Endocrine

Adrenal insufficiency: primary and secondary

Clinical Overview and When to Suspect Adrenal Insufficiency

Adrenal insufficiency (AI) = inadequate cortisol production. Two major categories:

Classic patient profiles:

Suspect AI when:

— Unexplained fatigue, weight loss, orthostatic hypotension

— Hyponatremia ± hyperkalemia (primary) or isolated hyponatremia (secondary)

— Hyperpigmentation of skin creases, gums, scars (primary only)

Board pearl: Hyperpigmentation distinguishes primary from secondary AI — it results from ↑ ACTH/MSH cleavage from POMC, which is low in secondary AI.

Primary AI (Addison disease): destruction/dysfunction of the adrenal cortex → ↓ cortisol, ↓ aldosterone, ↓ adrenal androgens; compensatory ↑ ACTH

Secondary AI: ↓ ACTH from pituitary or hypothalamic disease → ↓ cortisol; aldosterone is preserved (regulated by RAAS, not ACTH)

Tertiary AI (most common cause overall): chronic exogenous glucocorticoid use → HPA axis suppression → abrupt withdrawal → crisis

Primary: young woman with fatigue, weight loss, hyperpigmentation, salt craving, hypotension

Secondary: patient on long-term prednisone tapered too quickly; or pituitary tumor/surgery

Presentation Patterns and Key History Findings

Chronic AI (insidious):

Acute AI (adrenal crisis):

History clues to etiology:

— Autoimmune diseases (type 1 DM, Hashimoto, vitiligo) → autoimmune adrenalitis

— TB exposure or HIV → infectious adrenalitis

— Chronic steroid use → tertiary/secondary AI

— Known pituitary tumor, surgery, or radiation → secondary AI

— Anticoagulation + sudden flank pain → adrenal hemorrhage (Waterhouse-Friderichsen if meningococcal)

Next best step: In any ICU patient with refractory hypotension despite fluids/vasopressors, consider AI and draw a random cortisol before empiric stress-dose steroids.

Fatigue, malaise, anorexia, weight loss

Nausea, vomiting, abdominal pain (can mimic GI disease)

Salt craving (primary — aldosterone deficiency)

Postural dizziness / orthostatic hypotension

Myalgias, arthralgias

Loss of axillary/pubic hair in women (↓ adrenal androgens, primary)

Mood changes: depression, irritability

Hemodynamic collapse refractory to fluids and vasopressors

Severe abdominal pain mimicking acute abdomen

Fever, altered mental status

Triggered by: physiologic stress (infection, surgery, trauma) in undiagnosed or undertreated AI, or abrupt glucocorticoid withdrawal

Physical Exam and Distinguishing Primary vs Secondary AI

Primary AI exam findings:

Secondary AI exam findings:

Key distinction:

Board pearl: Isolated hyponatremia with normal K⁺ in a patient with a pituitary lesion → think secondary AI. Hyponatremia + hyperkalemia → think primary AI.

Hyperpigmentation — palmar creases, buccal mucosa, nipples, scars, pressure points (↑ ACTH → POMC → MSH)

Vitiligo (autoimmune association)

Orthostatic hypotension (volume depletion from aldosterone deficiency)

↓ Axillary and pubic hair (women)

Thin body habitus

No hyperpigmentation (ACTH is low)

Pallor (↓ MSH)

May have signs of other pituitary hormone deficiencies: amenorrhea, hypothyroidism, growth retardation

If pituitary mass: bitemporal hemianopia, headache

If prior exogenous steroid use: Cushingoid features may coexist with AI symptoms during taper

Primary AI → ↑ ACTH, ↓ aldosterone → hyperkalemia + hyponatremia + metabolic acidosis

Secondary AI → ↓ ACTH, aldosterone preserved → hyponatremia (↑ ADH from cortisol deficiency) but normal K⁺

Diagnostic Workup — Initial Laboratory Evaluation

First-line test: Early morning (8 AM) serum cortisol

Simultaneous plasma ACTH level:

Additional labs:

Next best step: If morning cortisol is indeterminate → cosyntropin (ACTH) stimulation test is the gold standard confirmatory test.

