Endocrine

Cushing syndrome: workup algorithm

Clinical Overview and When to Suspect Cushing Syndrome

— ACTH-dependent (~80%): pituitary adenoma (Cushing disease, ~70%), ectopic ACTH (small cell lung, bronchial carcinoid, MTC, pheo), rare ectopic CRH

— ACTH-independent (~20%): adrenal adenoma, adrenal carcinoma, bilateral macronodular or primary pigmented nodular adrenal hyperplasia

— Discriminatory features (high LR+): proximal myopathy, wide violaceous striae >1 cm, facial plethora, easy bruising, supraclavicular fat pads, unexplained osteoporosis in young patient

— Common but nonspecific: central obesity, HTN, T2DM, hirsutism, depression, menstrual irregularity, acne

— Red flag combos: new-onset diabetes + resistant HTN + hypokalemia, or osteoporotic fracture in a 30-year-old, or rapid virilization (suggests adrenal carcinoma)

Step 3 management: Before ordering any 24-h cortisol, document and discontinue contributing exogenous steroids when possible and screen for pseudo-Cushing mimickers (alcohol use disorder, severe depression, poorly controlled diabetes, obesity), which can produce false-positive screening tests. Workup proceeds in two sequential phases: (1) confirm hypercortisolism, then (2) localize the source—never skip ahead to pituitary MRI before biochemistry confirms disease.

Cushing syndrome (CS) = clinical state from chronic glucocorticoid excess, whether exogenous (iatrogenic, by far most common) or endogenous (ACTH-dependent vs ACTH-independent).

Endogenous etiologies:

When to suspect in ambulatory practice:

Always first ask about exogenous steroids: oral, inhaled, intra-articular, topical (potent fluorinated), nasal, even "herbal" supplements adulterated with dexamethasone. Iatrogenic CS does not require biochemical workup—taper steroid instead.

Endocrine Society recommends testing when ≥1 discriminatory feature, multiple progressive features, adrenal incidentaloma, or unusual features for age (e.g., osteoporosis, HTN in young adult).

Presentation Patterns and Key History

— Slow, classic phenotype over years: pituitary adenoma (Cushing disease)

— Rapid onset, severe hypokalemia, weight loss, hyperpigmentation, minimal classic habitus: ectopic ACTH (e.g., small cell lung CA) — cortisol so high it overwhelms 11β-HSD2, causing mineralocorticoid effects

— Virilization, rapid progression, abdominal mass: adrenocortical carcinoma

— Cyclic symptoms: cyclic Cushing (intermittent hypercortisolism—screening may be falsely negative; repeat testing)

— Full medication reconciliation including inhalers (fluticasone + ritonavir/cobicistat is a classic interaction causing iatrogenic CS), megestrol (intrinsic glucocorticoid activity), depot steroid injections

— Weight gain pattern: centripetal, dorsocervical (buffalo hump), temporal wasting

— Skin: easy bruising, poor wound healing, wide purple striae on abdomen/thighs/axillae/breasts

— Menstrual: oligo/amenorrhea; decreased libido in men

— Mood: depression, irritability, psychosis, insomnia, cognitive slowing

— Bone: fragility fractures, especially vertebral

— Infections: recurrent thrush, cellulitis, opportunistic infections

— Smoking history (small cell lung CA risk)

— Family history: MEN1, Carney complex, McCune-Albright

Board pearl: A patient on fluticasone inhaler who starts ritonavir for HIV develops florid Cushing within weeks—CYP3A4 inhibition blocks fluticasone clearance. ACTH and cortisol will be suppressed (iatrogenic pattern). Management: switch inhaler (beclomethasone is safer) and taper carefully to avoid adrenal crisis.

Key distinction: Weight loss with hypercortisolism is a classic ectopic ACTH or adrenal carcinoma feature—patients are catabolic from extreme cortisol burden, not the typical weight-gaining Cushing.

Tempo and pattern often hint at etiology:

History to obtain:

Pediatric/adolescent clue: growth deceleration with weight gain—children with CS get shorter and fatter simultaneously, unlike exogenous obesity (which accelerates growth).

Physical Exam Findings and Hemodynamic Assessment

— Proximal muscle weakness: ask patient to rise from a chair without using arms—often cannot

— Wide (>1 cm), violaceous striae on abdomen, thighs, axillae, breasts (distinguish from thin pink pregnancy/obesity striae)

— Facial plethora, especially over malar areas

— Spontaneous ecchymoses or thin "cigarette paper" skin (skinfold <2 mm on dorsum of hand suggests CS)

— Dorsocervical and supraclavicular fat pads (supraclavicular more specific than buffalo hump)

— HTN in ~80%, often resistant; may have hypokalemia if severe (mineralocorticoid effect of cortisol saturating 11β-HSD2—classic in ectopic ACTH)

— Check orthostatics if patient was recently weaned from exogenous steroids (adrenal insufficiency risk)

Board pearl: The four highest-LR exam findings for endogenous CS are proximal myopathy, wide violaceous striae, facial plethora, and easy bruising. The presence of ≥2 in a patient with metabolic syndrome should prompt biochemical screening even if "Cushingoid habitus" is absent.

