Chronic Primary Adrenal Insufficiency

Endocrine Disorder MONDO:0015129 Pathograph 9 Show in embeddings browser Adrenal Insufficiency

Chronic primary adrenal insufficiency (CPAI), known eponymously as Addison disease when chronic, is a syndrome of cortisol and (usually) aldosterone deficiency caused by destruction or dysfunction of the adrenal cortex itself, distinguishing it from secondary forms driven by pituitary or hypothalamic failure. In industrialized countries the dominant cause is autoimmune adrenalitis, frequently occurring in isolation or as a component of autoimmune polyendocrine syndromes type 1 (APS-1, AIRE-related) or type 2 (APS-2), while in resource-limited settings infectious adrenalitis (notably tuberculosis, and histoplasmosis or HIV-related opportunistic infections) remains an important cause. Genetic etiologies are disproportionately responsible for pediatric-onset disease and include X-linked adrenoleukodystrophy (ABCD1), adrenal hypoplasia congenita (NR0B1/DAX1), familial glucocorticoid deficiency (MC2R, MRAP), and congenital adrenal hyperplasia (CYP21A2). Less common causes include bilateral adrenal hemorrhage (e.g. Waterhouse-Friderichsen syndrome in fulminant meningococcemia), bilateral adrenal metastases, and infiltrative diseases. The clinical hallmarks — hyperpigmentation from elevated ACTH and POMC-derived melanocyte-stimulating hormone, hypotension, salt craving, hyponatremia, and hyperkalemia — reflect the combined glucocorticoid and mineralocorticoid deficit and the loss of cortisol-mediated negative feedback on the hypothalamic-pituitary-adrenal axis. Diagnosis rests on a subnormal cortisol response to synthetic ACTH (cosyntropin) together with elevated plasma ACTH and renin; treatment requires lifelong glucocorticoid and mineralocorticoid replacement plus stress-dose adjustments to prevent fatal adrenal crisis.

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4
Pathophys.
10
Phenotypes
9
Pathograph
6
Genes
4
Medical Actions
5
Subtypes
🏷

Classifications

Harrison's Chapter
ENDOCRINOLOGY_METABOLISM
◆

Subtypes

5
Autoimmune Adrenalitis (Autoimmune Addison disease) MONDO:0100480
Immune-mediated destruction of the adrenal cortex, accounting for the majority of CPAI in industrialized countries. May occur as isolated autoimmune Addison disease or as a component of APS-1 (AIRE-related, childhood onset) or APS-2 (adult onset, polygenic, HLA-associated). 21-hydroxylase autoantibodies are the diagnostic immunological marker.
Infectious Adrenalitis (TB, fungal, HIV-related)
Adrenal destruction by tuberculous infection (historically the leading cause worldwide and still dominant in high-prevalence regions), or by disseminated fungal infections (histoplasmosis, paracoccidioidomycosis) and opportunistic infections including HIV/CMV in immunocompromised hosts. Typically presents with enlarged or calcified adrenal glands on imaging.
Genetic / Inherited Adrenal Failure
Heterogeneous group of monogenic disorders disproportionately responsible for pediatric-onset CPAI, including X-linked adrenoleukodystrophy (ABCD1), congenital adrenal hypoplasia (NR0B1/DAX1), familial glucocorticoid deficiency (MC2R, MRAP), and steroidogenic enzyme defects such as 21-hydroxylase deficiency (CYP21A2) in congenital adrenal hyperplasia.
Bilateral Adrenal Hemorrhage / Waterhouse-Friderichsen
Acute-on-chronic adrenal failure from bilateral adrenal hemorrhage or infarction, classically described in fulminant meningococcemia (Waterhouse-Friderichsen syndrome) but also caused by antiphospholipid syndrome, anticoagulant therapy, sepsis, and trauma.
Infiltrative or Metastatic Disease
Replacement of adrenal parenchyma by bilateral metastatic tumor (most commonly lung, breast, melanoma, renal cell carcinoma, or lymphoma) or by infiltrative processes such as amyloidosis or hemochromatosis. CPAI only develops when more than approximately 90% of the cortex is destroyed.
⚙