< 3 µg/dL → strongly suggests AI

> 18 µg/dL → effectively excludes AI

3–18 µg/dL → indeterminate → proceed to ACTH stimulation test

↑ ACTH (often >100 pg/mL) + ↓ cortisol → Primary AI

↓ or inappropriately normal ACTH + ↓ cortisol → Secondary AI

BMP: hyponatremia (both), hyperkalemia (primary only), hypoglycemia, non-anion gap metabolic acidosis (primary)

CBC: eosinophilia, lymphocytosis (loss of cortisol's effect on WBC distribution)

↑ Renin, ↓ aldosterone (primary only)

21-hydroxylase antibodies → most common cause of autoimmune primary AI

DHEA-S: low in primary AI

Diagnostic Workup — ACTH Stimulation Test and Imaging

Standard-dose cosyntropin (250 µg) stimulation test:

Interpretation:

ITT (gold standard for secondary AI but rarely used):

Imaging:

Board pearl: A normal cosyntropin test does NOT rule out acute secondary AI — the adrenals need weeks of ACTH deprivation to atrophy.

Administer 250 µg IV/IM synthetic ACTH (cosyntropin)

Measure serum cortisol at 0, 30, and 60 minutes

Normal response: cortisol ≥ 18 µg/dL at 30 or 60 min

Abnormal (flat response): cortisol < 18 → confirms AI

Abnormal + high baseline ACTH → Primary AI

Abnormal + low baseline ACTH → Secondary AI (chronic ACTH deficiency → adrenal atrophy → cannot respond to exogenous ACTH)

Caveat: In acute/recent-onset secondary AI (e.g., pituitary apoplexy), adrenals may not yet be atrophied → cosyntropin test may be falsely normal → use low-dose (1 µg) cosyntropin or insulin tolerance test (ITT) if high clinical suspicion

Insulin-induced hypoglycemia (glucose <40) should stimulate cortisol >18; failure confirms central AI

Contraindicated in seizure disorders, elderly, CAD

Primary AI: CT abdomen → adrenal gland size/calcifications (TB, hemorrhage, infiltrative); small glands in autoimmune

Secondary AI: MRI pituitary with gadolinium → tumor, empty sella, infiltrative disease

First-Line Management — Chronic Replacement Therapy

Primary AI requires replacement of:

1. Glucocorticoid: Hydrocortisone 15–25 mg/day in 2–3 divided doses (largest dose in AM to mimic diurnal rhythm)

— Alternative: prednisone 3–5 mg/day or dexamethasone 0.25–0.75 mg/day

— Hydrocortisone preferred due to shorter half-life and physiologic dosing

2. Mineralocorticoid: Fludrocortisone 0.05–0.2 mg/day (only in primary AI)

— Titrate to normalize K⁺, Na⁺, blood pressure, and plasma renin activity (PRA)

3. DHEA replacement (optional, may improve well-being/libido in women): 25–50 mg/day

Secondary AI:

Key point: When replacing both cortisol and thyroid hormone in secondary AI, always start glucocorticoids FIRST — giving levothyroxine alone can precipitate adrenal crisis by accelerating cortisol metabolism.

Board pearl: Patients must carry a medical alert bracelet and an emergency injection kit of hydrocortisone (100 mg IM).

Glucocorticoid replacement only (same as above)

Fludrocortisone NOT needed — aldosterone is preserved via RAAS

Treat other pituitary hormone deficiencies as needed (thyroid, gonadal, GH)

Stress Dosing — Sick Day Rules and Perioperative Management

Cortisol demand ↑ 5–10× during physiologic stress. Patients with AI cannot mount this response.

Sick day rules (outpatient):

Perioperative stress dosing:

Next best step: Any AI patient presenting with acute illness, surgery, or hemodynamic compromise → give stress-dose steroids immediately; do not wait for labs.

Board pearl: Fludrocortisone is NOT increased during stress — only glucocorticoid is. High-dose hydrocortisone (≥50 mg) already provides adequate mineralocorticoid activity.

