Eduovisual
Endocrine
Primary adrenal insufficiency: diagnosis and replacement
— Distinguished from secondary AI (pituitary ACTH deficiency) and tertiary AI (hypothalamic CRH deficiency / exogenous steroid withdrawal), in which aldosterone is preserved because the renin–angiotensin axis is intact.
— Autoimmune adrenalitis accounts for ~80% of cases in developed countries; TB remains the leading cause worldwide.
— Other etiologies: bilateral adrenal hemorrhage (Waterhouse-Friderichsen, anticoagulation, antiphospholipid syndrome), metastatic disease (lung, breast, melanoma), HIV/CMV/disseminated fungal, infiltrative disease (amyloid, hemochromatosis), drugs (ketoconazole, etomidate, mitotane, checkpoint inhibitors), congenital adrenal hyperplasia, adrenoleukodystrophy.
— Chronic fatigue + weight loss + hyperpigmentation (palmar creases, buccal mucosa, scars).
— Unexplained hyponatremia with hyperkalemia, especially with hypotension or orthostasis.
— Recurrent hypoglycemia in a non-diabetic, or hypoglycemia in a T1DM patient whose insulin needs are dropping.
— Salt craving, postural lightheadedness, GI symptoms (nausea, vomiting, abdominal pain) misattributed to gastroenteritis.
— Adrenal crisis presenting as shock refractory to fluids/pressors, often triggered by infection, surgery, or missed steroid dose.
Board pearl: A patient with T1DM whose insulin requirement falls and who develops hyperpigmentation should trigger immediate evaluation for APS-2—check an 8 AM cortisol and ACTH before the next clinic visit.
— Constitutional: fatigue (100%), weakness, anorexia, weight loss (often 5–15 lb), low-grade fevers.
— GI: nausea (~85%), vomiting, vague abdominal pain, diarrhea or constipation; weight loss is a key differentiator from functional GI disorders.
— Neuropsychiatric: depression, apathy, poor concentration, decreased libido.
— Salt craving (~15–20%) is specific—ask explicitly; patients often add salt to everything or crave pickles, olives, salty broths.
— Postural symptoms: dizziness on standing from volume depletion and impaired vascular tone.
— Women: loss of axillary/pubic hair, amenorrhea, decreased libido (loss of adrenal androgens — DHEA).
— Hypotension or shock disproportionate to apparent illness, often refractory to IV fluids.
— Abdominal pain mimicking acute abdomen, vomiting, fever.
— Altered mental status, confusion, coma.
— Precipitants: infection (most common), surgery, trauma, MI, missed glucocorticoid doses, new medication that accelerates cortisol clearance (rifampin, phenytoin, phenobarbital, St. John's wort).
— Personal/family history of autoimmune disease (Hashimoto, Graves, T1DM, vitiligo, premature ovarian insufficiency, celiac).
— Recent or chronic glucocorticoid exposure (favors secondary or tertiary AI, not PAI).
— TB exposure, HIV status, anticoagulation, recent sepsis (DIC → hemorrhage).
— Use of checkpoint inhibitors (ipilimumab, pembrolizumab, nivolumab) — increasingly common cause of immune-related endocrinopathies.
Key distinction: Hyperpigmentation and salt craving point to primary AI (high ACTH/MSH, low aldosterone); their absence with similar symptoms suggests secondary AI. Hyperkalemia is essentially a primary AI finding.
— Orthostatic hypotension is the hallmark — check supine and standing BP/HR; drop ≥20 mmHg systolic or ≥10 mmHg diastolic suggests volume depletion from aldosterone deficiency.
— Resting tachycardia, low-normal or frankly low BP.
— In crisis: shock with cool extremities, often poorly responsive to fluid bolus until steroids given.
— Low-grade fever common even without infection; high fever suggests precipitant.
— Driven by elevated POMC-derived peptides (ACTH shares a precursor with α-MSH), which stimulate cutaneous melanocortin-1 receptors.
— Distribution: sun-exposed areas, palmar creases, knuckles, elbows, knees, buccal mucosa and gingival margins, areolae, perineum, recent scars (old scars do not darken — useful timing clue), nail beds.
— Vitiligo coexists in ~10–20% (autoimmune association).