Pathophysiology

4
Adrenal Cortex Destruction
Across CPAI etiologies, the proximal lesion is loss of the steroidogenic cells of the adrenal cortex (zona fasciculata for cortisol, zona glomerulosa for aldosterone, zona reticularis for adrenal androgens). Mechanisms differ by subtype: immune-mediated destruction by autoreactive T cells and 21-hydroxylase autoantibodies in autoimmune adrenalitis; granulomatous destruction in tuberculosis; very long chain fatty acid accumulation and cell dysfunction in X-ALD; impaired adrenal organogenesis in adrenal hypoplasia congenita; ACTH signalling failure in familial glucocorticoid deficiency; or physical replacement of cortex by hemorrhage, metastasis, or infiltrate.
cortical cell of adrenal gland CL:0002097 CD8-positive, alpha-beta cytotoxic T cell CL:0000794 T-helper 1 cell CL:0000545 B cell CL:0000236
adaptive immune response GO:0002250 ↑ INCREASED glucocorticoid biosynthetic process GO:0006704 ↓ DECREASED mineralocorticoid biosynthetic process GO:0006705 ↓ DECREASED
adrenal cortex UBERON:0001235 zona glomerulosa of adrenal gland UBERON:0002053 zona fasciculata of adrenal gland UBERON:0002054
Downstream
Cortisol Deficiency and Loss of HPA Feedback
Aldosterone Deficiency and RAAS Disinhibition
Show evidence (3 references)
PMID:29631795 SUPPORT Human Clinical
"Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries"
Confirms that autoimmune destruction of the adrenal cortex is the leading mechanism of CPAI in industrialized populations.
PMID:30144040 SUPPORT Human Clinical
"Autoimmune Addison's disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease"
Establishes autoimmune adrenalitis as a classical organ-specific autoimmune disease targeting the adrenal cortex.
PMID:28132947 SUPPORT Human Clinical
"Addison's disease is characterized by the destruction of the adrenal cortex. Autoimmune adrenalitis is the main cause of adrenal insufficiency."
Directly supports destruction of the adrenal cortex as the unifying pathology.
Cortisol Deficiency and Loss of HPA Feedback
Loss of cortisol output removes negative feedback on the hypothalamic-pituitary-adrenal axis, driving compensatory hypersecretion of corticotropin-releasing hormone and ACTH. Because ACTH is processed from the POMC precursor that also yields alpha- and gamma-melanocyte stimulating hormones, sustained POMC over-production produces the characteristic hyperpigmentation of CPAI. Loss of cortisol also impairs gluconeogenesis and stress responses, contributing to hypoglycemia and reduced vascular tone.
glucocorticoid metabolic process GO:0008211 ↓ DECREASED gluconeogenesis GO:0006094 ↓ DECREASED
adrenal cortex UBERON:0001235
Downstream
Hyperpigmentation Phenotype Cascade
Hypoglycemia Cortisol deficiency impairs gluconeogenesis and stress counter-regulation, predisposing to hypoglycemia during decompensation.
Show evidence (2 references)
PMID:22066755 SUPPORT Human Clinical
"progressors were significantly more likely to have elevated ACTH"
Demonstrates that elevated ACTH precedes overt CPAI, reflecting loss of cortisol-mediated negative feedback.
PMID:16828409 SUPPORT Human Clinical
"Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
Confirms that loss of cortisol-mediated negative feedback drives elevated ACTH in CPAI.
Aldosterone Deficiency and RAAS Disinhibition
Loss of aldosterone output from a damaged zona glomerulosa disinhibits the renin-angiotensin-aldosterone system — plasma renin activity rises in response to volume depletion — but the absent adrenal response leaves sodium retention impaired and renal potassium excretion reduced. The result is the characteristic mineralocorticoid-deficient electrolyte phenotype of CPAI: hyponatremia, volume depletion with hypotension, and hyperkalemia.
mineralocorticoid biosynthetic process GO:0006705 ↓ DECREASED
zona glomerulosa of adrenal gland UBERON:0002053
Downstream
Hypotension Aldosterone deficiency causes sodium loss and hypovolemia, lowering blood pressure.
Hyponatremia Loss of mineralocorticoid action impairs renal sodium retention, producing sodium loss and hyponatremia.
Hyperkalemia Aldosterone deficiency reduces renal potassium excretion, causing hyperkalemia.
Show evidence (2 references)
PMID:6091953 SUPPORT Human Clinical
"impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
Connects aldosterone deficiency to the characteristic hyponatremia, hypovolemia/hypotension, and hyperkalemia of CPAI.
PMID:16828409 SUPPORT Human Clinical
"Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
Confirms that loss of aldosterone-mediated negative feedback on the RAAS elevates plasma renin in CPAI.
Hyperpigmentation Phenotype Cascade
Elevated POMC-derived peptides (ACTH itself, alpha-MSH) act on cutaneous melanocortin-1 receptors to upregulate melanogenesis, producing diffuse hyperpigmentation that is accentuated in sun-exposed skin, palmar creases, recent scars, friction sites, the vermilion border, and oral and genital mucosae. This phenotype distinguishes primary from secondary (pituitary) adrenal insufficiency, where ACTH is low.
melanin biosynthetic process GO:0042438 ↑ INCREASED
Downstream
Hyperpigmentation POMC-derived melanocortin signaling increases melanogenesis, producing the characteristic hyperpigmentation phenotype.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa."
Describes the characteristic distribution of hyperpigmentation in CPAI driven by elevated POMC-derived peptides.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Chronic Primary Adrenal Insufficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

10
Cardiovascular 1
Hypotension FREQUENT Hypotension HP:0002615
Show evidence (1 reference)
PMID:6091953 SUPPORT Human Clinical
"impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
Establishes hypotension as a direct consequence of mineralocorticoid deficiency in CPAI.
Digestive 1
Nausea and Vomiting Nausea and vomiting HP:0002017
Integument 1
Hyperpigmentation VERY_FREQUENT Hyperpigmentation of the skin HP:0000953
Distinguishes primary from secondary adrenal insufficiency; most prominent in sun-exposed skin, palmar creases, friction sites, recent scars, and mucosal surfaces.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa."
Documents the characteristic hyperpigmentation pattern of chronic primary adrenal insufficiency.
Metabolism 3
Hyponatremia FREQUENT Hyponatremia HP:0002902
Reflects aldosterone deficiency with impaired renal sodium retention and free water retention from cortisol deficiency.
Show evidence (1 reference)
PMID:6091953 SUPPORT Human Clinical
"impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
Directly attributes sodium loss (hyponatremia) to impaired adrenal steroid secretion.
Hyperkalemia FREQUENT Hyperkalemia HP:0002153
Reflects aldosterone deficiency with impaired renal potassium excretion.
Show evidence (1 reference)
PMID:6091953 SUPPORT Human Clinical
"impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
Directly attributes hyperkalemia to impaired adrenal steroid secretion in CPAI.
Hypoglycemia Hypoglycemia HP:0001943
Due to impaired gluconeogenesis from cortisol deficiency; more prominent in children and during adrenal crisis.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis"
Documents hypoglycemia as a characteristic feature of acute adrenal crisis in CPAI.
Nervous System 1
Salt Craving Salt craving HP:0030083
Compensatory behaviour in response to mineralocorticoid deficiency and sodium wasting.
Constitutional 1
Fatigue Fatigue HP:0012378
Growth 1
Weight Loss Weight loss HP:0001824
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"chronic primary adrenal insufficiency presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain"
Documents weight loss as part of the insidious chronic presentation of primary adrenal insufficiency.
Other 1
Adrenal Crisis
Acute life-threatening decompensation with severe hypotension, hyponatremia, hyperkalemia, and shock; classically precipitated by intercurrent illness, surgery, trauma, or abrupt steroid withdrawal in a patient with chronic adrenal insufficiency.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis"
Documents the clinical signature of acute adrenal crisis in primary adrenal insufficiency.
🧬