Step 3 management: Document baseline weight, BP, fasting glucose, and bone density at diagnosis—these become monitoring parameters during treatment and tapering.

High-specificity findings (most useful at the bedside):

Less specific but supportive: moon facies, central obesity, hirsutism, acne, acanthosis nigricans

Hemodynamics:

Skin pigmentation: hyperpigmentation of palmar creases, buccal mucosa, scars, knuckles → markedly elevated ACTH (Cushing disease severe, or more commonly ectopic ACTH)

Virilization signs (temporal balding, clitoromegaly, deep voice, severe acne) → suspect adrenocortical carcinoma producing androgens

Visual fields: bitemporal hemianopsia from pituitary macroadenoma (uncommon since most corticotroph adenomas are micros)

Abdominal exam: palpable flank mass → large adrenal tumor; hepatomegaly may indicate metastatic adrenal carcinoma.

BMI, waist circumference, BP in both arms, fundoscopy for hypertensive changes.

Diagnostic Workup — Initial Screening Tests

— 1 mg overnight dexamethasone suppression test (DST): 1 mg PO at 11 pm; measure 8 am cortisol. Normal: <1.8 µg/dL. Sensitive but many false positives (estrogen-containing OCPs raise CBG; CYP3A4 inducers like phenytoin, rifampin accelerate dex clearance → false positive).

— Late-night salivary cortisol ×2 separate nights: loss of circadian nadir is hallmark of CS. Convenient, outpatient. Avoid if shift worker or recent licorice/chewing tobacco use.

— 24-hour urinary free cortisol (UFC) ×2 collections: measures unbound, biologically active cortisol. >4× ULN is virtually diagnostic. Mild elevations are nonspecific. Requires complete collection; check urine creatinine for adequacy.

— Pregnancy, estrogen therapy → ↑CBG → falsely elevated total cortisol (use salivary or UFC)

— Severe obesity, depression, alcohol use, uncontrolled diabetes → can elevate cortisol but typically normal salivary nadir

— Shift workers: disrupted circadian rhythm invalidates salivary test

CCS pearl: Order 1 mg overnight DST + late-night salivary cortisol ×2 as your initial outpatient panel. Advance the clock by 1–2 weeks, then recheck and order ACTH and confirmatory testing. Do not order pituitary MRI yet—imaging without biochemical confirmation leads to chasing incidental pituitary microadenomas (present in ~10% of healthy adults).

Key distinction: Screening tests confirm whether hypercortisolism exists; ACTH and dynamic testing determine where it comes from.

First, exclude exogenous glucocorticoids. If present and CS is iatrogenic, no biochemical screening is needed.

Endocrine Society first-line screening (choose at least two of three; need two abnormal tests of different types to confirm):

Pitfalls and pseudo-Cushing:

Confirmation: if any first-line test is abnormal, repeat with a second different test. Two concordant abnormal tests → biochemical CS confirmed; proceed to localization.

If results discordant or borderline: longer low-dose DST (2 mg/day × 48 h) or dexamethasone-CRH test.

Diagnostic Workup — Localization After Biochemical Confirmation

— ACTH <5 pg/mL (suppressed) → ACTH-independent (adrenal source) → obtain adrenal CT with contrast

— ACTH >20 pg/mL → ACTH-dependent → pituitary vs ectopic

— Intermediate 5–20 pg/mL → use CRH stimulation; ACTH rise suggests pituitary

— Adrenal CT: adenoma (<4 cm, lipid-rich, washout >50%), carcinoma (>4 cm, heterogeneous, necrosis, irregular margins, low washout), bilateral nodular hyperplasia

— DHEAS: low in adenoma (atrophic contralateral gland), elevated in carcinoma

— High-dose dexamethasone suppression (8 mg): pituitary adenomas usually suppress >50%; ectopic tumors do not. Imperfect; not stand-alone.

— CRH stimulation test: pituitary corticotrophs respond with ACTH/cortisol rise; ectopic sources typically do not.

— Pituitary MRI with dynamic gadolinium: identifies adenoma in ~60% of Cushing disease (many micros <6 mm escape detection); ~10% false-positive incidentalomas in healthy adults.

— Inferior petrosal sinus sampling (IPSS) = gold standard when biochemistry suggests pituitary but MRI is negative, equivocal, or shows lesion <6 mm. Central-to-peripheral ACTH ratio >2 at baseline or >3 after CRH confirms pituitary source. Performed at experienced centers.

— CT chest/abdomen/pelvis, then somatostatin receptor PET (Ga-68 DOTATATE) for occult carcinoid; consider FDG-PET; calcitonin for MTC; plasma metanephrines for pheo.

Board pearl: IPSS is the single most accurate test for differentiating pituitary from ectopic ACTH-dependent Cushing—order it when MRI is non-diagnostic before committing to transsphenoidal surgery.