Minor illness (cold, mild gastroenteritis): double or triple the daily oral hydrocortisone dose for 2–3 days

Vomiting/unable to take PO: IM hydrocortisone 100 mg (self-administered from emergency kit) → seek medical attention

Minor procedure (dental, local anesthesia): take usual dose

Moderate surgery (cholecystectomy, joint replacement): hydrocortisone 50 mg IV before induction → 25 mg q8h × 24–48 h → taper to baseline

Major surgery (CABG, trauma): hydrocortisone 100 mg IV bolus → 50 mg IV q8h × 48–72 h → taper to maintenance

Treatment of Adrenal Crisis

Adrenal crisis = life-threatening emergency → mortality approaches 50% if untreated.

Triggers: infection, surgery, trauma, nonadherence, undiagnosed AI under stress

Management algorithm:

1. IV hydrocortisone 100 mg bolus → then 50 mg IV q6–8h (or continuous infusion 200 mg/24h)

2. Aggressive IV normal saline (0.9% NaCl) — often 1–3 L in first hours for volume repletion and correction of hyponatremia

3. IV dextrose (D5NS) if hypoglycemic

4. Identify and treat precipitant (infection, MI, etc.)

5. Monitor: BP, heart rate, glucose, electrolytes, urine output

6. Taper to oral maintenance over 1–3 days as patient stabilizes

Do NOT:

Board pearl: If you suspect adrenal crisis but want diagnostic data, draw a random cortisol + ACTH BEFORE giving hydrocortisone, or give dexamethasone 4 mg IV (which does not interfere with the cortisol assay) and perform cosyntropin stimulation test afterward.

Delay steroids for confirmatory testing in a crashing patient

Use dexamethasone unless you want to perform a cosyntropin test simultaneously (dexamethasone does not cross-react with cortisol assays)

Special Populations — Pregnancy

Board pearl: Rising cortisol levels in pregnancy are physiologic — do not diagnose AI based solely on a 'normal-looking' total cortisol in a symptomatic pregnant patient.

Pregnancy increases cortisol-binding globulin (CBG) → total cortisol rises but free cortisol also increases by third trimester → standard cortisol cutoffs may be unreliable

Cosyntropin test can still be used; however, normal cutoff may need to be higher (~25 µg/dL in third trimester)

Hydrocortisone is the preferred glucocorticoid in pregnancy — it is inactivated by placental 11β-HSD2 → minimal fetal exposure

Prednisone is also acceptable (also inactivated by placental enzyme)

Dexamethasone crosses the placenta (NOT inactivated) → avoid unless specifically treating a fetal condition (e.g., congenital adrenal hyperplasia)

Fludrocortisone dose may need ↑ in primary AI due to anti-mineralocorticoid effect of progesterone

Labor and delivery: treat as major stress → stress-dose hydrocortisone 100 mg IV at onset of labor → 50 mg q6–8h → taper postpartum

Special Populations — Pediatric, Elderly, and Comorbid Patients

Pediatric considerations:

Elderly:

Renal impairment:

Hepatopathy:

Board pearl: In CAH, ambiguous genitalia in a 46,XX neonate with hyperkalemia and hyponatremia → 21-hydroxylase deficiency until proven otherwise.

Congenital adrenal hyperplasia (CAH) — most common cause of primary AI in neonates (21-hydroxylase deficiency)

Salt-wasting crisis in first 1–2 weeks of life: vomiting, dehydration, hyperkalemia, hyponatremia, ambiguous genitalia in 46,XX

Newborn screening: ↑ 17-hydroxyprogesterone

Weight-based hydrocortisone dosing: 8–10 mg/m²/day divided TID

Overtreatment risk → growth suppression; monitor growth velocity

Higher susceptibility to adrenal crisis during illness

Symptoms overlap with depression, frailty, deconditioning → high index of suspicion needed