Genetic Associations

6
AIRE (Biallelic loss-of-function mutations cause autoimmune polyendocrine syndrome type 1 (APS-1), of which autoimmune Addison disease is a defining component.)
Gene: AIRE hgnc:360
Show evidence (2 references)
PMID:33717087 SUPPORT Human Clinical
"The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene"
Confirms AIRE as the monogenic cause of APS-1, which includes autoimmune CPAI as a defining feature.
PMID:33717087 SUPPORT Human Clinical
"AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin"
Supports the mechanistic basis for the AIRE note — AIRE promotes thymic self-antigen representation and central tolerance, so its loss allows autoreactive clones (including against adrenal antigens) to escape deletion.
CYP21A2 (Encodes steroid 21-hydroxylase, the dominant autoantigen in autoimmune CPAI and the deficient enzyme in classic congenital adrenal hyperplasia.)
Gene: CYP21A2 hgnc:2600
Show evidence (1 reference)
PMID:30144040 SUPPORT Human Clinical
"one major dominant self-antigen, the cytochrome P450 21-hydroxylase enzyme, which is targeted by both autoantibodies and autoreactive T cells"
Establishes CYP21A2 (21-hydroxylase) as the dominant autoantigen in autoimmune CPAI.
ABCD1 (Mutations cause X-linked adrenoleukodystrophy (X-ALD), in which very long chain fatty acid accumulation produces adrenal failure (often the presenting feature) and cerebral demyelination.)
Gene: ABCD1 hgnc:61
MC2R (Loss-of-function mutations cause familial glucocorticoid deficiency type 1 (ACTH resistance) with isolated glucocorticoid deficiency and preserved mineralocorticoid function.)
Gene: MC2R hgnc:6930
CTLA4 (Risk variants in this immune checkpoint regulator increase susceptibility to autoimmune CPAI by reducing T-cell inhibition.)
Gene: CTLA4 hgnc:2505
Show evidence (1 reference)
PMID:26204230 SUPPORT Human Clinical
"The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004)"
Demonstrates CTLA4 as a genetic susceptibility locus for autoimmune CPAI.
HLA-DR3-DQ2 / HLA-DR4-DQ8 (Major histocompatibility complex class II haplotypes are the strongest non-monogenic genetic risk factor for autoimmune CPAI.)
Show evidence (1 reference)
PMID:26204230 SUPPORT Human Clinical
"the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4"
Confirms the HLA class II haplotypes DR3-DQ2 and DR4 as the strongest genomic risk association in autoimmune Addison disease.
💊

Medical Actions

4
Glucocorticoid Replacement
Action: Pharmacotherapy NCIT:C15986
Agent: cortisol CHEBI:17650
Lifelong glucocorticoid replacement with hydrocortisone (preferred) or other glucocorticoids, divided across the day to approximate physiological cortisol secretion.
Show evidence (1 reference)
PMID:24755997 SUPPORT Human Clinical
"Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone."
Documents hydrocortisone (cortisol) as the standard glucocorticoid for CPAI replacement therapy.
Mineralocorticoid Replacement
Action: Pharmacotherapy NCIT:C15986
Agent: fludrocortisone CHEBI:50885
Lifelong fludrocortisone to replace aldosterone, titrated to blood pressure, electrolytes, and plasma renin activity.
Show evidence (1 reference)
PMID:24755997 SUPPORT Human Clinical
"Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone."
Documents fludrocortisone as the standard mineralocorticoid replacement in CPAI.
Stress-Dose Glucocorticoid Adjustment
Action: Pharmacotherapy NCIT:C15986
Agent: cortisol CHEBI:17650
Two- to three-fold increase in glucocorticoid dose during intercurrent illness, surgery, or trauma to prevent adrenal crisis; parenteral hydrocortisone for severe stress, inability to take oral medication, or impending crisis.
Patient Education and Emergency Identification
Action: supportive care MAXO:0000950
Patient and family education on stress dosing, injectable emergency hydrocortisone kits, and medical alert identification are core to preventing fatal adrenal crisis.
Show evidence (1 reference)
PMID:31321757 SUPPORT Human Clinical
"continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD"
Reinforces ongoing patient education as a lifesaving non-pharmacological intervention in CPAI.
🌍

Environmental Factors

2
Tuberculosis and other adrenal infections
Infectious agent exposure ECTO:3000000
Adrenal tuberculosis was historically the leading worldwide cause of CPAI and remains important in high-incidence regions; disseminated fungal infections (histoplasmosis, paracoccidioidomycosis) and HIV-related opportunistic infections also cause adrenal destruction.
Show evidence (1 reference)
PMID:27210825 SUPPORT Human Clinical
"In industrialized countries, autoimmune adrenalitis accounts for the majority of cases of PAI."
Sets the geographic context — autoimmunity dominates in industrialized settings, infectious causes elsewhere remain important.
Glucocorticoid Therapy Withdrawal (precipitant of crisis)
Iatrogenic suppression of the HPA axis by chronic glucocorticoid therapy is a major cause of central adrenal insufficiency; in patients with established CPAI, abrupt withdrawal or failure to stress-dose precipitates adrenal crisis.
🔬