Step 1: Plasma ACTH (8 am) divides etiology:

ACTH-independent pathway:

ACTH-dependent pathway — distinguish pituitary (Cushing disease) from ectopic:

If ectopic ACTH suspected (rapid course, hypokalemia, very high ACTH, no suppression, negative IPSS):

Risk Stratification and Management Logic

— Severity markers: UFC >5× ULN, severe hypokalemia, psychosis, opportunistic infection, uncontrolled diabetes, thromboembolism, severe HTN → expedite treatment

— Cushing patients are hypercoagulable (↑ factor VIII, vWF, ↓fibrinolysis); VTE risk persists perioperatively

— Cushing disease: transsphenoidal selective adenomectomy (first-line); remission ~80% for micros, ~50% for macros at experienced centers

— Adrenal adenoma: laparoscopic unilateral adrenalectomy

— Adrenal carcinoma: open adrenalectomy with en bloc resection + adjuvant mitotane; consider RT

— Ectopic ACTH: resect primary tumor when localized; if occult or metastatic, medical therapy ± bilateral adrenalectomy

— Bilateral macronodular hyperplasia: bilateral adrenalectomy

— Control hypercortisolism medically (ketoconazole, metyrapone, osilodrostat) if severe

— Correct hypokalemia, treat HTN (spironolactone helpful), optimize glycemia, VTE prophylaxis

— Stress-dose steroids perioperatively (HPA axis will be suppressed post-op)

— Transient adrenal insufficiency requires glucocorticoid replacement for months to years until HPA axis recovers

— Monitor 8 am cortisol off hydrocortisone for >24 h; post-op cortisol <2 µg/dL predicts remission in Cushing disease

Step 3 management: A confirmed pituitary microadenoma case: refer to high-volume pituitary surgeon (outcomes are volume-dependent), start enoxaparin VTE prophylaxis perioperatively, give hydrocortisone 50 mg IV at induction, taper to physiologic replacement post-op, and counsel patient on adrenal crisis precautions (medical alert bracelet, stress dosing for illness/surgery).

Once etiology established, severity and surgical candidacy dictate sequencing:

Definitive treatment by source:

Preoperative optimization:

Post-operative expectations:

Pharmacotherapy — Medical Treatment of Hypercortisolism

— Ketoconazole: inhibits multiple CYP enzymes; hepatotoxicity (monitor LFTs; black box warning), QT prolongation, gynecomastia, drug interactions (CYP3A4)

— Metyrapone: blocks 11β-hydroxylase; rapid onset; causes ↑androgens and mineralocorticoid precursors → hirsutism, HTN, hypokalemia

— Osilodrostat: oral 11β-hydroxylase inhibitor; FDA-approved for Cushing disease; monitor QT, adrenal insufficiency, androgen excess

— Mitotane: adrenolytic; first-line for adrenal carcinoma; slow onset, teratogenic, neurotoxic, requires glucocorticoid + mineralocorticoid replacement

— Etomidate IV: rapid cortisol lowering in ICU/crisis when oral route unavailable

— Pasireotide (somatostatin analog): for Cushing disease; hyperglycemia is major AE (often requires insulin)

— Cabergoline: dopamine agonist; modest efficacy

— Mifepristone: blocks peripheral GR; FDA-approved for CS with hyperglycemia/diabetes; cortisol levels rise (cannot monitor with cortisol—follow clinical response, glucose, BP); contraindicated in pregnancy; risk of hypokalemia, endometrial hyperplasia, adrenal insufficiency that is hard to detect

Board pearl: Pasireotide → hyperglycemia in ~70%; mifepristone → cortisol rises, so monitor by glucose and clinical response; ketoconazole → LFTs; metyrapone → androgens/HTN. Each drug has a signature side effect Step 3 loves to test.

Key distinction: Inhibiting steroidogenesis lowers cortisol; blocking the receptor (mifepristone) does not—conventional biochemical monitoring fails on mifepristone.

Medical therapy used as: bridge to surgery, post-op residual disease, non-surgical candidates, or ectopic ACTH with occult primary.

Steroidogenesis inhibitors (most commonly used):

Pituitary-directed:

Glucocorticoid receptor antagonist:

Monitoring on therapy: UFC, late-night salivary cortisol, glucose, K+, LFTs, ECG (QT), and clinical signs of adrenal insufficiency—patients can swing from hyper- to hypocortisolism.

Procedures — Surgical and Interventional Management

— Endoscopic endonasal approach by experienced pituitary surgeon

— Remission criterion: morning serum cortisol <2 µg/dL within 7 days off glucocorticoid

— Complications: transient/permanent DI, CSF leak, hypopituitarism, meningitis

— Repeat TSS or stereotactic radiosurgery (Gamma Knife) for persistent/recurrent disease; radiation effect delayed months–years and requires interim medical therapy

— Laparoscopic for benign adenomas <6 cm without features of malignancy

— Open for suspected adrenocortical carcinoma (avoid capsular rupture and seeding)

— Pre-op: control BP, K+, glucose; perioperative stress-dose steroids; post-op physiologic replacement until contralateral gland recovers (months)

— Reserved for refractory ACTH-dependent CS (failed TSS, no ectopic source resectable) or severe ectopic ACTH from occult primary

— Patient becomes permanently dependent on glucocorticoid + mineralocorticoid replacement

— Nelson syndrome risk (~20%): pituitary corticotroph adenoma grows in absence of cortisol feedback → hyperpigmentation, mass effect; some advocate prophylactic pituitary RT

— Surgical resection of bronchial carcinoid, thymic carcinoid, MTC, pheochromocytoma per source-specific protocols

— Hepatic artery embolization or PRRT (peptide receptor radionuclide therapy) for metastatic neuroendocrine tumors

CCS pearl: Post-adrenalectomy CCS sequence: hydrocortisone 100 mg IV intra-op → 50 mg q8h day 1 → taper to 15–25 mg/day oral hydrocortisone divided, plus fludrocortisone 0.1 mg daily after bilateral adrenalectomy. Counsel on stress dosing, prescribe emergency hydrocortisone IM kit, and ensure medical alert bracelet before discharge.