— Loss of axillary and pubic hair in women (adrenal androgen deficiency); men are unaffected because testicular androgens dominate.
— Generalized muscle wasting, decreased grip strength.
— Mild diffuse abdominal tenderness without peritoneal signs in crisis.
— Hypoglycemia signs in children or fasting adults: tremor, diaphoresis, altered mentation.
— Calcifications of ear cartilage rarely (chronic disease).
— Distributive + hypovolemic shock picture: low SVR (cortisol deficiency impairs vascular response to catecholamines) plus volume depletion (aldosterone deficiency → renal sodium wasting).
— Pressors are often ineffective until hydrocortisone is given — cortisol permits catecholamine receptor function.
Step 3 management: If a hypotensive patient with hyperpigmentation, hyponatremia, and hyperkalemia fails to respond to 2 L crystalloid and norepinephrine, give empiric IV hydrocortisone 100 mg before further workup. Do not delay treatment to confirm the diagnosis — draw a cortisol/ACTH/aldosterone/renin tube first if it takes <60 seconds.
— Hyponatremia (~90%): cortisol deficiency → impaired free water excretion + aldosterone deficiency → renal Na+ wasting.
— Hyperkalemia (~65%): aldosterone deficiency → impaired distal K+ secretion. Absent in secondary AI.
— Non-anion-gap metabolic acidosis (hyperchloremic): type 4 RTA physiology from hypoaldosteronism.
— Hypoglycemia: more common in children; cortisol is counter-regulatory.
— Hypercalcemia (~5–10%): hemoconcentration and decreased renal Ca clearance — resolves with replacement.
— Mild normocytic anemia, eosinophilia, lymphocytosis (cortisol normally suppresses eosinophils/lymphocytes).
— Prerenal azotemia from volume depletion.
— 8 AM serum cortisol is the screening test.
— Cortisol <5 µg/dL (138 nmol/L) → strongly suggestive, proceed to confirmatory testing.
— Cortisol >18 µg/dL (>500 nmol/L) → effectively excludes AI.
— Indeterminate range (5–18) requires dynamic testing.
— Plasma ACTH: drawn simultaneously. In PAI, ACTH is markedly elevated (>2× upper limit, often >100 pg/mL) — this distinguishes primary from secondary AI before any stim test.
— Plasma renin activity (high) and aldosterone (low or inappropriately normal): confirms mineralocorticoid deficiency, a primary AI hallmark.
— DHEA-S: low in PAI.
— Cortisol-binding globulin falls in inflammation; total cortisol may underestimate free cortisol. A random cortisol >18 in a stressed ICU patient generally excludes AI; <10 supports it.
— Estrogen (OCPs, pregnancy) raises CBG and total cortisol; interpret with caution or measure free cortisol.
CCS pearl: In suspected crisis, on the order screen: draw cortisol + ACTH + CMP + renin + aldosterone, then immediately give hydrocortisone 100 mg IV and NS bolus. Don't wait for results.
— Administer 250 µg synthetic ACTH IV or IM; measure cortisol at baseline, 30 min, and 60 min.
— Normal response: peak cortisol ≥18 µg/dL (some labs use ≥20 with newer assays).
— PAI: blunted/absent response (peak <18) at both 30 and 60 min, with elevated baseline ACTH.
— Secondary AI: also blunted if chronic (atrophic adrenals), but baseline ACTH is low/inappropriately normal.
— Can be performed at any time of day; does not require fasting.
— Acute secondary AI (e.g., recent pituitary surgery, postpartum Sheehan within days) may have a falsely normal cosyntropin response because adrenals haven't atrophied yet — use insulin tolerance test or metyrapone in that setting.
— 21-hydroxylase antibodies — positive in ~85% of autoimmune Addison; first-line test.
— If antibody-negative or atypical: adrenal CT (look for enlargement/hemorrhage/calcification suggesting TB, infection, infiltration, malignancy).
— Autoimmune cases: adrenals are small/atrophic.
— TB or fungal: enlarged adrenals ± calcifications.
— Hemorrhage: bilateral enlargement with high attenuation on non-contrast CT.
— Very-long-chain fatty acids in young men with PAI and neurologic symptoms → adrenoleukodystrophy (X-linked).
