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endo.cushing_syndrome.v1PRODUCTION
endo.cushing_syndrome.v1

Cushing syndrome (endogenous + exogenous excluded)

endocrinologychronicsubacuteadult
Hard-required inputs
0 / 10
Care setting:

Encounter flow

12/12 authored

Canonical 12-phase frame with authored status for this dossier.

Current phase

Frame

Detailed

Rule out exogenous steroid; confirm hypercortisolism on ≥2 different first-line tests; determine ACTH-dependent vs not (ADA 2026)

Inputs
5
Actions
0
Advance rule
Set
Advance when

Hypercortisolism confirmed and ACTH status known

Patient inputs (15)

Different cause distribution by age (ADA 2026)

Cardinal first exclusion (inhaled / topical / injected / OTC) (ADA 2026)

Pseudo-Cushing differential (ADA 2026)

Drug interactions + steroid review (ADA 2026)

First-line confirmation; ≥2× ULN suggestive (ADA 2026)

First-line confirmation; high specificity (ADA 2026)

First-line confirmation; cortisol <1.8 µg/dL excludes (ADA 2026)

ACTH-dependent (>20 pg/mL pituitary or ectopic) vs independent (<5 adrenal) (ADA 2026)

Comorbidities; hypoK common; new DM (ADA 2026)

Drug dosing (ADA 2026)

Pituitary vs ectopic in ACTH-dependent (ADA 2026)

Pituitary adenoma (ADA 2026)

Adrenal mass (ADA 2026)

Ectopic source localisation (lung SCC, carcinoid) (ADA 2026)

Gold standard pituitary vs ectopic when MRI equivocal (ADA 2026)

* = hard-required. Engine cannot meaningfully run until these are filled.

Severity triggers (7)

7 need judgement
  • informationallife_threateningsevere_cushing_with_hypoK_psychosis
    UFC ≥5× ULN with hypokalemia + psychosis or infection (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationallife_threateningpostop_adrenal_insufficiency
    Postop hypotension with hyponatremia / hyperkalemia / hypoglycemia (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverecushing_VTE_risk
    Cushing patient hospitalised (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalseverepituitary_surgery_recurrence
    Cushing disease recurrence after transsphenoidal surgery (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereadrenal_carcinoma_suspect
    Adrenal mass >4 cm, irregular margins, high HU, mixed cortisol + sex steroid excess (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalsevereectopic_acth_lung_carcinoid
    ACTH-dependent Cushing with negative pituitary MRI; consider ectopic (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.
  • informationalmoderatepseudo_cushing
    Hypercortisolism with depression / alcohol use / severe obesity / pregnancy (ADA 2026)
    Trigger could not be auto-evaluated — needs clinician judgement.

Workflow calculators

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Recommended regimen

Medical management bridge / unresectable / recurrence (ADA 2026)
axis: cushing_medical_bridge_or_recurrence
Selected axis "Medical management bridge / unresectable / recurrence (ADA 2026)" by default fallback (first axis)
  • ketoconazole
    first line
    steroidogenesis_inhibitor
    200–400 mg BID, titrate • PO • BID/TID
    triggers: cushing_medical_bridge, unresectable
    Inhibits multiple steroidogenic enzymes; LFT mandatory (ADA 2026)
    rxcui 6135
  • metyrapone
    first line
    11_beta_hydroxylase_inhibitor
    250–500 mg q4h • PO • q4–6h
    triggers: cushing_medical_bridge, pregnancy_consider
    Rapid cortisol lowering; can cause adrenal insufficiency (ADA 2026)
    rxcui 6923
  • osilodrostat
    first line
    11_beta_hydroxylase_inhibitor
    2 mg BID, titrate • PO • BID
    triggers: cushing_disease_recurrence, unresectable
    LINC-3; FDA-approved Cushing disease (ADA 2026)
    rxcui 2286252
  • mitotane
    second line
    adrenolytic
    500 mg BID, titrate to 1–4 g/d • PO • TID
    triggers: adrenocortical_carcinoma, severe_unresectable
    Cytotoxic to adrenal cortex; ACC
    rxcui 7004
  • mifepristone
    add on
    glucocorticoid_receptor_antagonist
    300 mg, titrate to 1200 mg • PO • daily
    triggers: glucose_intolerance_dominant
    SEISMIC — improves glucose control; UFC unchanged (ADA 2026)
    rxcui 6964
  • pasireotide
    second line
    somatostatin_analog
    600 mcg SC BID or 10–40 mg LAR IM monthly • SC/IM • BID or monthly
    triggers: cushing_disease_unresectable_recurrent
    PASPORT; hyperglycemia common (ADA 2026)
    rxcui 1364105
  • cabergoline
    add on
    D2_agonist
    0.5 mg twice weekly, titrate • PO • 2× weekly
    triggers: mild_cushing_disease, pregnancy
    Off-label (ADA 2026)
    rxcui 47579
  • hydrocortisone
    rescue
    glucocorticoid
    15–25 mg/day divided • PO • BID/TID
    triggers: post_op_adrenal_insufficiency, after_steroidogenesis_inhibitor
    Replacement post-op or after enzyme inhibitor block-and-replace (Endocrine Society 2015 treatment guideline)
    rxcui 5492

