Addison's disease
Enable an AI agent to recognise supported descriptions of Addison's disease, assess disease control and crisis risk, and identify appropriate clinician-directed next actions.
Research draft, second pass
A second pass drafted this model: the structure a model of this thing needs, and what is known about it in the world. The line under this one says how the second half was obtained - researched against sources, or recalled without web access, in which case nothing here was read anywhere and every claim is a lead to verify. Unreviewed either way.
Researched by: Codex + Grok
Purpose and description
Enable an AI agent to recognise supported descriptions of Addison's disease, assess disease control and crisis risk, and identify appropriate clinician-directed next actions.
Addison's disease is chronic primary adrenal insufficiency: destruction or intrinsic failure of the adrenal cortex that depletes cortisol (and, in most patients, aldosterone and adrenal androgens) and drives a compensatory rise in pituitary ACTH.
It can be Compare a disease assertion with its diagnostic evidence and identify unresolved localisation or testing issues.; Assemble a clinician-reviewable account of adrenal deficits, probable cause and conflicting findings.; Track replacement delivery, symptoms and relevant observations to flag possible under- or over-replacement.; Retrieve the applicable clinician-authorised illness or procedure plan and identify missing coverage.; Flag suspected adrenal crisis for immediate emergency escalation without waiting for diagnostic confirmation.; Audit emergency medication access, training and continuity of replacement..
Distinguishing features
Confirmed cortisol deficiency with markedly elevated ACTH supports adrenal rather than pituitary or hypothalamic failure; preserve assay limits and treatment context. [Endocrine Society guideline](https://www.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency)
An inadequate cortisol response to ACTH stimulation supports adrenal insufficiency but does not alone distinguish Addison's disease from longstanding secondary insufficiency. [NIDDK diagnosis](https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/diagnosis)
Aldosterone deficiency assessed with renin supports a mineralocorticoid component; absence of that component must not automatically exclude primary adrenal insufficiency. [Endocrine Society guideline](https://www.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency)
Adrenal autoantibodies can support autoimmune attribution, but antibody status and functional adrenal failure require separate records. [NIDDK diagnosis](https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/diagnosis)
An adrenal crisis is an acute complication requiring urgent action, not a synonym for the underlying chronic disease. [Endocrine Society guideline](https://www.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency)
Scope
+ Evidence supporting or challenging primary adrenal insufficiency described as Addison's disease.
+ Cortisol reserve and mineralocorticoid function, including uncertainty and measurement context.
+ Attribution of adrenal failure to autoimmune or other supported causes.
+ Current manifestations, replacement adequacy and longitudinal disease burden.
+ Adrenal crisis recognition, stress coverage and emergency preparedness.
- Full models of secondary, tertiary and glucocorticoid-induced adrenal insufficiency.
- Independent models of underlying infections, malignancies and inherited adrenal disorders.
- Complete models of associated autoimmune diseases and polyglandular syndromes.
- Drug manufacture, general pharmacology and prescription execution.
- The complete patient record and general emergency resuscitation procedures.
Characteristics
- Diagnostic standing
- suspected | supported | confirmed | disputed | excluded; assessor and date Prevents a symptom-based suspicion or historical label from becoming an established diagnosis.
- Cortisol reserve
- nmol/L or µg/dL; basal or stimulated, collection times, assay and applicable reference limits Makes evidence of deficient cortisol production interpretable.
- Paired ACTH
- pg/mL or pmol/L; laboratory reference interval and paired cortisol specimen Supports localisation of failure within the adrenal axis.
- Mineralocorticoid function
- preserved | deficient | indeterminate | not assessed; linked aldosterone and renin results with original units Distinguishes cortisol replacement needs from salt and volume regulation needs.
- Adrenal failure cause
- autoimmune | infectious | hemorrhagic | infiltrative | genetic | iatrogenic | other | unknown; certainty recorded separately Guides causal investigation and links to neighbouring models without assuming autoimmunity.
- Circulatory and biochemical observations
- blood pressure in mmHg with posture; sodium and potassium in mmol/L; glucose in mmol/L or mg/dL; timestamp Supports assessment of physiological compromise and change over time.