Lower threshold for stress dosing during hospitalizations

Monitor bone density — chronic glucocorticoid replacement → osteoporosis risk

Hyperkalemia from primary AI + CKD → compounded risk; monitor K⁺ closely

Fludrocortisone may exacerbate hypertension/edema — titrate carefully

CBG synthesis ↓ → total cortisol may appear low with adequate free cortisol

Use free cortisol or salivary cortisol if CBG status is uncertain

Complications and Emergencies

Adrenal crisis (see Chunk 8):

Adrenal hemorrhage (Waterhouse-Friderichsen syndrome):

Hyponatremia complications:

Hypoglycemia:

Osteoporosis:

Board pearl: Bilateral adrenal hemorrhage in an anticoagulated patient with sudden back/flank pain, hypotension, and ↑ ACTH → emergency CT abdomen → stress-dose steroids immediately.

Mortality ~6% per episode even with treatment; higher if delayed

Most common cause of death in AI patients → preventable with education

Bilateral adrenal hemorrhage in meningococcemia → acute primary AI + DIC + shock

Also seen with: heparin/warfarin therapy, antiphospholipid syndrome, postoperative state

CT: bilateral adrenal enlargement with hemorrhage

Treatment: emergent hydrocortisone + supportive care + antibiotics

Severe (Na⁺ <120): seizures, cerebral edema

Correct with IV NS + glucocorticoid replacement; avoid overly rapid correction (risk of osmotic demyelination)

More common in children and secondary AI (co-existing GH deficiency)

Cortisol is a counter-regulatory hormone → absence leads to impaired gluconeogenesis

Long-term glucocorticoid replacement, even at physiologic doses → monitor DEXA

When to Escalate Care — Inpatient vs Outpatient Decision-Making

Admit to hospital / ICU:

Manage outpatient:

Refer to endocrinology:

Next best step: Any patient with suspected adrenal crisis → give hydrocortisone 100 mg IV immediately without waiting for labs or consult. Diagnostic workup can follow stabilization.

Adrenal crisis: hemodynamic instability, altered mental status, severe electrolyte derangements

New diagnosis with severe symptoms (significant hyponatremia, hypoglycemia, hypotension)

Inability to tolerate oral medications (vomiting)

Concurrent serious illness requiring stress dosing and monitoring

Stable chronic AI on replacement therapy with good adherence

Mild illness manageable with sick-day rules

Routine follow-up every 3–6 months

All new diagnoses of AI for confirmation and dose optimization

Suspected secondary AI → pituitary workup (MRI + other pituitary axes)

Difficulty titrating replacement doses

Pregnancy planning in AI patients

Suspected autoimmune polyglandular syndrome (APS-1 or APS-2)

Key Differentials — Primary AI vs Other Causes of Hyperpigmentation and Fatigue

Hyperpigmentation differential:

Fatigue + weight loss differential:

Key distinction: Hyperpigmentation + hyperkalemia + hyponatremia + low cortisol + high ACTH = primary AI. No other diagnosis matches this full constellation.

Board pearl: Nelson syndrome — always consider in a patient with prior bilateral adrenalectomy who develops progressive hyperpigmentation and an enlarging pituitary mass.

Primary AI (Addison) → diffuse, accentuated in creases, scars, mucosa (↑ ACTH/MSH)

Hemochromatosis → 'bronze diabetes'; ↑ ferritin, ↑ transferrin sat

Nelson syndrome → post-bilateral adrenalectomy → pituitary corticotroph tumor expansion → very high ACTH → severe hyperpigmentation

Ectopic ACTH syndrome → some tumors (small cell lung cancer) → ↑ ACTH → pigmentation (though Cushing features dominate)

Peutz-Jeghers → mucosal pigmentation + GI polyps

Hypothyroidism → ↑ TSH, but causes weight gain

Depression → may coexist; cortisol testing differentiates

Malignancy → investigate with age-appropriate screening

Chronic infection (TB, HIV) → can ALSO cause AI

Anorexia nervosa → voluntary restriction; cortisol is usually ↑

Key Differentials — Secondary AI vs Other Causes of Hyponatremia

Secondary AI presents with hyponatremia (↑ ADH from cortisol deficiency) + normal K⁺ → mimics SIADH.