outpatient playbook — drug actions (3)

  1. 1. ketoconazole or metyrapone
    ket 200–400 mg BID OR met 250 mg q4–6h • PO • BID/q4h
    trigger: Bridge or unresectable (ADA 2026)
    Cortisol control (ADA 2026)
  2. 2. osilodrostat
    2 mg BID • PO • BID
    trigger: Cushing disease recurrence (ADA 2026)
    LINC-3 (ADA 2026)
  3. 3. mifepristone
    300 mg, titrate to 1200 mg • PO • daily
    trigger: Glucose intolerance dominant (ADA 2026)
    SEISMIC (ADA 2026)

Auto-drafted A&P note

outpatient

Subjective

- Possible entry pathways: Central obesity, moon facies, buffalo hump, purple striae, proximal myopathy, easy bruising (ADA 2026); Rapid weight gain, hirsutism, amenorrhea, mood change (ADA 2026); New hypokalemic HTN with new diabetes (ADA 2026).

Objective

- No vitals, labs, or imaging entered for this encounter.

Assessment

**Cushing syndrome (endogenous + exogenous excluded)** (endo.cushing_syndrome.v1).
Phenotype framing: Cushing disease (pituitary) vs ectopic ACTH vs adrenal adenoma vs ACC vs macronodular hyperplasia vs pseudo-Cushing
Scope: Rule out exogenous steroid; confirm hypercortisolism on ≥2 different first-line tests; determine ACTH-dependent vs not (ADA 2026)

No severity triggers fired against current inputs.

Plan

Regimen axis: **Medical management bridge / unresectable / recurrence (ADA 2026)**.
1. ketoconazole 200–400 mg BID, titrate PO BID/TID (steroidogenesis_inhibitor, first line) — Inhibits multiple steroidogenic enzymes; LFT mandatory (ADA 2026)
2. metyrapone 250–500 mg q4h PO q4–6h (11_beta_hydroxylase_inhibitor, first line) — Rapid cortisol lowering; can cause adrenal insufficiency (ADA 2026)
3. osilodrostat 2 mg BID, titrate PO BID (11_beta_hydroxylase_inhibitor, first line) — LINC-3; FDA-approved Cushing disease (ADA 2026)
4. mitotane 500 mg BID, titrate to 1–4 g/d PO TID (adrenolytic, second line) — Cytotoxic to adrenal cortex; ACC
5. mifepristone 300 mg, titrate to 1200 mg PO daily (glucocorticoid_receptor_antagonist, add on) — SEISMIC — improves glucose control; UFC unchanged (ADA 2026)
6. pasireotide 600 mcg SC BID or 10–40 mg LAR IM monthly SC/IM BID or monthly (somatostatin_analog, second line) — PASPORT; hyperglycemia common (ADA 2026)
7. cabergoline 0.5 mg twice weekly, titrate PO 2× weekly (D2_agonist, add on) — Off-label (ADA 2026)
8. hydrocortisone 15–25 mg/day divided PO BID/TID (glucocorticoid, rescue) — Replacement post-op or after enzyme inhibitor block-and-replace (Endocrine Society 2015 treatment guideline)