- Replacement regimen
- linked clinician-authorised glucocorticoid and, where indicated, mineralocorticoid plans Connects disease state to prescribed coverage and actual administration.
- Current clinical state
- stable on replacement | possible under-replacement | possible over-replacement | acute deterioration | suspected crisis | recovering | unknown Separates chronic diagnostic certainty from immediate action needs.
- Emergency readiness
- current | incomplete | unavailable | unverified; supporting plan, supplies and training Makes preventable gaps in crisis response visible.
Also called
Where this came from
wikidata · CC0 1.0
Drafted structure
Bundle to layer to finding to question, as the second pass will find it: 7 bundles · 13 layers · 20 findings · 34 questions.
Diagnostic identity What the Addison's disease assertion means and what supports it.
The agent must distinguish the registered concept from a nonspecific adrenal insufficiency label.
Label and localisation
Meaning, authorship and anatomical basis of the diagnosis.
Primary adrenal failure assertion
Record whether the diagnosis identifies adrenal cortical failure and who established that interpretation.
- Does Addison's disease here mean established primary adrenal insufficiency, a suspected condition or an unverified historical label? definition
- Which clinician assessment or source record supports adrenal rather than central failure? provenance
Functional confirmation
Cortisol testing and the limits of its interpretation.
Interpretable cortisol evidence
Retain sampling conditions, stimulation protocol, assay limits and medication exposure alongside results.
- What were the basal and stimulated cortisol results, collection times, protocol and assay-specific decision limits? measurement
- Could recent glucocorticoids, acute illness or altered cortisol-binding proteins affect interpretation? boundary
- What evidence remains necessary before the diagnosis can be confirmed or revised? action
Adrenal deficit profile The separate functional deficits attributed to adrenal failure.
A single disease label does not describe which replacement functions are required.
Cortisol and ACTH
Relationship between demonstrated cortisol deficiency and pituitary drive.
Axis localisation evidence
Represent paired hormone evidence and unresolved contradictions without inferring localisation from stimulation testing alone.
- What ACTH result and reference interval accompany the evidence of cortisol deficiency? measurement
- Do results support primary failure, suggest central insufficiency or remain confounded by treatment? boundary
Aldosterone and volume
Evidence of impaired mineralocorticoid function and its physiological expression.
Mineralocorticoid deficit evidence
Connect aldosterone and renin interpretation with salt balance, posture-related symptoms and current therapy.
- What simultaneous aldosterone and renin measurements exist, with units, reference intervals and sampling conditions? measurement
- How do electrolytes, postural blood pressure and relevant medicines affect the deficit assessment? boundary
Cause and associated disease Evidence explaining adrenal failure and identifying related conditions.
Cause changes investigation and follow-up while associated diseases retain their own models.
Causal attribution
Supported explanations, alternatives and unresolved etiology.
Adrenal injury mechanism
Separate a suspected cause from one supported by antibodies, imaging, microbiology, genetics or treatment history.
- Which cause is proposed, and which reviewed evidence supports that attribution? provenance
- Which alternatives remain plausible when autoimmune evidence is absent or inconclusive? boundary
Associated condition links
Disease-specific reasons to consult neighbouring models.
Associated disease review
Record relevant associated conditions and the rationale for targeted screening or referral.
- Which associated autoimmune or inherited conditions are documented, suspected or assessed as absent? provenance
- What cause-specific screening or specialist review is due under the applicable care guidance? action
Replacement and clinical control How prescribed hormone replacement relates to delivered treatment and observed wellbeing.
Agents need to detect coverage gaps and possible treatment imbalance without autonomously prescribing.
Prescribed and delivered coverage
Maintenance plans and whether their intended doses reach the patient.
Replacement delivery
Record medicine, formulation, dose, timing, route, authorisation and barriers to administration.
- What glucocorticoid and mineralocorticoid regimens are currently authorised, and by whom? provenance
- Have missed doses, vomiting, supply interruption or interacting medicines compromised intended coverage? measurement
Response and burden
Longitudinal assessment of replacement adequacy and daily functioning.