— HIV testing, QuantiFERON for TB, fungal serologies if epidemiologically appropriate.
— Screen for associated autoimmunity: TSH, free T4, TPO antibodies, fasting glucose/A1c, B12, tTG-IgA, parathyroid panel, gonadal function.
Board pearl: In a young woman with new PAI, always check TSH and consider thyroid replacement only AFTER starting glucocorticoids — initiating levothyroxine first can precipitate adrenal crisis by accelerating cortisol metabolism.
— Pathway A — Adrenal crisis (acute, life-threatening):
— Pathway B — Chronic stable PAI (outpatient diagnosis):
1. IV access ×2, draw cortisol/ACTH/CMP/glucose simultaneously.
2. Hydrocortisone 100 mg IV bolus, then 50 mg IV q6h (or 200 mg/24h continuous infusion).
3. 1–2 L NS bolus for hypovolemia; D5NS if hypoglycemic.
4. Identify and treat precipitant: cultures, broad-spectrum antibiotics if sepsis suspected.
5. Continuous telemetry — hyperkalemia + volume shifts increase arrhythmia risk.
6. Reassess at 1 h, 6 h, 24 h; transition to oral steroids once tolerating PO and hemodynamically stable (usually 24–72 h).
— At hydrocortisone ≥50 mg/day, the drug provides adequate mineralocorticoid activity; fludrocortisone is not needed acutely and can be added when transitioning back to maintenance dosing (<50 mg/day hydrocortisone).
— Avoid dexamethasone for chronic replacement (no mineralocorticoid activity) but it can be used acutely if cosyntropin testing is planned within hours — it doesn't interfere with cortisol assays.
Step 3 management: Never wait for confirmatory ACTH stim test results before treating suspected crisis. Treat first, confirm later.
— Hydrocortisone is first-line: 15–25 mg/day divided 2–3 times daily, mimicking diurnal rhythm.
— Alternatives:
— Fludrocortisone 0.05–0.2 mg PO once daily (typical 0.1 mg).
— Titrate based on: BP, orthostatic vitals, serum Na/K, plasma renin activity (target upper-normal range), edema.
— Increase in hot weather, strenuous exercise, high sweat losses; reduce if hypertension or edema develops.
— Salt intake should be liberal/ad libitum — do not restrict.
— DHEA 25–50 mg PO daily can be considered in women with persistent low mood, low libido, or fatigue despite adequate gluco/mineralocorticoid replacement.
— Not routinely recommended; modest evidence; not FDA-approved as a prescription drug in the US (sold OTC).
— CYP3A4 inducers (rifampin, phenytoin, phenobarbital, carbamazepine, St. John's wort) accelerate cortisol metabolism — increase hydrocortisone dose by 50–100%.
— CYP3A4 inhibitors (ritonavir, itraconazole) → reduce dose or monitor for Cushingoid features.
— Levothyroxine initiation increases cortisol clearance — always start steroids first in newly diagnosed coexistent disease.
Board pearl: A PAI patient started on rifampin for latent TB who suddenly feels fatigued and orthostatic needs doubled hydrocortisone, not a new diagnosis.
— Rule of 2s and 3s: double or triple usual oral hydrocortisone dose for febrile illness, significant infection, vomiting/diarrhea, major dental work.
— Vomiting or unable to keep oral down: patient or family must inject hydrocortisone 100 mg IM (Solu-Cortef Act-O-Vial) and go to ED.
— Provide every patient with:
— Minor procedures (dental, skin biopsy, colonoscopy without sedation issues): take usual morning dose + extra 20 mg hydrocortisone preop.
— Moderate surgery (hernia, laparoscopic cholecystectomy, joint replacement): hydrocortisone 50 mg IV at induction, then 25 mg IV q8h × 24 h, then taper to maintenance over 1–2 days.
— Major surgery (open abdominal, cardiothoracic, trauma): hydrocortisone 100 mg IV at induction, then 50 mg IV q6h or 200 mg/24h infusion × 24–48 h, then taper over 3–5 days.
— Labor and delivery: treat as major surgery — 100 mg IV at active labor onset, then q6–8h until delivery, then taper.