Setting playbook (outpatient) — Diagnose and localise; surgical referral; medical bridge if needed; manage comorbidities (ADA 2026)
9. ketoconazole or metyrapone ket 200–400 mg BID OR met 250 mg q4–6h PO BID/q4h — Bridge or unresectable (ADA 2026) (Cortisol control (ADA 2026))
10. osilodrostat 2 mg BID PO BID — Cushing disease recurrence (ADA 2026) (LINC-3 (ADA 2026))
11. mifepristone 300 mg, titrate to 1200 mg PO daily — Glucose intolerance dominant (ADA 2026) (SEISMIC (ADA 2026))

Non-pharmacologic actions:
- Pituitary or adrenal surgery referral (ADA 2026)
- VTE prophylaxis pre + postop (high VTE risk in Cushing) (ADA 2026)
- Glucose / BP / lipid management (ADA 2026)
- Mental health support (ADA 2026)
- Bone protection (DEXA, vit D, bisphosphonate) (ADA 2026)

AVOID / contraindication checks:
- Ketoconazole LFT q1m and DDI (ADA 2026)
- Mifepristone pregnancy block (ADA 2026)
- Pasireotide hyperglycemia monitor (ADA 2026)
- Steroidogenesis inhibitor monitor cortisol for adrenal insufficiency (ADA 2026)

Monitoring

Regimen monitoring:
- 24h UFC or late night salivary q1 3m (ADA 2026)
- LFT q1m on ketoconazole (ADA 2026)
- glucose BP q1m (ADA 2026)
- electrolytes q3m (ADA 2026)

Setting (outpatient) monitoring:
- UFC q1–3 m (ADA 2026)
- Glucose, BP, K, weight (ADA 2026)

Follow-up plan: Endo q3–6 mo; surveillance lifelong (Cushing disease recurrence ~20%) (ADA 2026)
- Close-out criterion: Follow-up booked

Monitoring phase: Cortisol, ACTH, K+, glucose, BP, BMI, mental health; recurrence surveillance lifelong (ADA 2026)

Disposition

Current setting: outpatient — Diagnose and localise; surgical referral; medical bridge if needed; manage comorbidities (ADA 2026)

Disposition criteria:
- Continue diagnostic + surgical pathway (ADA 2026)

Escalation triggers (move to higher acuity):
- Severe hypoK / infection / psychosis → ED (ADA 2026)

Earlier-Return Triggers

Return-precaution thresholds (watch for):
- [LIFE_THREATENING] UFC ≥5× ULN with hypokalemia + psychosis or infection (ADA 2026)
- [LIFE_THREATENING] Postop hypotension with hyponatremia / hyperkalemia / hypoglycemia (ADA 2026)
- [SEVERE] Cushing patient hospitalised (ADA 2026)

Citations

- Endocrine Society 2008 Cushing diagnosis (Nieman); 2015 treatment; Pituitary Society 2021 Cushing disease consensus (Fleseriu) [PMID:18334580](https://pubmed.ncbi.nlm.nih.gov/18334580/)
- Cited evidence (PMID 26222757) [PMID:26222757](https://pubmed.ncbi.nlm.nih.gov/26222757/)
- Cited evidence (PMID 34687601) [PMID:34687601](https://pubmed.ncbi.nlm.nih.gov/34687601/)
- Cited evidence (PMID 32730798) [PMID:32730798](https://pubmed.ncbi.nlm.nih.gov/32730798/)

Last reconciled with current guidelines: 2026-05-22.
References
  • Endocrine Society 2008 Cushing diagnosis (Nieman); 2015 treatment; Pituitary Society 2021 Cushing disease consensus (Fleseriu) — PMID:18334580
  • Cited evidence (PMID 26222757) — PMID:26222757
  • Cited evidence (PMID 34687601) — PMID:34687601
  • Cited evidence (PMID 32730798) — PMID:32730798