Board pearl: Persistent post-op morning cortisol <2 µg/dL = surgical cure; >5 µg/dL = persistent disease requiring further intervention.

Transsphenoidal surgery (TSS) for Cushing disease:

Adrenalectomy:

Bilateral adrenalectomy:

Ectopic source procedures:

Special Populations — Elderly and Renal/Hepatic Impairment

— CS often misattributed to "aging" or metabolic syndrome—central obesity, HTN, diabetes, osteoporosis, depression overlap

— Discriminatory features less prominent; bruising and proximal weakness may be the only clues

— Higher operative risk; medical therapy often preferred initially; weigh frailty

— Bone protection crucial—bisphosphonates or denosumab alongside cortisol control

— 24-hour UFC unreliable when CrCl <60 mL/min (decreased filtration → falsely low UFC); rely on late-night salivary cortisol and DST

— Drug dosing: ketoconazole, metyrapone—generally hepatically metabolized but monitor; osilodrostat reduced dose in severe renal impairment

— Avoid ketoconazole (hepatotoxic; black box); use metyrapone or osilodrostat with caution

— Reduced CBG production may lower total cortisol (use salivary)

— CYP3A4 inducers (phenytoin, carbamazepine, rifampin, St. John's wort) accelerate dexamethasone metabolism → false-positive DST

— Estrogens/OCPs increase CBG → spuriously high total serum cortisol (UFC and salivary unaffected); ideally stop estrogen 6 weeks before testing

— Fluticasone + ritonavir/cobicistat → iatrogenic CS

Step 3 management: Elderly woman on HRT with new HTN, diabetes, and vertebral fracture: stop estrogen 6 weeks before biochemical workup, use late-night salivary cortisol (not UFC if CKD), and start vitamin D + bisphosphonate empirically while workup proceeds.

Board pearl: Phenytoin causes false-positive 1 mg DST—repeat with salivary cortisol or longer DST.

Elderly:

Renal impairment:

Hepatic impairment:

Drug-drug interactions to remember:

Cognitive impairment: hypercortisolism causes reversible cognitive decline and hippocampal atrophy; can mimic dementia in elderly—screen for CS in atypical "dementia" with metabolic features.

Special Populations — Pregnancy and Pediatrics

— Rare but high-risk: maternal HTN, preeclampsia, gestational diabetes, heart failure; fetal IUGR, prematurity, fetal loss

— Physiologic ↑CBG and ↑placental CRH cause physiologic hypercortisolism:

— Total cortisol and UFC rise 2–3×; DST is unreliable (false positives)

— Use late-night salivary cortisol (most preserved circadian rhythm) and UFC >3× ULN as suggestive

— Etiology shift in pregnancy: adrenal adenomas predominate (~50%) over pituitary disease, because estrogen-driven inhibition of ACTH partially suppresses Cushing disease

— MRI pituitary without gadolinium preferred; CT adrenals avoided in 1st trimester

— Treatment: surgery (adrenalectomy or TSS) in 2nd trimester preferred; metyrapone is the medical agent of choice in pregnancy; avoid mitotane (teratogen), mifepristone (abortifacient), ketoconazole (teratogen, anti-androgen)

— Cardinal clue: growth failure with weight gain (↓height velocity + ↑BMI)—almost pathognomonic versus exogenous obesity (which accelerates growth)

— Etiologies: pre-pubertal—adrenal tumors more common; adolescent—Cushing disease (pituitary) predominates

— Pubertal delay, virilization (carcinoma), striae, hypertension

— Workup same algorithm but interpret with pediatric reference ranges; IPSS feasible in older children

— Genetic syndromes: Carney complex (PRKAR1A), McCune-Albright (GNAS, infantile CS), MEN1, familial isolated pituitary adenoma

Board pearl: Child with declining growth percentile and rising BMI percentile + striae = Cushing until proven otherwise. Exogenous obesity grows tall.

Key distinction: In pregnancy, late-night salivary cortisol is the screening test of choice; 1 mg DST is unreliable due to elevated CBG and altered dexamethasone metabolism.