— Bowel prep causes volume depletion → pretreat with extra fluids and stress-dose steroids.
— Iodinated contrast itself is not a reason for stress dosing, but underlying anxiety/NPO may warrant a single extra dose.
CCS pearl: On an OR-bound PAI patient's CCS order screen, always include: "Hydrocortisone 100 mg IV preoperatively, continue stress dose × 24–48h." Forgetting this is the classic exam pitfall and can trigger intraoperative crisis.
— Diagnosis often delayed — fatigue, weight loss, and orthostasis attributed to aging, polypharmacy, or cardiac disease.
— Hyperpigmentation may be less obvious in patients with darker baseline pigmentation or sun-damaged skin.
— Higher risk of iatrogenic over-replacement complications: osteoporosis, fractures, glucose intolerance, hypertension.
— Fludrocortisone increases BP and can worsen CHF; titrate cautiously in patients with HFpEF or HFrEF.
— Drug interactions matter more (anticonvulsants, rifampin if treated for prosthetic joint infection, azoles).
— PAI itself can cause prerenal AKI from volume depletion — resolves with replacement.
— Hyperkalemia management: in CKD patients with PAI, fludrocortisone is essential — do not underdose because of CKD; titrate to normokalemia and acceptable BP.
— Avoid ACEi/ARBs/spironolactone/eplerenone — they worsen hyperkalemia in PAI.
— Hydrocortisone is metabolized hepatically; no renal dose adjustment.
— Hydrocortisone activation/metabolism may be slowed; clinical effect generally preserved.
— Prednisone requires hepatic conversion to prednisolone — in severe liver disease, use prednisolone or hydrocortisone directly.
— CBG is synthesized in the liver; cirrhosis lowers CBG → total cortisol underestimates free cortisol. Use clinical response and free cortisol if available.
— Avoid NSAIDs (GI risk additive with steroids).
— PPI long-term: monitor B12 and bone density.
— Anticoagulants: GI bleed risk increases on steroids.
Step 3 management: In an elderly PAI patient with new osteoporosis, reduce hydrocortisone to lowest tolerated dose (e.g., 15 mg/day), optimize calcium/vitamin D, and start bisphosphonate if T-score ≤ −2.5 or fragility fracture.
— Cortisol and CBG both rise physiologically; total cortisol is unreliable. Use free cortisol or interpret stim test with trimester-specific cutoffs (peak ≥25 µg/dL in T2/T3).
— Replacement adjustments:
— Labor and delivery: hydrocortisone 100 mg IV at onset of active labor, then 50 mg IV q6–8h until delivery; rapid taper over 48 h postpartum back to prepregnancy dose.
— Avoid dexamethasone (crosses placenta, fetal HPA suppression). Hydrocortisone and prednisolone are largely inactivated by placental 11β-HSD2.
— Breastfeeding compatible at physiologic replacement doses.
— Most common cause in children is congenital adrenal hyperplasia (21-hydroxylase deficiency) — newborn screening detects elevated 17-OH progesterone.
— Salt-wasting CAH presents in first 2 weeks: vomiting, dehydration, hyponatremia, hyperkalemia, ambiguous genitalia in 46,XX infants.
— Replacement:
— Stress dosing: triple dose or use hydrocortisone 50 mg/m² IM for sick days/inability to tolerate PO.
— Monitor growth velocity, bone age annually; over- or under-replacement both impair final height.
Board pearl: A neonate with hyperkalemia, hyponatremia, hypotension, and ambiguous genitalia → classic salt-wasting CAH; give IV fluids + hydrocortisone immediately, then send 17-OH progesterone and karyotype.
— Adrenal crisis — recurrent crises occur in ~5–10 per 100 patient-years; mortality 0.5/100 patient-years even with treatment.
— Most common precipitants: GI illness (vomiting), infection, surgery, missed doses, emotional stress, new medications affecting cortisol metabolism.
— Hypoglycemia, especially in children or fasting adults.
— Chronic fatigue, reduced quality of life and work productivity even on adequate replacement.
— Iatrogenic Cushing features: central obesity, moon facies, striae, easy bruising — usually with hydrocortisone >30 mg/day equivalent.
— Osteoporosis and fragility fractures — risk rises with cumulative steroid exposure; baseline and serial DEXA.