Replacement adequacy review
Assess symptoms and observations clinically; routine glucocorticoid adjustment should not target ACTH normalisation. [Endocrine Society guideline](https://www.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency)
- How have energy, weight, postural symptoms, blood pressure and daily functioning changed since the last regimen review? measurement
- Which observations warrant clinician review for under-replacement, over-replacement or another cause of persistent symptoms? action
Stress and adrenal crisis Recognition and management interfaces for acute loss of adequate cortisol coverage.
Acute deterioration changes action urgency even when the chronic diagnosis remains uncertain.
Acute deterioration
Time-sensitive evidence of possible adrenal crisis.
Crisis suspicion and escalation
Suspected crisis requires immediate treatment and emergency escalation without awaiting confirmatory testing. [Endocrine Society guideline](https://www.endocrine.org/clinical-practice-guidelines/primary-adrenal-insufficiency)
- Are hypotension, collapse, persistent vomiting, confusion or other acute changes raising concern for crisis? measurement
- Which emergency pathway applies, and have escalation and emergency treatment been initiated? action
- What precipitant, last retained glucocorticoid dose and treatment times must accompany the handover? provenance
Stress coverage and readiness
Individual plans for illness, procedures and inability to take oral replacement.
Usable emergency plan
Link applicable stress instructions to accessible medication, trained assistance and escalation arrangements. [NIDDK treatment](https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/treatment)
- Which clinician-authorised instructions cover the present illness or procedure and inability to retain oral medication? action
- Are emergency medication, administration training and medical identification available and current? measurement
Life course and care continuity Context changes and handovers that alter the interpretation or delivery of Addison's disease care.
Replacement dependence persists across growth, pregnancy, travel and changes of care setting.
Age and pregnancy context
Population-specific applicability of testing, monitoring and replacement plans.
Context-appropriate care
Record age, growth or pregnancy context and the specialist plan applicable to it.
- Do childhood growth, pregnancy or postpartum status require a different assessment or treatment plan? boundary
- Which specialist has confirmed the applicable monitoring and replacement instructions? provenance
Handover and recurrence
Continuity of replacement and learning from previous decompensation.
Continuity and crisis history
Connect previous crises and access failures to concrete follow-up responsibilities.
- Which previous crises or near misses occurred, and what documented factors contributed? provenance
- Who owns prescription continuity, emergency supply renewal and endocrine follow-up during the next care transition? action
Evidence and external alignment What the world already says about this thing, gathered so the model can be checked against it.
A model that cannot be lined up against existing standards, identifiers and practice cannot be adopted by anyone who already uses them.
Reported evidence
Findings from the breadth pass, kept separate from the structural claims.
Kinds and varieties
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Isolated autoimmune primary adrenal insufficiency (21-hydroxylase/CYP21A2 autoantibody-positive adrenalitis; the usual form in high-income practice)
- Autoimmune polyendocrine syndrome type 1 (APS-1/APECED; AIRE-related, with candidiasis and hypoparathyroidism)
- Autoimmune polyendocrine syndrome type 2 (APS-2/Schmidt syndrome; Addison plus autoimmune thyroid disease and/or type 1 diabetes)
- Infectious adrenalitis (tuberculous historically and still in TB-endemic regions; also fungal, HIV-associated opportunistic infection)
- Monogenic/metabolic gland failure presenting as primary AI (notably X-linked adrenoleukodystrophy in males; rarer defects such as familial glucocorticoid deficiency)
- Bilateral adrenal hemorrhage or infarction (including meningococcal Waterhouse-Friderichsen syndrome and anticoagulant-associated hemorrhage)
- Infiltrative, metastatic, or surgical loss of both glands (metastasis, amyloid, lymphoma, bilateral adrenalectomy)
- Drug-induced cortical failure (mitotane, high-dose azoles, etomidate, immune-checkpoint inhibitors)
- Which of these kinds and varieties hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Identifiers and schemes
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Wikidata - Q36649 - Item for Addison's disease / primary adrenal insufficiency as commonly catalogued.
- ICD-10 / ICD-10-CM - E27.1 - Primary adrenocortical insufficiency; Addisonian crisis is separately E27.2.
- MeSH - D000224 - Heading Addison Disease.