Biochemical Markers

5
Cortisol (Decreased)
Context: Basal and ACTH-stimulated serum cortisol are reduced; subnormal peak cortisol response to cosyntropin defines biochemical CPAI.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"Synthetic adrenocorticotropin 1-24 at a dose of 250 microg works well as a dynamic test."
Describes the cosyntropin stimulation test used to demonstrate subnormal cortisol response in CPAI.
ACTH (Adrenocorticotropic Hormone) (Increased)
Context: Elevated because of loss of cortisol-mediated negative feedback on the pituitary corticotrophs; drives both CPAI hyperpigmentation and the diagnostic ACTH-cortisol mismatch.
Show evidence (3 references)
PMID:16828409 SUPPORT Human Clinical
"Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
Confirms that elevated ACTH (alongside elevated renin) is the diagnostic biochemical signature of CPAI.
PMID:22066755 SUPPORT Human Clinical
"progressors were significantly more likely to have elevated ACTH"
Demonstrates that ACTH elevation precedes overt CPAI and tracks loss of cortisol feedback.
PMID:22066755 SUPPORT Human Clinical
"Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol"
In a prospective cohort of 21-hydroxylase-antibody-positive subjects, a moderate rise in ACTH was the best early sentinel of impending overt disease, outperforming autoantibody, renin, and peak-cortisol measures in the 2 years before onset.
Aldosterone (Decreased)
Context: Reduced output from a damaged zona glomerulosa; key driver of hyponatremia, hyperkalemia, and orthostatic hypotension.
Show evidence (1 reference)
PMID:6091953 SUPPORT Human Clinical
"impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
Documents the consequences of reduced mineralocorticoid output in CPAI.
Plasma Renin Activity (Increased)
Context: Compensatory rise from volume depletion and absent aldosterone-mediated feedback on the renin-angiotensin-aldosterone system.
Show evidence (1 reference)
PMID:16828409 SUPPORT Human Clinical
"Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
Confirms elevated renin as a hallmark of CPAI alongside elevated ACTH.
21-Hydroxylase Autoantibodies (Increased)
Context: Diagnostic immunological marker of autoimmune CPAI; positive in the great majority of autoimmune adrenalitis cases and can precede biochemical disease by years.
Show evidence (1 reference)
PMID:22066755 SUPPORT Human Clinical
"Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD)."
Establishes 21-hydroxylase autoantibodies as a predictive biomarker for autoimmune CPAI.
{ }