— Type 2 diabetes / impaired glucose tolerance — screen yearly fasting glucose or A1c.
— Hypertension, edema, hypokalemia — usually from excess fludrocortisone; check BP and electrolytes at every visit.
— Cataracts, peptic ulcer (less common at physiologic doses), skin thinning, mood lability.
— Avascular necrosis is unusual at replacement doses.
— Persistent fatigue, orthostasis, salt craving, hyperkalemia, elevated PRA → increase fludrocortisone.
— Up to 50% of autoimmune PAI patients develop additional autoimmune diseases over time — Hashimoto, T1DM, premature ovarian insufficiency, pernicious anemia, celiac, vitiligo, alopecia.
— Annual screening: TSH, fasting glucose/A1c, CBC (B12 if macrocytic), tTG-IgA, menstrual history.
— Anxiety about crisis, medication dependence, travel, employment in physically demanding jobs.
— Increased rates of depression — screen at follow-up visits.
Key distinction: Cushingoid features in a PAI patient ≠ a new diagnosis; it means over-replacement — recheck doses, consolidate to lowest effective regimen, and review for unnecessary stress doses being given for trivial illness.
— Hemodynamic instability requiring vasopressors.
— Altered mental status, seizures, or coma attributed to crisis.
— Severe hyperkalemia (K+ >6.5 or ECG changes) requiring continuous monitoring.
— Severe hyponatremia (Na <120) with neurologic symptoms — careful correction to avoid osmotic demyelination.
— Concurrent sepsis with end-organ dysfunction (qSOFA ≥2, lactate ≥4).
— DIC or bilateral adrenal hemorrhage with hemodynamic compromise.
— Newly diagnosed PAI requiring IV steroid initiation and observation.
— Crisis responding to initial therapy but unable to tolerate PO.
— Failure of outpatient sick-day plan (recurrent vomiting, dehydration) without shock.
— Identified infection requiring IV antibiotics.
— Newly diagnosed PAI (etiologic workup, antibody panel, education).
— Recurrent crises despite appropriate replacement.
— Pregnancy planning or established pregnancy.
— Difficulty distinguishing primary vs. secondary AI.
— Suspected polyglandular syndrome.
— Pediatric cases (pediatric endo).
— Infectious disease: TB, HIV, fungal, or checkpoint-inhibitor-related adrenalitis.
— Oncology: metastatic adrenal disease, checkpoint inhibitor management.
— Genetics: APS-1 (AIRE), adrenoleukodystrophy (ABCD1), familial glucocorticoid deficiency.
— Hematology: antiphospholipid syndrome with adrenal hemorrhage.
— Tolerating oral steroids ≥24 h with stable vitals/electrolytes.
— Patient + family education completed: sick-day rules, injection technique, MedicAlert ordered.
— Endocrinology follow-up scheduled within 1–2 weeks.
— Prescriptions: oral hydrocortisone, fludrocortisone, hydrocortisone 100 mg IM emergency kit.
CCS pearl: Closing a CCS case without ordering a MedicAlert bracelet and an emergency hydrocortisone injection kit for a newly diagnosed PAI patient costs points — these are considered standard of care.
— Causes: pituitary mass, surgery, radiation, apoplexy, Sheehan syndrome (postpartum hemorrhage → pituitary necrosis), lymphocytic hypophysitis (postpartum or checkpoint-inhibitor-induced), trauma, infiltrative disease (sarcoidosis, hemochromatosis).
— Distinguishing features vs PAI: no hyperpigmentation (low ACTH), no hyperkalemia (aldosterone intact), often other anterior pituitary deficits (hypothyroidism with low TSH, hypogonadism, growth hormone deficiency).
— Treatment: glucocorticoid only; no fludrocortisone needed.
— Chronic exogenous glucocorticoid use with HPA axis suppression.
— Any patient on prednisone >5 mg/day (or equivalent) for >3–4 weeks is at risk; high-dose courses for >1 week also suppress.
— Inhaled, topical, intra-articular, and even nasal steroids can suppress at high doses.
— Management: taper slowly, expect 6–12 month axis recovery; stress dose during taper for illness/surgery.