- OMIM - 240200 - Autoimmune Addison disease; other OMIM entries cover syndromic/monogenic causes (e.g. AIRE, ABCD1).
- Orphanet - ORPHA:85138 - Addison disease as a rare disorder entry.
- SNOMED CT - 363732003 - Addison's disease (disorder); confirm against the edition in use.
- UMLS CUI - C0001403 - Addison's disease.
- Which of these identifiers and schemes hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Standards and regulation
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Endocrine Society Clinical Practice Guideline (Bornstein et al., J Clin Endocrinol Metab 2016) - diagnosis, replacement, and crisis treatment of primary adrenal insufficiency.
- NICE guidance and CKS on Addison's disease / adrenal insufficiency (UK) - identification in primary care, emergency steroid cards, and perioperative cover.
- Society for Endocrinology (UK) emergency guidance on adrenal crisis - parenteral hydrocortisone, fluids, and sick-day rules used on NHS wards and in ambulance protocols.
- EMA/FDA product licences for replacement glucocorticoids (hydrocortisone, including modified-release and paediatric granules) and fludrocortisone - dosing, labelling, and pharmacovigilance, not disease definition.
- NHS Steroid Emergency Card programme (UK, from 2020) - mandatory alert for patients on replacement or long-term glucocorticoids at crisis risk.
- Which of these standards and regulation hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Real-world use
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Encountered in endocrinology and in emergency medicine as new or recurrent adrenal crisis (hypotension, vomiting, hyponatremia) rather than as a laboratory curiosity.
- Lifelong oral hydrocortisone (or equivalent) plus fludrocortisone in most primary cases, with written sick-day rules and an emergency injection kit.
- Perioperative and intercurrent-illness 'stress dosing' in anaesthesia, obstetrics, and acute medicine.
- Case-finding in APS-1/APS-2 kindreds, in males with unexplained AI (VLCFA for adrenoleukodystrophy), and in TB-endemic work-ups of extra-pulmonary tuberculosis.
- Medical-alert jewellery, steroid cards, and ambulance/ED protocols that treat suspected crisis with parenteral hydrocortisone before confirmatory labs.
- Which of these real-world use hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Typical measurements
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Morning serum cortisol (untreated, highly suggestive of AI) - <140 (often ~50-140 when the patient is unwell); 140-500 is indeterminate and needs a stimulation test - nmol/L
- Peak serum cortisol after 250 µg cosyntropin/tetracosactide - failure below ~400-500 (assay-dependent; older 18 µg/dL ≈ 500 nmol/L cut-off; some newer assays use ~350-400) - nmol/L
- Plasma ACTH (untreated primary AI) - typically more than twice the upper reference limit, commonly ~100-1000 - ng/L (numerically equal to pg/mL)
- Daily hydrocortisone replacement (chronic, adult) - 15-25 in two or three divided doses - mg/day
- Fludrocortisone replacement (adult) - 50-200 (most patients ~100) - µg/day
- Serum sodium (untreated or in crisis) - often 115-135 - mmol/L
- Serum potassium (untreated or in crisis) - often 5.0-7.0 - mmol/L
- Which of these typical measurements hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Failure modes and hazards
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Adrenal (Addisonian) crisis: vasodilatory shock, hyponatremia, hyperkalemia, hypoglycemia, death if parenteral glucocorticoid and saline are delayed.
- Missed or late diagnosis after years of fatigue, weight loss, salt craving, or 'gastroenteritis'.
- Failure to escalate glucocorticoid during infection, vomiting, trauma, or surgery (broken sick-day rules).
- Chronic under-replacement (fatigue, crisis risk) or over-replacement (iatrogenic Cushing features, bone loss, adverse metabolic profile).
- Omission of mineralocorticoid when aldosterone is also lost (postural hypotension, hyponatremia, high renin).
- Unrecognised X-linked adrenoleukodystrophy in a male labelled as isolated autoimmune Addison's.
- Checkpoint-inhibitor or other drug-induced AI presenting as unexplained shock in oncology.
- Which of these failure modes and hazards hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Regional variation
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- High-income Northern Europe/North America: autoimmune adrenalitis dominates (~80-90% of primary AI); tuberculosis is now uncommon.