Source YAML

click to show 
name: Chronic Primary Adrenal Insufficiency
creation_date: '2026-05-13T00:00:00Z'
updated_date: '2026-05-14T00:00:00Z'
description: >-
  Chronic primary adrenal insufficiency (CPAI), known eponymously as Addison
  disease when chronic, is a syndrome of cortisol and (usually) aldosterone
  deficiency caused by destruction or dysfunction of the adrenal cortex
  itself, distinguishing it from secondary forms driven by pituitary or
  hypothalamic failure. In industrialized countries the dominant cause is
  autoimmune adrenalitis, frequently occurring in isolation or as a component
  of autoimmune polyendocrine syndromes type 1 (APS-1, AIRE-related) or type
  2 (APS-2), while in resource-limited settings infectious adrenalitis
  (notably tuberculosis, and histoplasmosis or HIV-related opportunistic
  infections) remains an important cause. Genetic etiologies are
  disproportionately responsible for pediatric-onset disease and include
  X-linked adrenoleukodystrophy (ABCD1), adrenal hypoplasia congenita
  (NR0B1/DAX1), familial glucocorticoid deficiency (MC2R, MRAP), and
  congenital adrenal hyperplasia (CYP21A2). Less common causes include
  bilateral adrenal hemorrhage (e.g. Waterhouse-Friderichsen syndrome in
  fulminant meningococcemia), bilateral adrenal metastases, and infiltrative
  diseases. The clinical hallmarks — hyperpigmentation from elevated ACTH and
  POMC-derived melanocyte-stimulating hormone, hypotension, salt craving,
  hyponatremia, and hyperkalemia — reflect the combined glucocorticoid and
  mineralocorticoid deficit and the loss of cortisol-mediated negative
  feedback on the hypothalamic-pituitary-adrenal axis. Diagnosis rests on a
  subnormal cortisol response to synthetic ACTH (cosyntropin) together with
  elevated plasma ACTH and renin; treatment requires lifelong glucocorticoid
  and mineralocorticoid replacement plus stress-dose adjustments to prevent
  fatal adrenal crisis.
category: Endocrine Disorder
parents:
- Adrenal Insufficiency
disease_term:
  preferred_term: chronic primary adrenal insufficiency
  term:
    id: MONDO:0015129
    label: chronic primary adrenal insufficiency
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
has_subtypes:
- name: Autoimmune Adrenalitis
  display_name: Autoimmune Adrenalitis (Autoimmune Addison disease)
  subtype_term:
    preferred_term: autoimmune primary adrenal insufficiency
    term:
      id: MONDO:0100480
      label: autoimmune primary adrenal insufficiency
  description: >-
    Immune-mediated destruction of the adrenal cortex, accounting for the
    majority of CPAI in industrialized countries. May occur as isolated
    autoimmune Addison disease or as a component of APS-1 (AIRE-related,
    childhood onset) or APS-2 (adult onset, polygenic, HLA-associated).
    21-hydroxylase autoantibodies are the diagnostic immunological marker.
- name: Infectious
  display_name: Infectious Adrenalitis (TB, fungal, HIV-related)
  description: >-
    Adrenal destruction by tuberculous infection (historically the leading
    cause worldwide and still dominant in high-prevalence regions), or by
    disseminated fungal infections (histoplasmosis, paracoccidioidomycosis)
    and opportunistic infections including HIV/CMV in immunocompromised
    hosts. Typically presents with enlarged or calcified adrenal glands on
    imaging.
- name: Genetic
  display_name: Genetic / Inherited Adrenal Failure
  description: >-
    Heterogeneous group of monogenic disorders disproportionately responsible
    for pediatric-onset CPAI, including X-linked adrenoleukodystrophy
    (ABCD1), congenital adrenal hypoplasia (NR0B1/DAX1), familial
    glucocorticoid deficiency (MC2R, MRAP), and steroidogenic enzyme defects
    such as 21-hydroxylase deficiency (CYP21A2) in congenital adrenal
    hyperplasia.
- name: Adrenal Hemorrhage
  display_name: Bilateral Adrenal Hemorrhage / Waterhouse-Friderichsen
  description: >-
    Acute-on-chronic adrenal failure from bilateral adrenal hemorrhage or
    infarction, classically described in fulminant meningococcemia
    (Waterhouse-Friderichsen syndrome) but also caused by antiphospholipid
    syndrome, anticoagulant therapy, sepsis, and trauma.
- name: Infiltrative
  display_name: Infiltrative or Metastatic Disease
  description: >-
    Replacement of adrenal parenchyma by bilateral metastatic tumor (most
    commonly lung, breast, melanoma, renal cell carcinoma, or lymphoma) or
    by infiltrative processes such as amyloidosis or hemochromatosis. CPAI
    only develops when more than approximately 90% of the cortex is
    destroyed.
prevalence:
- population: Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_low: 9.3
  rate_high: 22.0
  notes: >-
    Reported prevalence of autoimmune Addison disease is 93-220 per million in
    Europe (9.3-22 per 100,000); the range straddles the 1-9/100,000 and
    1-9/10,000 Orphanet bands, so the coarse band is set to the tier containing
    the upper estimates.
  evidence:
  - reference: PMID:29631795
    reference_title: "Autoimmune Addison's disease - An update on pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prevalence estimates ranging from 93-220 per million in Europe"
    explanation: Provides the European prevalence estimate for autoimmune Addison disease.
pathophysiology:
- name: Adrenal Cortex Destruction
  description: >-
    Across CPAI etiologies, the proximal lesion is loss of the steroidogenic
    cells of the adrenal cortex (zona fasciculata for cortisol, zona
    glomerulosa for aldosterone, zona reticularis for adrenal androgens).
    Mechanisms differ by subtype: immune-mediated destruction by autoreactive
    T cells and 21-hydroxylase autoantibodies in autoimmune adrenalitis;
    granulomatous destruction in tuberculosis; very long chain fatty acid
    accumulation and cell dysfunction in X-ALD; impaired adrenal
    organogenesis in adrenal hypoplasia congenita; ACTH signalling failure
    in familial glucocorticoid deficiency; or physical replacement of cortex
    by hemorrhage, metastasis, or infiltrate.
  cell_types:
  - preferred_term: cortical cell of adrenal gland
    term:
      id: CL:0002097
      label: cortical cell of adrenal gland
  - preferred_term: CD8-positive, alpha-beta cytotoxic T cell
    term:
      id: CL:0000794
      label: CD8-positive, alpha-beta cytotoxic T cell
  - preferred_term: T-helper 1 cell
    term:
      id: CL:0000545
      label: T-helper 1 cell
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: adaptive immune response
    term:
      id: GO:0002250
      label: adaptive immune response
    modifier: INCREASED
  - preferred_term: glucocorticoid biosynthetic process
    term:
      id: GO:0006704
      label: glucocorticoid biosynthetic process
    modifier: DECREASED
  - preferred_term: mineralocorticoid biosynthetic process
    term:
      id: GO:0006705
      label: mineralocorticoid biosynthetic process
    modifier: DECREASED
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  - preferred_term: zona glomerulosa of adrenal gland
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  - preferred_term: zona fasciculata of adrenal gland
    term:
      id: UBERON:0002054
      label: zona fasciculata of adrenal gland
  downstream:
  - target: Cortisol Deficiency and Loss of HPA Feedback
  - target: Aldosterone Deficiency and RAAS Disinhibition
  evidence:
  - reference: PMID:29631795
    reference_title: "Autoimmune Addison's disease - An update on pathogenesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries"