— Functional cortisol deficiency relative to severity of illness; controversial dynamic testing.
— Septic shock unresponsive to fluids + pressors → hydrocortisone 200 mg/day per Surviving Sepsis.
— 21-hydroxylase deficiency most common; salt-wasting and non–salt-wasting variants.
— Adolescents/adults: late-onset CAH presents with hirsutism and oligomenorrhea, not crisis.
— Hyporeninemic hypoaldosteronism (type 4 RTA): diabetes, NSAIDs, CKD — hyperkalemia and acidosis but normal cortisol.
Key distinction: Hyperpigmentation + hyperkalemia + high ACTH = primary. Low/normal ACTH + normal K+ + other pituitary hormone deficits = secondary. Recent steroid taper or chronic prednisone = tertiary.
— Malignancy (lung, GI, pancreatic, lymphoma) — adrenal mets can also cause PAI.
— Hyperthyroidism — but usually tachycardia and increased appetite.
— Depression, anorexia nervosa — weight loss and fatigue without electrolyte changes.
— Chronic infection — TB, HIV, endocarditis — can cause AI or mimic it.
— SIADH: euvolemic, low uric acid, no hyperkalemia, no orthostasis.
— Cerebral salt wasting: volume-depleted but in neurosurgical/SAH context.
— Hypothyroidism: can cause hyponatremia; check TSH always.
— Thiazide-induced: medication history.
— Psychogenic polydipsia: dilute urine, history of polydipsia.
— CKD/AKI.
— Type 4 RTA / hyporeninemic hypoaldosteronism (DM, NSAIDs).
— Drugs: ACEi/ARB, spironolactone, eplerenone, trimethoprim, heparin, tacrolimus, cyclosporine.
— Rhabdomyolysis, tumor lysis, hemolysis.
— Pseudohyperkalemia (hemolyzed specimen, severe leukocytosis/thrombocytosis).
— Hemochromatosis: "bronze diabetes" — check ferritin, transferrin saturation.
— Wilson disease, porphyria cutanea tarda.
— Drug-induced: amiodarone, minocycline, chemotherapy.
— Ethnic baseline pigmentation; sun exposure; acanthosis nigricans (insulin resistance).
— Ectopic ACTH syndrome (small cell lung cancer) — paradoxically hyperpigmented with Cushingoid features, hypokalemia, alkalosis.
— Sepsis with CIRCI, anaphylaxis, cardiogenic shock, severe hypothyroidism (myxedema coma), adrenal crisis — empirically dose hydrocortisone when in doubt.
Board pearl: A smoker with hypokalemic metabolic alkalosis, hyperpigmentation, and weight loss has ectopic ACTH from small cell lung cancer, not Addison disease — both have high ACTH and pigmentation, but the potassium tells the story.
— Hydrocortisone 10 mg AM, 5 mg noon, 5 mg late afternoon (adjust per body size).
— Fludrocortisone 0.1 mg PO daily.
— Hydrocortisone 100 mg IM emergency kit (Solu-Cortef Act-O-Vial) with written instructions.
— Sick-day oral plan: double/triple dose during illness.
— Calcium 1000–1200 mg + vitamin D 800–1000 IU daily.
— Never miss a dose. If a dose is missed by >4 h, take it as soon as remembered.
— 2-3-4 rule: double for mild illness, triple for fever/moderate illness, IM injection if vomiting or unable to tolerate PO.
— Carry written emergency letter detailing diagnosis and dosing.
— MedicAlert bracelet/necklace.
— Inform every healthcare provider — dentist, surgeon, anesthesiologist — of steroid dependence.
— Travel: extra supply (3× expected use), prescription letter for customs, time zone dose adjustment.
— Clinic visit every 3–4 months in first year, then every 6–12 months.
— Each visit: BP supine/standing, weight, symptom screen (fatigue, orthostasis, edema, salt craving), electrolytes, glucose.
— Annual: TSH, A1c, lipid panel, CBC, vitamin D, B12, tTG-IgA (autoimmune screen).
— Plasma renin activity periodically to guide fludrocortisone dose.
— DEXA at diagnosis and every 2 years.