Pregnancy:

Pediatrics:

Complications and Adverse Outcomes

— HTN, LVH, accelerated atherosclerosis, MI, stroke

— Cardiomyopathy can persist after biochemical cure

— Type 2 diabetes / insulin resistance in ~30–50%

— Dyslipidemia (↑TG, ↑LDL)

— Central obesity, hepatic steatosis

— VTE risk ~10× baseline; PE is a major perioperative cause of death

— Hypercoagulable from ↑factor VIII, vWF, fibrinogen; ↓fibrinolysis

— Extended VTE prophylaxis perioperatively (often 4 weeks)

— Osteoporosis with vertebral fractures in ~50%; bone loss begins early and may persist

— Avascular necrosis (femoral head)

— Proximal myopathy

— Opportunistic infections (PJP, mycoses, reactivation TB) at high cortisol or during overlap with steroid therapy

— Consider PJP prophylaxis with cortisol >5× normal or prolonged high exposure

— Depression, anxiety, psychosis, suicidality; cognitive impairment; hippocampal atrophy (partially reversible)

— Hypogonadotropic hypogonadism, infertility, menstrual irregularity

— Adrenal insufficiency (months–years)—lifelong risk of adrenal crisis without education

— Steroid withdrawal syndrome: arthralgias, malaise, depression even with adequate replacement

— Nelson syndrome after bilateral adrenalectomy

Board pearl: Cushing syndrome carries a standardized mortality ratio of 2–4, driven by CV disease and VTE. Even after cure, CV risk remains elevated for years—aggressive secondary prevention is essential.

Step 3 management: All Cushing patients: statin if dyslipidemia, ASA in selected high-risk, bone protection (Ca/Vit D + bisphosphonate/denosumab), VTE prophylaxis perioperatively, screen for OSA, optimize glycemia.

Cardiovascular (leading cause of excess mortality, ~4× general population):

Metabolic:

Thromboembolic:

Musculoskeletal:

Infectious:

Psychiatric/neurocognitive:

Reproductive:

Dermatologic: tinea versicolor, severe acne, poor wound healing

Post-cure complications:

When to Escalate Care — ICU, Consult, Inpatient Triage

— Any confirmed biochemical CS for localization and management

— Adrenal incidentaloma with subclinical CS

— Equivocal screening results

— Pre-op planning and post-op replacement

— Severe hypokalemia (<3.0) or refractory HTN

— Hyperglycemic crisis (DKA/HHS)

— Suspected adrenal crisis during medical therapy or after surgery

— Psychosis, suicidality

— Suspected PE/DVT

— Opportunistic infection

— Severe ectopic ACTH (UFC >10× ULN) with multi-organ involvement—often small cell lung CA

— Cushing-related cardiomyopathy with pulmonary edema

— Septic shock (relatively immunocompromised)

— Severe psychosis with safety risk

— IV etomidate infusion (subhypnotic dose) in ICU rapidly inhibits 11β-hydroxylase; must monitor for adrenal insufficiency and provide hydrocortisone replacement once cortisol normalizes (block-and-replace strategy)

— Combination metyrapone + ketoconazole + mitotane for severe cases unresponsive to monotherapy

— Pituitary neurosurgery for Cushing disease

— Endocrine surgery for adrenalectomy

— Thoracic surgery for resectable ectopic sources

CCS pearl: Patient with rapid-onset hypokalemia (K+ 2.4), HTN, hyperglycemia, weight loss, ACTH 250 pg/mL, UFC 15× ULN—admit, endocrine + pulm/onc consults, CT chest/abdomen/pelvis + Ga-68 DOTATATE, K+ replacement + spironolactone, insulin, VTE prophylaxis, start metyrapone or osilodrostat, escalate to IV etomidate if cortisol not controlled within 24–48 h.

Board pearl: Hypokalemia is present in >95% of ectopic ACTH but only ~10% of Cushing disease—severe hypokalemia is a key escalation signal.

Endocrinology consultation indicated for:

Inpatient admission triggers:

ICU criteria:

Acute medical lowering of cortisol in critical illness:

Surgical consultation:

Multidisciplinary referral: cardiology (cardiomyopathy), psychiatry (depression/psychosis), bone health, infectious disease, oncology (carcinoma)

Key Differentials — Same-Category (Endocrine/Hypercortisolism Mimickers)

— Severe depression/anxiety: blunted suppression on DST; dex-CRH test helps differentiate

— Alcohol use disorder: alcoholic pseudo-Cushing; resolves with abstinence in weeks

— Poorly controlled diabetes: mild UFC elevation

— Severe obesity: nonspecific elevation; salivary cortisol usually normal

— Eating disorders (anorexia, bulimia)

— Pregnancy: physiologic hypercortisolism (see chunk 10)

— Chronic exercise/physical stress

— Salivary cortisol nadir usually preserved in pseudo-Cushing

— Discriminatory clinical features (proximal myopathy, wide striae, plethora) absent

— Dexamethasone-CRH test: in true CS, cortisol >1.4 µg/dL after CRH despite dex pretreatment; in pseudo-Cushing, suppressed

— Desmopressin stimulation: ACTH response in Cushing disease, blunted in pseudo-Cushing

— Cortisol after 1 mg DST 1.8–5 µg/dL = possible autonomy; >5 µg/dL = autonomous cortisol secretion

— Associated with HTN, diabetes, osteoporosis, increased CV mortality even without overt CS

— Management: surgery if metabolic complications, otherwise monitor

— ACTH and cortisol both low (vs endogenous ACTH-independent where ACTH low but cortisol high)

— Most common cause of Cushingoid appearance overall

Key distinction: Iatrogenic CS = low ACTH + low cortisol (suppressed by exogenous steroid). Endogenous adrenal CS = low ACTH + high cortisol. Endogenous ACTH-dependent CS = high ACTH + high cortisol. This ACTH/cortisol pattern is the highest-yield Step 3 framework.