- TB-endemic regions: tuberculous adrenalitis remains a leading cause; calcification and extra-adrenal TB support that aetiology.
- APS-1 is enriched in founder populations (Finland, Sardinia, Iranian Jews) because of AIRE variants.
- Naming: many specialists and the Endocrine Society treat 'Addison's disease' as synonymous with all primary adrenal insufficiency; some clinicians, especially in the UK, reserve 'Addison's' for autoimmune disease and say 'primary adrenal insufficiency' for the rest.
- Crisis kit and alert practice differs: NHS steroid emergency card versus US MedicAlert-style jewellery; parenteral hydrocortisone availability in the community is uneven.
- Which of these regional variation hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Neighbouring kinds and how to tell them apart
Reported by the breadth pass; each item needs checking against its source before it becomes normative.
- Secondary (pituitary) adrenal insufficiency - Plasma ACTH is low or inappropriately normal, not high; aldosterone is usually preserved (renin-angiotensin intact); no ACTH-driven hyperpigmentation; look for other pituitary deficits and exogenous glucocorticoid history.
- Tertiary / glucocorticoid-induced adrenal suppression - History of pharmacologic glucocorticoids; ACTH low; mineralocorticoids preserved; cosyntropin test may still fail until the axis recovers.
- Classic 21-hydroxylase congenital adrenal hyperplasia - Markedly raised 17-hydroxyprogesterone (and androstenedione); presentation is usually neonatal or in childhood, not adult autoimmune Addison's.
- Isolated hypoaldosteronism / type 4 (hyperkalemic) renal tubular acidosis - Cortisol and ACTH stimulation remain normal; the defect is aldosterone production or renal response, not combined cortical failure.
- Sepsis or other distributive shock without known AI - Crisis is favoured by known primary AI, hyperpigmentation, combined hyponatremia plus hyperkalemia, and very high ACTH; do not delay hydrocortisone if crisis is plausible.
- Primary hypothyroidism or depression/chronic fatigue (non-endocrine) - TSH/free T4 separate thyroid disease (which may coexist in APS-2); a normal ACTH stimulation test excludes untreated Addison's as the cause of fatigue.
- X-linked adrenoleukodystrophy (male with 'Addison's') - Not a mimic so much as a cause to unmask: elevated very-long-chain fatty acids and ABCD1 sequencing; 21-hydroxylase antibodies are typically negative.
- Which of these neighbouring kinds and how to tell them apart hold for the sense of Addison's disease this model covers, and on what evidence? provenance
Sources
- Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline - Specialist definition of primary adrenal insufficiency as Addison's disease; diagnostic thresholds (morning cortisol, cosyntropin test, ACTH); replacement doses; adrenal-crisis management; etiological work-up including 21-hydroxylase antibodies and VLCFA in males.
- Adrenal Insufficiency & Addison's Disease - Public-facing NIH account of causes, distinction from secondary adrenal insufficiency, clinical features (including crisis), and lifelong glucocorticoid/mineralocorticoid replacement.
- Addison's disease (Clinical Knowledge Summary) - UK primary-care framing of Addison's disease, sick-day rules, emergency steroid cards, and the practical differential from secondary insufficiency and other fatigue/hyponatremia syndromes.
- Adrenal insufficiency - Lancet review (Charmandari, Nicolaides, Chrousos, 2014) of epidemiology by region (autoimmune vs tuberculosis), diagnostic biochemistry, and crisis as the principal hazard.
What the second pass must settle
- Should this registry entry use Addison's disease for all primary adrenal insufficiency or a narrower acquired-disease concept, particularly at congenital and postsurgical boundaries?
- Which current assay-specific cortisol thresholds and interference rules should the model reference for each laboratory and patient context?
- Which evidence standards and investigation pathways should govern uncertain autoimmune, infectious, genetic and other causal attributions?
- Which jurisdiction-specific emergency, pediatric, pregnancy and perioperative protocols should be linked, and how will their versions be maintained?
- Which measures and review intervals best distinguish persistent disease burden from replacement imbalance or associated illness?