— Annual influenza, age-appropriate pneumococcal (PCV20 or PCV15→PPSV23), COVID-19, shingles, Tdap. PAI is not immunosuppression at physiologic doses, but illnesses precipitate crisis.
— Liberal sodium intake.
— Regular exercise encouraged; stress-dose for prolonged endurance activities only.
— Limit alcohol (impairs symptom recognition, GI upset).
Step 3 management: At every clinic visit, verify the patient still has an unexpired emergency injection kit and can demonstrate technique — this single intervention prevents the majority of fatal crises.
— There is no validated biomarker for hydrocortisone dose adequacy. Do NOT routinely check cortisol or ACTH to titrate (ACTH typically remains elevated in well-replaced PAI patients).
— Assess with symptoms:
— Adjust hydrocortisone by 2.5–5 mg increments and reassess in 4–6 weeks.
— BP normotensive without orthostatic drop.
— Serum Na/K in normal range.
— Plasma renin activity in upper-normal range (suppressed PRA → over-replaced; elevated PRA → under-replaced).
— No edema, normal weight.
— DEXA at diagnosis, repeat every 2 years.
— Calcium 1000–1200 mg/day total intake, vitamin D 800–1000 IU/day.
— Treat osteoporosis per standard guidelines (bisphosphonate, denosumab).
— Weight-bearing exercise.
— Annual lipid panel, fasting glucose/A1c, BP.
— PAI has a small mortality excess driven mainly by cardiovascular disease and crisis.
— Screen with PHQ-2/PHQ-9 annually.
— Refer to peer support groups (NADF — National Adrenal Diseases Foundation).
— Consider DHEA replacement in women with persistent low mood/libido after optimization.
— Fertility usually preserved; counsel pregnant or planning patients on third-trimester dose escalation and labor/delivery plan.
— Women: monitor for premature ovarian insufficiency (autoimmune association).
Board pearl: Persistently elevated ACTH in a well-replaced PAI patient is expected and not a reason to escalate hydrocortisone. Treat the patient, not the lab.
— A small number of patients (often with adherence challenges, mental illness, or substance use) refuse glucocorticoid replacement.
— Document decisional capacity assessment: do they understand the diagnosis, that refusal will cause death from crisis, the alternatives, and can they communicate the choice consistently?
— In capacitated refusal: respect autonomy, document, arrange close follow-up, engage social work and outpatient care manager. In capacity loss: emergency treatment under implied consent during crisis.
— Highest-risk handoffs: ED → floor, OR → PACU, hospital → home, primary care → specialist, pediatric → adult care.
— Common failures:
— Mitigation: medication reconciliation at every transition; explicit handoff that includes "steroid-dependent — must receive hydrocortisone"; 30-day discharge supply; pharmacy auto-refill; teach-back education.
— Tuberculosis as cause of PAI is reportable in all US states.
— HIV-associated PAI: report per state law; partner notification per public health.
— Polypharmacy: ensure no new prescriber starts a CYP3A4 inducer without dose adjustment.
— Driver/pilot/commercial occupations: stable PAI is generally not disqualifying but document plan; sudden hypoglycemia or orthostasis risk must be addressed (FAA Special Issuance for pilots).
— Schools/employers should know about the emergency kit; provide an action plan.
— Failure of parents/guardians to administer maintenance or emergency steroids constitutes medical neglect — involve CPS if pattern of missed doses leads to repeat ED visits.
Step 3 management: At every transition of care, the safest practice is to write hydrocortisone orders explicitly in the discharge summary with sick-day instructions and call the next provider directly — verbal handoff plus written documentation halves crisis readmission rates.
— APS-1 (APECED): AIRE gene mutation, autosomal recessive, childhood onset. Triad = chronic mucocutaneous candidiasis + hypoparathyroidism + adrenal insufficiency.
— APS-2 (Schmidt): adult onset, polygenic. PAI + autoimmune thyroid disease ± T1DM. HLA-DR3/DR4 associations.
— Adrenolytic: mitotane (used in adrenocortical carcinoma).
— Steroidogenesis blockade: ketoconazole, etomidate (single dose can cause 24 h suppression — avoid in septic intubation), metyrapone, abiraterone.
— Accelerated cortisol metabolism: rifampin, phenytoin, phenobarbital, carbamazepine, St. John's wort.