Board pearl: Adrenal incidentaloma found on abdominal CT: workup includes 1 mg DST, plasma metanephrines, aldosterone/renin ratio if HTN—even asymptomatic patients need screening for subclinical CS.

Pseudo-Cushing states (biochemical hypercortisolism without true CS):

Differentiating from true CS:

Subclinical (autonomous) cortisol secretion from adrenal incidentaloma:

Exogenous (iatrogenic) Cushing:

Key Differentials — Other-Category Mimickers

— Central adiposity, HTN, T2DM, dyslipidemia overlap with CS

— Lacks proximal myopathy, wide violaceous striae, plethora, easy bruising, osteoporosis

— Late-night salivary cortisol normal

— Hirsutism, oligomenorrhea, acne, insulin resistance, central obesity

— No cortisol excess; check 17-OHP to exclude nonclassic CAH; free testosterone, LH/FSH

— Hirsutism, virilization; elevated 17-OHP

Board pearl: HTN + hypokalemia differential: primary aldosteronism (low renin, high aldosterone), Cushing/ectopic ACTH (high cortisol), renovascular disease (high renin), Liddle syndrome (low renin and aldosterone), licorice ingestion (apparent mineralocorticoid excess).

Step 3 management: Patient with resistant HTN + spontaneous hypokalemia → simultaneously screen for primary aldosteronism (ARR), Cushing (1 mg DST), and pheo (plasma metanephrines)—don't anchor on one diagnosis.

Metabolic syndrome / obesity:

Polycystic ovary syndrome (PCOS):

Nonclassic congenital adrenal hyperplasia:

Chronic alcohol use: facial plethora, central obesity, hypertension, easy bruising—can mimic CS; pseudo-Cushing biochemically

Anabolic steroid abuse: muscle hypertrophy (opposite of CS myopathy), acne, but suppressed gonadotropins

Familial partial lipodystrophy: central fat redistribution

Hypothyroidism: weight gain, fatigue, depression—but bradycardia, cold intolerance, ↑TSH

Acromegaly: comorbid HTN, diabetes; coarse features, acral enlargement; ↑IGF-1

Pheochromocytoma: paroxysmal HTN, headaches, palpitations; plasma/urine metanephrines

Primary aldosteronism: HTN + hypokalemia (overlap with severe CS); aldosterone/renin ratio, low cortisol

Renal artery stenosis / secondary HTN: HTN + hypokalemia without Cushingoid features

Steroid-responsive conditions (RA, IBD, asthma) on chronic glucocorticoids — iatrogenic CS

Secondary Prevention / Discharge Medications / Long-Term Plan

— Hydrocortisone 15–25 mg/day divided (e.g., 15 mg AM + 5–10 mg early afternoon); some prefer prednisone 4–5 mg AM

— Stress-dose instructions: double for febrile illness, triple for major stress; IM hydrocortisone 100 mg for vomiting/inability to take PO

— Medical alert bracelet stating "adrenal insufficiency, steroid-dependent"

— Counsel partner/family on emergency injection

— Bone: DEXA at diagnosis and yearly; vitamin D 1000–2000 IU, calcium 1000–1200 mg; bisphosphonate or denosumab if osteoporosis or fragility fracture

— CV risk: BP target <130/80, statin for ASCVD risk ≥7.5%, smoking cessation

— Glycemia: continue diabetes care; cortisol-induced diabetes may remit after cure

— VTE prophylaxis: extended (often 4 weeks) post-op LMWH

— Mood: continue antidepressant/psychiatry follow-up; depression may persist post-cure

— OSA screening (common in CS)

— Recurrence rate ~15–25% over 10 years even after initial remission

— Annual late-night salivary cortisol or UFC

— Reassess if symptoms recur

Step 3 management: Discharge checklist after TSS for Cushing disease: hydrocortisone replacement + taper schedule, medical alert bracelet, emergency IM hydrocortisone kit, DDAVP if transient DI, endocrine follow-up at 1–2 weeks, DEXA, statin if indicated, VTE prophylaxis.

Board pearl: Recurrence in Cushing disease can occur years after surgery—lifelong biochemical surveillance is mandatory.

Post-curative surgery discharge regimen (Cushing disease or unilateral adrenalectomy):

After bilateral adrenalectomy: add fludrocortisone 0.05–0.1 mg/day; lifelong replacement

Comorbidity management (ongoing even after cure):

Surveillance for recurrence in Cushing disease:

Genetic counseling if MEN1, Carney complex, or familial isolated pituitary adenoma suspected

Pituitary axis evaluation post-TSS: check for other deficiencies (TSH, gonadotropins, GH, ACTH, DI/SIADH).