    explanation: Confirms that autoimmune destruction of the adrenal cortex is the leading mechanism of CPAI in industrialized populations.
  - reference: PMID:30144040
    reference_title: "The potential role for infections in the pathogenesis of autoimmune Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoimmune Addison's disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease"
    explanation: Establishes autoimmune adrenalitis as a classical organ-specific autoimmune disease targeting the adrenal cortex.
  - reference: PMID:28132947
    reference_title: "An Addison disease revealed with a serious hyponatremia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Addison's disease is characterized by the destruction of the adrenal cortex. Autoimmune adrenalitis is the main cause of adrenal insufficiency."
    explanation: Directly supports destruction of the adrenal cortex as the unifying pathology.
- name: Cortisol Deficiency and Loss of HPA Feedback
  description: >-
    Loss of cortisol output removes negative feedback on the
    hypothalamic-pituitary-adrenal axis, driving compensatory hypersecretion
    of corticotropin-releasing hormone and ACTH. Because ACTH is processed
    from the POMC precursor that also yields alpha- and gamma-melanocyte
    stimulating hormones, sustained POMC over-production produces the
    characteristic hyperpigmentation of CPAI. Loss of cortisol also impairs
    gluconeogenesis and stress responses, contributing to hypoglycemia and
    reduced vascular tone.
  biological_processes:
  - preferred_term: glucocorticoid metabolic process
    term:
      id: GO:0008211
      label: glucocorticoid metabolic process
    modifier: DECREASED
  - preferred_term: gluconeogenesis
    term:
      id: GO:0006094
      label: gluconeogenesis
    modifier: DECREASED
  locations:
  - preferred_term: adrenal cortex
    term:
      id: UBERON:0001235
      label: adrenal cortex
  downstream:
  - target: Hyperpigmentation Phenotype Cascade
  - target: Hypoglycemia
    causal_link_type: DIRECT
    description: Cortisol deficiency impairs gluconeogenesis and stress counter-regulation, predisposing to hypoglycemia during decompensation.
    evidence:
    - reference: PMID:16828409
      reference_title: "Addison's disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis"
      explanation: The review identifies hypoglycemia as a characteristic feature of adrenal crisis in primary adrenal insufficiency, supporting impaired cortisol counter-regulation as the upstream mechanism.
  evidence:
  - reference: PMID:22066755
    reference_title: "Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressors were significantly more likely to have elevated ACTH"
    explanation: Demonstrates that elevated ACTH precedes overt CPAI, reflecting loss of cortisol-mediated negative feedback.
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
    explanation: Confirms that loss of cortisol-mediated negative feedback drives elevated ACTH in CPAI.
- name: Aldosterone Deficiency and RAAS Disinhibition
  description: >-
    Loss of aldosterone output from a damaged zona glomerulosa disinhibits
    the renin-angiotensin-aldosterone system — plasma renin activity rises
    in response to volume depletion — but the absent adrenal response
    leaves sodium retention impaired and renal potassium excretion reduced.
    The result is the characteristic mineralocorticoid-deficient electrolyte
    phenotype of CPAI: hyponatremia, volume depletion with hypotension, and
    hyperkalemia.
  biological_processes:
  - preferred_term: mineralocorticoid biosynthetic process
    term:
      id: GO:0006705
      label: mineralocorticoid biosynthetic process
    modifier: DECREASED
  locations:
  - preferred_term: zona glomerulosa of adrenal gland
    term:
      id: UBERON:0002053
      label: zona glomerulosa of adrenal gland
  evidence:
  - reference: PMID:6091953
    reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
    explanation: Connects aldosterone deficiency to the characteristic hyponatremia, hypovolemia/hypotension, and hyperkalemia of CPAI.
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
    explanation: Confirms that loss of aldosterone-mediated negative feedback on the RAAS elevates plasma renin in CPAI.
  downstream:
  - target: Hypotension
    causal_link_type: DIRECT
    description: Aldosterone deficiency causes sodium loss and hypovolemia, lowering blood pressure.
    evidence:
    - reference: PMID:6091953
      reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
      explanation: The cited review directly links impaired adrenal steroid secretion to hypotension and hypovolemia.
  - target: Hyponatremia
    causal_link_type: DIRECT
    description: Loss of mineralocorticoid action impairs renal sodium retention, producing sodium loss and hyponatremia.
    evidence:
    - reference: PMID:6091953
      reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
      explanation: Sodium loss with hypovolemia supports the hyponatremic phenotype downstream of aldosterone deficiency.
  - target: Hyperkalemia
    causal_link_type: DIRECT
    description: Aldosterone deficiency reduces renal potassium excretion, causing hyperkalemia.
    evidence:
    - reference: PMID:6091953
      reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
      explanation: The cited review directly links impaired adrenal steroid secretion to hyperkalemia.
- name: Hyperpigmentation Phenotype Cascade
  description: >-
    Elevated POMC-derived peptides (ACTH itself, alpha-MSH) act on
    cutaneous melanocortin-1 receptors to upregulate melanogenesis,
    producing diffuse hyperpigmentation that is accentuated in sun-exposed
    skin, palmar creases, recent scars, friction sites, the vermilion
    border, and oral and genital mucosae. This phenotype distinguishes
    primary from secondary (pituitary) adrenal insufficiency, where ACTH
    is low.
  biological_processes:
  - preferred_term: melanin biosynthetic process
    term:
      id: GO:0042438
      label: melanin biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa."
    explanation: Describes the characteristic distribution of hyperpigmentation in CPAI driven by elevated POMC-derived peptides.
  downstream:
  - target: Hyperpigmentation
    causal_link_type: DIRECT
    description: POMC-derived melanocortin signaling increases melanogenesis, producing the characteristic hyperpigmentation phenotype.
    evidence:
    - reference: PMID:16828409
      reference_title: "Addison's disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa."
      explanation: The source describes the same characteristic cutaneous hyperpigmentation pattern represented by this phenotype.
phenotypes:
- category: Endocrine
  name: Hyperpigmentation
  description: >-
    Diffuse darkening of the skin and mucous membranes is the most distinctive
    sign of chronic primary adrenal insufficiency, driven by overproduction of
    POMC-derived ACTH and alpha-melanocyte-stimulating hormone acting on
    cutaneous melanocortin-1 receptors. It is accentuated in sun-exposed areas,
    palmar creases, recent scars, friction sites, the vermilion border, and
    oral and genital mucosae, and its presence distinguishes primary disease
    from secondary (pituitary) adrenal insufficiency, in which ACTH is low.
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: Distinguishes primary from secondary adrenal insufficiency; most prominent in sun-exposed skin, palmar creases, friction sites, recent scars, and mucosal surfaces.
  phenotype_term:
    preferred_term: Hyperpigmentation
    term:
      id: HP:0000953
