamethasone as routine chronic replacement rather than reserving it for situations where other agents genuinely cannot be used.
• Missing hyperpigmentation as the clinical clue that distinguishes primary from secondary/tertiary adrenal insufficiency — a patient without it can still have adrenal insufficiency, but its presence should immediately raise suspicion of the primary form specifically.
• Forgetting perioperative or dental stress dosing before a planned procedure with sedation, or not confirming the surgical/dental team already knows the diagnosis well before the appointment.
• Letting a patient leave a visit without a current emergency injection kit, a legible sick-day plan, and medical alert identification — or not checking the kit's expiry date at routine refills.
• Starting or increasing levothyroxine before glucocorticoid replacement is adequately established in a patient with combined adrenal insufficiency and hypothyroidism — this sequencing error can precipitate a crisis.
• Missing a new interacting drug (rifampin, phenytoin, carbamazepine) that silently increases glucocorticoid requirement without any dose change having been made.
• Attributing vague fatigue, weight loss, or GI symptoms to depression, burnout, or a functional GI disorder without checking a morning cortisol when hyperpigmentation, salt craving, or unexplained hyponatremia/hyperkalemia are also present.

How to use this table: Doses are adult doses and require patient-specific confirmation. Select any linked drug name to open its complete Pharmasist Drug Database page. The Database's existing oral "hydrocortisone" and "prednisone"/"prednisolone" entries are either formulation mismatches (a topical cream) or not currently published as a distinct oral-tablet monograph, so both are named as text only below rather than linked — see the chapter note at the top of this source file for the full explanation.

Glucocorticoid replacement — chronic maintenance

Dosed to mimic the normal cortisol circadian rhythm: the largest dose on waking, tapering through the day, with nothing taken in the evening.

Mineralocorticoid replacement — chronic maintenance

For primary adrenal insufficiency only — secondary/tertiary adrenal insufficiency does not need mineralocorticoid replacement, since the renin-angiotensin-aldosterone axis is intact.

Sick-day and perioperative stress dosing

The oral increase is a temporary multiple of the patient's own usual dose, not a fixed number — confirm the patient's baseline dose before advising the multiple.

Adrenal crisis — emergency parenteral therapy

Give hydrocortisone immediately on clinical suspicion — never delay it to wait for a confirmatory cortisol or ACTH result.