Follow-Up, Monitoring Parameters, and Counseling

— Morning cortisol off glucocorticoid for 24 h: confirm remission (<2 µg/dL = cure)

— Watch for transient DI (polyuria, hypernatremia) and delayed SIADH day 5–10 post-TSS (hyponatremia)—sodium check at 1 week is standard

— Adrenal insufficiency symptoms: nausea, fatigue, dizziness, hypotension—reinforce stress dosing

— Wean hydrocortisone slowly as HPA axis recovers; periodic AM cortisol off replacement (>10 µg/dL suggests recovery; ACTH stimulation test confirms)

— Anterior pituitary panel: free T4/TSH, IGF-1, LH/FSH/testosterone or estradiol, prolactin

— Repeat pituitary MRI at 3 months baseline post-op

— Reassess BP, glucose, lipids, weight at every visit

— Annual late-night salivary cortisol or UFC for recurrence

— DEXA every 1–2 years until bone density stable

— CV risk reassessment annually

— Mediterranean diet, weight loss, structured exercise once myopathy improves (PT referral)

— Tobacco/alcohol cessation

— Sleep hygiene; OSA evaluation

— Mental health support; expect slow improvement in cognition, mood, body habitus over 6–24 months

CCS pearl: Post-TSS day 7 patient calls with polyuria and thirst—order serum Na, urine osmolality, urine specific gravity, start DDAVP if hypernatremia with dilute urine confirms central DI. Then at day 10, monitor for switch to SIADH with hyponatremia (the classic "triphasic response").

Board pearl: Counsel patients that Cushingoid features (moon face, central obesity, striae) take 6–12+ months to resolve after biochemical cure—failure to set expectations leads to perceived treatment failure and patient distress.

Post-op short-term (weeks):

Medium-term (months):

Long-term (years):

Lifestyle counseling:

Driving and work: counsel about fatigue during recovery; many patients miss months of work

Ethical, Legal, and Patient Safety Considerations

— Disclose specific risks: CSF leak, meningitis, DI, hypopituitarism (TSS); adrenal insufficiency lifelong (bilateral adrenalectomy)

— Discuss alternatives (medical therapy, radiation) and likelihood of cure vs recurrence

— Surgeon volume matters: ethical duty to refer to high-volume pituitary center—document referral discussion

— Every steroid-dependent patient must have: medical alert bracelet, written stress-dose plan, emergency IM hydrocortisone kit, and partner/family training

— Transition-of-care risk: hospital discharge without explicit steroid education is a sentinel event; ED visits and surgical procedures must trigger stress dosing

— Pharmacy and PCP must be looped in to prevent abrupt steroid discontinuation

— Ketoconazole hepatotoxicity—black box warning; document LFT monitoring

— Mifepristone — contraindicated in pregnancy (abortifacient); pregnancy testing and contraception counseling required

— Mitotane — teratogen; contraception for ≥2 years post-discontinuation

— Cortisol-induced psychosis or severe depression may impair decision-making; involve psychiatry, assess capacity for surgical consent

— Suicide risk screening—elevated in active CS and during steroid withdrawal

— When excessive prescribed steroid causes CS, disclose openly per medical error policies; root-cause analysis (e.g., fluticasone-ritonavir interaction)

Step 3 management: A patient discharged after bilateral adrenalectomy without a written stress-dose plan presents to an outside ED in DKA-like crisis—this is a preventable adverse event. The discharging physician's safety duty includes explicit written instructions, kit prescription, primary care handoff, and medical alert bracelet ordering before the patient leaves.

Informed consent for transsphenoidal surgery / adrenalectomy:

Adrenal crisis prevention = highest patient-safety priority:

Medication safety:

Capacity and psychiatric safety:

Disclosure of iatrogenic Cushing:

Genetic counseling and family screening for MEN1, Carney complex

Pregnancy in steroid-dependent patient: requires obstetric–endocrine coordination; stress dosing during labor (hydrocortisone 100 mg IV at delivery).

High-Yield Associations and Rapid-Fire Clinical Facts

Board pearl: When a board stem describes a patient with rapid-onset hyperpigmentation, severe hypokalemia, hyperglycemia, weight loss, and metabolic alkalosis—the answer is ectopic ACTH from small cell lung cancer.

Most common cause of Cushing syndrome overall = exogenous glucocorticoids

Most common endogenous cause = Cushing disease (pituitary ACTH-secreting adenoma), ~70%

Most common ectopic ACTH source = small cell lung carcinoma; bronchial carcinoid is the most common occult/benign ectopic source

Most common adrenal cause = adrenal adenoma

Best screening tests (per Endocrine Society): 1 mg overnight DST, late-night salivary cortisol ×2, 24-h UFC ×2 — need two positive different tests

Best confirmatory test for pituitary vs ectopic when MRI inconclusive = IPSS

Highest-yield discriminatory features: proximal myopathy, wide violaceous striae, facial plethora, easy bruising

Hypokalemia + Cushing → think ectopic ACTH

Virilization + abdominal mass + rapid course → adrenocortical carcinoma

Hyperpigmentation → high ACTH (Cushing disease or ectopic)

Pasireotide → hyperglycemia in most patients

Mifepristone → cortisol levels rise; monitor clinically

Mitotane → first-line for adrenal carcinoma

Etomidate IV → ICU cortisol lowering

Nelson syndrome → after bilateral adrenalectomy

Carney complex: cardiac myxomas, spotty pigmentation, primary pigmented nodular adrenocortical disease (PPNAD), PRKAR1A mutation