      label: Hyperpigmentation of the skin
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cutaneous manifestations include darkening of the skin especially in sun-exposed areas and hyperpigmentation of the palmar creases, frictional surfaces, vermilion border, recent scars, genital skin, and oral mucosa."
    explanation: Documents the characteristic hyperpigmentation pattern of chronic primary adrenal insufficiency.
- category: Cardiovascular
  name: Hypotension
  description: >-
    Low blood pressure, often with orthostatic features, reflects the combined
    loss of mineralocorticoid-driven sodium and volume retention and the
    permissive role of cortisol in maintaining vascular tone and
    catecholamine responsiveness. It is a prominent feature of chronic primary
    adrenal insufficiency and can progress to circulatory collapse during
    adrenal crisis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypotension
    term:
      id: HP:0002615
      label: Hypotension
  evidence:
  - reference: PMID:6091953
    reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
    explanation: Establishes hypotension as a direct consequence of mineralocorticoid deficiency in CPAI.
- category: Metabolic
  name: Hyponatremia
  description: >-
    Low serum sodium is among the most common biochemical abnormalities in
    chronic primary adrenal insufficiency. It arises from aldosterone
    deficiency with impaired renal sodium retention and renal sodium wasting,
    compounded by cortisol deficiency that permits increased vasopressin
    secretion and free-water retention. Hyponatremia may be the presenting
    laboratory clue and worsens acutely during adrenal crisis.
  frequency: FREQUENT
  notes: Reflects aldosterone deficiency with impaired renal sodium retention and free water retention from cortisol deficiency.
  phenotype_term:
    preferred_term: Hyponatremia
    term:
      id: HP:0002902
      label: Hyponatremia
  evidence:
  - reference: PMID:6091953
    reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
    explanation: Directly attributes sodium loss (hyponatremia) to impaired adrenal steroid secretion.
- category: Metabolic
  name: Hyperkalemia
  description: >-
    Elevated serum potassium reflects aldosterone deficiency, which reduces
    distal nephron sodium-potassium exchange and impairs renal potassium
    excretion. Unlike secondary adrenal insufficiency, where mineralocorticoid
    function is preserved, hyperkalemia is characteristic of primary adrenal
    insufficiency and, together with hyponatremia, signals the
    mineralocorticoid-deficient electrolyte pattern of the disease.
  frequency: FREQUENT
  notes: Reflects aldosterone deficiency with impaired renal potassium excretion.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: PMID:6091953
    reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
    explanation: Directly attributes hyperkalemia to impaired adrenal steroid secretion in CPAI.
- category: Endocrine
  name: Fatigue
  description: >-
    Profound, progressive fatigue and weakness are near-universal early
    symptoms of chronic primary adrenal insufficiency, reflecting cortisol
    deficiency with impaired gluconeogenesis and stress response together with
    the volume depletion and electrolyte disturbance of mineralocorticoid
    deficiency. Because the onset is insidious and nonspecific, fatigue often
    delays diagnosis until an adrenal crisis or other acute decompensation
    occurs.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
- category: Endocrine
  name: Salt Craving
  description: >-
    A strong craving for salty foods is a relatively specific symptom of
    chronic primary adrenal insufficiency, arising as a compensatory
    behavioral response to aldosterone deficiency and ongoing renal sodium
    wasting. Its presence in a patient with fatigue and hyperpigmentation
    should prompt evaluation for adrenal insufficiency.
  notes: Compensatory behaviour in response to mineralocorticoid deficiency and sodium wasting.
  phenotype_term:
    preferred_term: Salt craving
    term:
      id: HP:0030083
      label: Salt craving
- category: Systemic
  name: Weight Loss
  description: >-
    Unintentional weight loss accompanies the insidious chronic presentation of
    primary adrenal insufficiency, driven by anorexia, nausea, and the
    catabolic, low-energy state produced by combined glucocorticoid and
    mineralocorticoid deficiency. It frequently occurs alongside malaise,
    gastrointestinal symptoms, and generalized weakness.
  phenotype_term:
    preferred_term: Weight loss
    term:
      id: HP:0001824
      label: Weight loss
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic primary adrenal insufficiency presents with a more insidious history of malaise, anorexia, diarrhea, weight loss, joint, and back pain"
    explanation: Documents weight loss as part of the insidious chronic presentation of primary adrenal insufficiency.
- category: Metabolic
  name: Hypoglycemia
  description: >-
    Low blood glucose results from cortisol deficiency, which impairs hepatic
    gluconeogenesis and counter-regulatory responses to fasting and stress. It
    is more pronounced in children and during acute adrenal crisis, and can be
    severe when adrenal insufficiency coexists with other pituitary hormone
    deficiencies or intercurrent illness.
  notes: Due to impaired gluconeogenesis from cortisol deficiency; more prominent in children and during adrenal crisis.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis"
    explanation: Documents hypoglycemia as a characteristic feature of acute adrenal crisis in CPAI.
- category: Gastrointestinal
  name: Nausea and Vomiting
  description: >-
    Nausea and vomiting, often with anorexia, abdominal pain, and diarrhea, are
    common gastrointestinal manifestations of chronic primary adrenal
    insufficiency related to cortisol deficiency and the accompanying
    electrolyte disturbances. Worsening vomiting is an important warning sign of
    impending adrenal crisis, since it both reflects decompensation and prevents
    absorption of oral glucocorticoid replacement.
  phenotype_term:
    preferred_term: Nausea and vomiting
    term:
      id: HP:0002017
      label: Nausea and vomiting
- category: Systemic
  name: Adrenal Crisis
  description: >-
    Adrenal crisis is the acute, life-threatening decompensation of adrenal
    insufficiency, characterized by severe hypotension or shock, hyponatremia,
    hyperkalemia, hypoglycemia, and often fever and abdominal symptoms. It is
    typically precipitated by intercurrent illness, surgery, trauma, or abrupt
    glucocorticoid withdrawal in a patient with chronic adrenal insufficiency,
    and it remains a major cause of preventable mortality unless treated
    promptly with parenteral hydrocortisone and fluid resuscitation.
  phenotype_term:
    preferred_term: Adrenal Crisis
  diagnostic: true
  notes: Acute life-threatening decompensation with severe hypotension, hyponatremia, hyperkalemia, and shock; classically precipitated by intercurrent illness, surgery, trauma, or abrupt steroid withdrawal in a patient with chronic adrenal insufficiency.
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthostatic hypotension, fever, and hypoglycemia characterize acute adrenal crisis"
    explanation: Documents the clinical signature of acute adrenal crisis in primary adrenal insufficiency.
biochemical:
- name: Cortisol
  presence: Decreased
  context: Basal and ACTH-stimulated serum cortisol are reduced; subnormal peak cortisol response to cosyntropin defines biochemical CPAI.