Distinguishing secondary AI from SIADH:

Other causes of central hypocortisolism:

Board pearl: Never diagnose SIADH without first ruling out adrenal insufficiency and hypothyroidism — both can mimic euvolemic hyponatremia and both are easily treatable.

Both: euvolemic hyponatremia, low serum osmolality, urine osmolality >100

Key difference: in secondary AI, administering glucocorticoids corrects hyponatremia; in SIADH, it does not

Always check a cortisol level before diagnosing SIADH

Pituitary apoplexy: sudden headache, visual field defects, hypotension → hemorrhage/infarction of pituitary adenoma → acute panhypopituitarism → secondary AI

Sheehan syndrome: postpartum pituitary necrosis after hemorrhagic delivery → failure to lactate, fatigue, ↓ all pituitary hormones

Lymphocytic hypophysitis: autoimmune, especially postpartum or with checkpoint inhibitor immunotherapy

Empty sella syndrome

Craniopharyngioma (children and young adults)

Preventive Care, Screening, and Follow-Up Monitoring

Monitoring parameters for chronic AI on replacement:

Screening for associated autoimmune conditions in primary AI (APS-2):

Follow-up: every 3–6 months in stable patients; more frequently after diagnosis, dose changes, or intercurrent illness.

Board pearl: Over-replacement with glucocorticoids is more dangerous than mild under-replacement — causes osteoporosis, metabolic syndrome, and adrenal crisis risk if doses are abruptly cut.

Clinical: energy, weight, blood pressure (sitting and standing), signs of over-replacement (Cushingoid features, weight gain) or under-replacement (fatigue, hypotension)

Labs: AM cortisol NOT routinely useful for dose adjustment — rely on clinical assessment

Electrolytes: Na⁺, K⁺ — especially when adjusting fludrocortisone

Plasma renin activity (PRA): target upper-normal range for fludrocortisone titration in primary AI

DHEA-S: if supplementing

Bone density (DEXA): baseline, then every 2–3 years

Fasting glucose / HbA1c: glucocorticoids can impair glucose tolerance

TSH annually → autoimmune thyroid disease

Fasting glucose → type 1 DM

Vitamin B12, CBC → pernicious anemia

Celiac serologies if symptomatic

Screening Intervals and HPA Axis Recovery After Exogenous Steroids

Who is at risk for HPA suppression?

HPA axis recovery after chronic steroids:

During taper:

Board pearl: A patient on chronic prednisone who undergoes surgery without stress-dose steroids may develop intraoperative cardiovascular collapse — always ask about prior steroid use in the preoperative assessment.

Any patient receiving ≥ prednisone 5 mg/day (or equivalent) for > 3 weeks

High-dose inhaled or potent topical steroids (rare but possible)

Intra-articular steroid injections (transient suppression)

Taper glucocorticoids gradually — no universally agreed protocol; commonly reduce by 10–20% every 1–2 weeks

After reaching physiologic dose (hydrocortisone ~10 mg/day or prednisone ~5 mg/day), switch to AM-only dosing

Test HPA axis recovery: 8 AM cortisol after holding morning dose → cortisol > 10–15 µg/dL suggests recovery

If uncertain: cosyntropin stimulation test → cortisol ≥ 18 confirms recovery → can discontinue replacement

Full recovery may take 6–12 months; some patients never fully recover

Patient must have stress-dosing instructions

Carry emergency hydrocortisone kit until HPA recovery confirmed

Ethical, Legal, and Patient Safety Considerations

— Teach sick-day rules, stress dosing, and self-injection technique

— Provide written emergency action plan

— In emergency settings, this can be lifesaving if the patient is unconscious

— Family members/caregivers should be trained in administration

Board pearl: The most common preventable cause of adrenal crisis death is failure of the healthcare team to administer stress-dose steroids during a known physiologic stressor.