McCune-Albright: café-au-lait, polyostotic fibrous dysplasia, precocious puberty, infantile CS (GNAS mutation)

MEN1: parathyroid, pancreas, pituitary—pituitary CS possible

Standardized mortality ratio in active CS: ~2–4× normal

Post-TSS triphasic response: DI (days 1–5) → SIADH (days 5–10) → permanent DI (variable)

Cortisol <2 µg/dL post-TSS = remission

Adrenal mass >4 cm + heterogeneous + low washout = carcinoma until proven otherwise

DHEAS elevated = adrenal carcinoma; suppressed = adenoma (atrophic gland)

Fluticasone + ritonavir = classic iatrogenic CS interaction

Board Question Stem Patterns

Board pearl: When stem asks "next best step" after Cushingoid features, the answer is biochemical screening (1 mg DST or salivary cortisol), not imaging.

Stem 1 — Cushing disease classic: 35-year-old woman with weight gain, moon facies, wide purple abdominal striae, proximal weakness, HTN. UFC 4× ULN, ACTH 80 pg/mL, high-dose DST suppresses cortisol >50%. Answer: pituitary MRI → transsphenoidal surgery.

Stem 2 — Ectopic ACTH: 60-year-old smoker with 6-month rapid weight loss, K+ 2.6, BP 180/100, hyperpigmented palms, ACTH 300 pg/mL, no suppression on high-dose DST. Answer: CT chest for small cell lung CA; ± Ga-68 DOTATATE.

Stem 3 — Adrenal adenoma: hypertensive woman, ACTH <5 pg/mL, cortisol elevated, UFC high. CT shows 3 cm lipid-rich adrenal mass with washout 70%. Answer: laparoscopic adrenalectomy; check DHEAS (low confirms benign).

Stem 4 — Adrenal carcinoma: 45-year-old with rapid virilization, abdominal pain, 7 cm heterogeneous adrenal mass, elevated DHEAS and cortisol. Answer: open adrenalectomy + mitotane.

Stem 5 — Iatrogenic: HIV patient on ritonavir + fluticasone inhaler develops Cushingoid features. Low ACTH and low cortisol. Answer: switch inhaler, taper steroid carefully.

Stem 6 — Pseudo-Cushing: depressed alcoholic with mildly elevated UFC and abnormal DST but normal late-night salivary cortisol; lacks discriminatory features. Answer: dex-CRH test or treat depression/abstinence and retest.

Stem 7 — IPSS scenario: confirmed ACTH-dependent CS, pituitary MRI shows 3 mm lesion, equivocal high-dose DST. Answer: IPSS before surgery.

Stem 8 — Pregnancy: gravid woman with new HTN, easy bruising, striae; UFC 4× ULN. Answer: late-night salivary cortisol, MRI w/o gad, etiologic workup—adrenal adenoma most likely; metyrapone if medical therapy needed.

Stem 9 — Pediatric: 12-year-old with decelerating growth curve and rising BMI. Answer: screen for endogenous CS.

Stem 10 — Post-op crisis: patient s/p bilateral adrenalectomy presents with hypotension, hyponatremia, hyperkalemia after stopping hydrocortisone. Answer: adrenal crisis—IV hydrocortisone 100 mg + fluids.

One-Line Recap

Cushing syndrome workup proceeds in two sequential phases: first confirm hypercortisolism biochemically with two different abnormal first-line tests (1 mg DST, late-night salivary cortisol, or 24-h UFC), then localize the source by measuring ACTH—suppressed ACTH directs you to adrenal imaging, elevated ACTH directs you to differentiate pituitary from ectopic disease using high-dose DST, pituitary MRI, and IPSS when needed.

Board pearl: The Step 3 trap is ordering pituitary MRI before biochemistry—confirm hypercortisolism with two abnormal screening tests, measure ACTH, then image accordingly; the second trap is forgetting that iatrogenic steroid use is the most common cause of any Cushingoid patient.

Step 3 management: When in doubt on the algorithm: (1) stop and screen for exogenous steroids; (2) two screening tests; (3) ACTH; (4) targeted imaging; (5) IPSS if needed; (6) surgery first-line; (7) lifelong adrenal-insufficiency safety net.

Always exclude exogenous steroids first—iatrogenic CS is the most common cause overall and requires no biochemical workup, only a careful taper.

ACTH is the pivotal localization test: <5 pg/mL = adrenal (image with CT); >20 pg/mL = ACTH-dependent (Cushing disease vs ectopic—use high-dose DST, CRH stim, MRI, and IPSS).

Definitive treatment is source-specific: transsphenoidal surgery for Cushing disease, adrenalectomy for adrenal causes, resection of ectopic tumor when localized; medical therapy (ketoconazole, metyrapone, osilodrostat, pasireotide, mifepristone, mitotane, etomidate) bridges to surgery or treats unresectable disease.

Post-cure care is lifelong: stress-dose steroid education with medical alert bracelet and emergency IM kit, bone protection, CV risk reduction, VTE prophylaxis perioperatively, and annual surveillance for recurrence (~15–25% over 10 years).