— Immunotherapy: checkpoint inhibitors cause hypophysitis (usually secondary AI) and rarely primary adrenalitis; ipilimumab > nivolumab/pembrolizumab.
— Autoimmune PAI: small atrophic adrenals.
— TB/fungal/histoplasma: enlarged adrenals with calcifications.
— Hemorrhage (Waterhouse-Friderichsen, antiphospholipid, anticoagulation): bilateral enlargement, high attenuation on non-contrast CT.
— Metastases: bilateral masses, often lung primary.
— Hyponatremia + hyperkalemia + non-AG metabolic acidosis + eosinophilia + hyperpigmentation = PAI until proven otherwise.
— Hyperpigmentation in scars = primary AI (ACTH/MSH effect).
— Salt craving = aldosterone deficiency.
— T1DM with falling insulin needs = think APS-2.
— Young boy with PAI + behavior/neurologic changes = adrenoleukodystrophy (check VLCFA).
— Postpartum hemorrhage + agalactia + amenorrhea + AI = Sheehan (secondary AI).
— Anticoagulated patient with new flank pain + shock = bilateral adrenal hemorrhage.
— Sepsis with meningococcemia and shock = Waterhouse-Friderichsen.
Board pearl: Etomidate, even as a single induction dose, causes measurable adrenal suppression for ~24 h — relevant in septic intubation; many programs now favor ketamine.
"A 35-year-old woman with vitiligo presents with 6 months of fatigue, 10-lb weight loss, salt craving, and darkening of her palmar creases. BP 95/60 supine, 80/55 standing. Na 128, K 5.8, glucose 65."
→ Next step: 8 AM cortisol and ACTH; confirmatory cosyntropin stim test; treat with hydrocortisone + fludrocortisone.
"A 45-year-old man on chronic prednisone for RA presents with vomiting and abdominal pain after stopping his medication 4 days ago for 'a stomach bug.' BP 80/40, K 5.2."
→ This is tertiary AI with crisis from HPA suppression. Give hydrocortisone 100 mg IV + fluids, identify trigger.
"A patient newly diagnosed with both hypothyroidism and adrenal insufficiency. What is the order of treatment?"
→ Start hydrocortisone BEFORE levothyroxine — reverse order can precipitate crisis.
"A patient with known Addison disease is scheduled for laparoscopic cholecystectomy. How do you manage steroids perioperatively?"
→ Hydrocortisone 50 mg IV at induction, then 25 mg q8h × 24 h, taper to maintenance over 2 days.
"Hyperpigmentation, hyponatremia, normal K+, low ACTH" → Secondary AI (e.g., pituitary cause). Wait — hyperpigmentation with low ACTH is contradictory; reread the stem — pigmentation in secondary AI is absent.
"Smoker with weight loss, hyperpigmentation, hypokalemic alkalosis, hyperglycemia" → Ectopic ACTH from small cell lung cancer, not Addison.
"Pregnant patient with known PAI presents in active labor."
→ Hydrocortisone 100 mg IV immediately, then q6–8h; rapid postpartum taper.
"Addison patient with gastroenteritis vomiting × 12 h, took oral steroid this morning but vomited it up."
→ Patient should inject IM hydrocortisone 100 mg and present to ED.
"Confirmed PAI, next test to determine cause?"
→ 21-hydroxylase antibodies; if negative → CT adrenals; if young male → VLCFA.
CCS pearl: The single most commonly missed CCS order in Addison cases is the emergency IM hydrocortisone kit at discharge — make it a habit.
Primary adrenal insufficiency is destruction of the adrenal cortex causing combined glucocorticoid + mineralocorticoid deficiency, recognized by the triad of hyperpigmentation, hyponatremia/hyperkalemia, and fatigue/orthostasis — diagnosed with paired 8 AM cortisol/ACTH and confirmed by cosyntropin stimulation, treated lifelong with hydrocortisone plus fludrocortisone with mandatory sick-day stress dosing.
Board pearl: When in doubt about adrenal crisis in a shocked patient, give hydrocortisone 100 mg IV first, draw labs second, confirm diagnosis third — the cost of unnecessary steroid is trivial; the cost of missed crisis is death.