Patient education is paramount — AI patients are at lifelong risk of adrenal crisis

Medical alert identification (bracelet/necklace) — essential for all AI patients

Emergency hydrocortisone kit prescription: every AI patient should have an IM hydrocortisone kit at home and when traveling

Medication access: glucocorticoids are inexpensive and widely available, but fludrocortisone cost can fluctuate → ensure patients can afford all medications

Disclosure and shared decision-making when tapering steroids — patients must understand the risk of adrenal crisis and the importance of gradual tapering

Medicolegal risk: failure to stress-dose a known AI patient during surgery or critical illness is a common and preventable cause of iatrogenic death

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: Etomidate is the only IV induction agent that suppresses adrenal function — a single intubating dose can precipitate crisis in a stressed patient.

Most common cause of primary AI worldwide: autoimmune adrenalitis (80–90% in developed countries); TB (most common in endemic regions)

Most common cause of secondary AI: exogenous glucocorticoid withdrawal

Autoimmune polyglandular syndrome type 2 (APS-2): Addison + autoimmune thyroid disease ± type 1 DM (Schmidt syndrome)

APS-1 (APECED): Addison + chronic mucocutaneous candidiasis + hypoparathyroidism (childhood onset, AIRE gene mutation)

Adrenoleukodystrophy: X-linked; young boys with neurologic deterioration + primary AI → very-long-chain fatty acids (VLCFA) elevated

Medications that cause AI: ketoconazole, etomidate (single dose can suppress adrenal function), rifampin (accelerates cortisol metabolism), phenytoin, mitotane, checkpoint inhibitors (immune-related hypophysitis)

Cortisol circadian rhythm: peaks 6–8 AM, nadir at midnight → always draw AM cortisol

↑ Eosinophils + ↑ lymphocytes on CBC → think cortisol deficiency

Hypercalcemia can occur in adrenal crisis (↑ calcium reabsorption + hemoconcentration)

Board Question Stem Patterns

35F, fatigue, weight loss, hyperpigmentation of palmar creases, Na⁺ 128, K⁺ 5.8, low AM cortisol, ACTH 450 → Primary AI → cosyntropin stimulation test → 21-hydroxylase antibodies

Patient on prednisone 20 mg × 6 months, abruptly discontinued, presents with hypotension and confusion → Adrenal crisis from HPA suppression → IV hydrocortisone 100 mg + NS

50M, bilateral adrenal calcifications on CT, history of TB → TB-related primary AI → cosyntropin test

28F, postpartum hemorrhage, failure to lactate, fatigue, Na⁺ 126, K⁺ 4.0, low cortisol, low ACTH → Sheehan syndrome → secondary AI → MRI pituitary

Euvolemic hyponatremia, low serum osm, urine osm >100, diagnosed as SIADH but fluid restriction fails → Check cortisol → secondary AI missed as SIADH mimic

Child with ambiguous genitalia, Na⁺ 125, K⁺ 7.0, ↑ 17-OHP → 21-hydroxylase deficiency (CAH) → hydrocortisone + fludrocortisone

ICU patient, septic shock refractory to vasopressors, random cortisol 8 µg/dL → Critical illness-related AI → stress-dose hydrocortisone 50 mg q6h

Patient with AI, upcoming elective surgery → Stress-dose steroids perioperatively based on surgical magnitude

AI patient started on levothyroxine without glucocorticoid → Risk of adrenal crisis → always start hydrocortisone before levothyroxine in secondary AI

One-Line Recap

Adrenal insufficiency is a deficiency of cortisol (± aldosterone in primary) caused by autoimmune adrenalitis (most common primary), exogenous steroid withdrawal (most common secondary/tertiary), or pituitary/hypothalamic disease — distinguished by ACTH level (↑ in primary, ↓ in secondary), presence of hyperpigmentation and hyperkalemia (primary only), and confirmed by a cosyntropin stimulation test (cortisol < 18 µg/dL) — managed with physiologic hydrocortisone replacement (± fludrocortisone in primary), mandatory stress dosing during illness/surgery, patient education including sick-day rules, medical alert identification, and an emergency IM hydrocortisone kit, with the understanding that adrenal crisis is the most dangerous and preventable complication, treated with IV hydrocortisone 100 mg bolus plus aggressive IV saline and identification of the precipitant.

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