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Synthetic adrenocorticotropin 1-24 at a dose of 250 microg works well as a dynamic test."
    explanation: Describes the cosyntropin stimulation test used to demonstrate subnormal cortisol response in CPAI.
- name: ACTH (Adrenocorticotropic Hormone)
  presence: Increased
  context: Elevated because of loss of cortisol-mediated negative feedback on the pituitary corticotrophs; drives both CPAI hyperpigmentation and the diagnostic ACTH-cortisol mismatch.
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
    explanation: Confirms that elevated ACTH (alongside elevated renin) is the diagnostic biochemical signature of CPAI.
  - reference: PMID:22066755
    reference_title: "Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressors were significantly more likely to have elevated ACTH"
    explanation: Demonstrates that ACTH elevation precedes overt CPAI and tracks loss of cortisol feedback.
  - reference: PMID:22066755
    reference_title: "Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Moderately elevated ACTH is a more useful early indicator of impending AD than 21OH-AA, PRA or peak cortisol"
    explanation: In a prospective cohort of 21-hydroxylase-antibody-positive subjects, a moderate rise in ACTH was the best early sentinel of impending overt disease, outperforming autoantibody, renin, and peak-cortisol measures in the 2 years before onset.
- name: Aldosterone
  presence: Decreased
  context: Reduced output from a damaged zona glomerulosa; key driver of hyponatremia, hyperkalemia, and orthostatic hypotension.
  evidence:
  - reference: PMID:6091953
    reference_title: "Disorders of the adrenal cortex: their effects on electrolyte metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "impaired secretion, as in Addison's disease or in congenital deficiencies of other steroid-synthesizing enzymes, leads to hypotension, sodium loss with hypovolaemia, and hyperkalaemia"
    explanation: Documents the consequences of reduced mineralocorticoid output in CPAI.
- name: Plasma Renin Activity
  presence: Increased
  context: Compensatory rise from volume depletion and absent aldosterone-mediated feedback on the renin-angiotensin-aldosterone system.
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
    explanation: Confirms elevated renin as a hallmark of CPAI alongside elevated ACTH.
- name: 21-Hydroxylase Autoantibodies
  presence: Increased
  context: Diagnostic immunological marker of autoimmune CPAI; positive in the great majority of autoimmune adrenalitis cases and can precede biochemical disease by years.
  evidence:
  - reference: PMID:22066755
    reference_title: "Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD)."
    explanation: Establishes 21-hydroxylase autoantibodies as a predictive biomarker for autoimmune CPAI.
diagnosis:
- name: ACTH (Cosyntropin) Stimulation Test
  notes: Gold-standard dynamic test; subnormal serum cortisol response to synthetic ACTH 1-24 defines biochemical adrenal insufficiency.
  diagnosis_term:
    preferred_term: ACTH (cosyntropin) stimulation test
    term:
      id: MAXO:0000604
      label: endocrine testing
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Synthetic adrenocorticotropin 1-24 at a dose of 250 microg works well as a dynamic test."
    explanation: Establishes the cosyntropin stimulation test as a reliable dynamic test for CPAI.
- name: Plasma ACTH and Renin
  notes: Elevated ACTH plus elevated renin (with low cortisol and aldosterone) confirms a primary, rather than secondary, adrenal insufficiency.
  diagnosis_term:
    preferred_term: plasma ACTH and renin measurement
    term:
      id: MAXO:0035005
      label: circulating hormone measurement
  evidence:
  - reference: PMID:16828409
    reference_title: "Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Elevated plasma levels of adrenocorticotropin and renin confirm the diagnosis."
    explanation: Documents that elevated ACTH plus renin is the confirmatory biochemical signature of CPAI.
- name: 21-Hydroxylase Antibody Testing
  notes: Identifies autoimmune etiology and can detect preclinical autoimmune CPAI.
  diagnosis_term:
    preferred_term: 21-hydroxylase autoantibody titer measurement
    term:
      id: MAXO:0020029
      label: antibody titer measurement
  evidence:
  - reference: PMID:22066755
    reference_title: "Predicting the onset of Addison's disease: ACTH, renin, cortisol and 21-hydroxylase autoantibodies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autoantibodies to 21-hydroxylase (21OH-AA) precede onset of autoimmune Addison's disease (AD)."
    explanation: Justifies use of 21OH antibody testing both to confirm autoimmune etiology and to predict overt disease.
genetic:
- name: AIRE
  association: Biallelic loss-of-function mutations cause autoimmune polyendocrine syndrome type 1 (APS-1), of which autoimmune Addison disease is a defining component.
  notes: Loss of AIRE-mediated thymic self-antigen expression breaks central T-cell tolerance, allowing autoreactive T cells against 21-hydroxylase and other adrenal antigens to escape thymic deletion.
  gene_term:
    preferred_term: AIRE
    term:
      id: hgnc:360
      label: AIRE
  evidence:
  - reference: PMID:33717087
    reference_title: "Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The autoimmune polyglandular syndrome type 1 (APS1) is caused by pathogenic variants of the autoimmune regulator (AIRE) gene"
    explanation: Confirms AIRE as the monogenic cause of APS-1, which includes autoimmune CPAI as a defining feature.
  - reference: PMID:33717087
    reference_title: "Autoimmune Addison's Disease as Part of the Autoimmune Polyglandular Syndrome Type 1: Historical Overview and Current Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "AIRE, enhances thymic self-representation and immune self-tolerance by localization to chromatin"
    explanation: Supports the mechanistic basis for the AIRE note — AIRE promotes thymic self-antigen representation and central tolerance, so its loss allows autoreactive clones (including against adrenal antigens) to escape deletion.
- name: CYP21A2
  association: Encodes steroid 21-hydroxylase, the dominant autoantigen in autoimmune CPAI and the deficient enzyme in classic congenital adrenal hyperplasia.
  notes: 21-hydroxylase autoantibodies are the immunological hallmark of autoimmune Addison disease; loss-of-function CYP21A2 variants cause CAH, a genetic cause of CPAI in children.
  gene_term:
    preferred_term: CYP21A2
    term:
      id: hgnc:2600
      label: CYP21A2
  evidence:
  - reference: PMID:30144040
    reference_title: "The potential role for infections in the pathogenesis of autoimmune Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "one major dominant self-antigen, the cytochrome P450 21-hydroxylase enzyme, which is targeted by both autoantibodies and autoreactive T cells"
    explanation: Establishes CYP21A2 (21-hydroxylase) as the dominant autoantigen in autoimmune CPAI.
- name: ABCD1
  association: Mutations cause X-linked adrenoleukodystrophy (X-ALD), in which very long chain fatty acid accumulation produces adrenal failure (often the presenting feature) and cerebral demyelination.
  notes: X-ALD should be excluded in any male presenting with otherwise unexplained CPAI, particularly with neurological features.
  gene_term:
    preferred_term: ABCD1
    term:
      id: hgnc:61
      label: ABCD1
- name: MC2R
  association: Loss-of-function mutations cause familial glucocorticoid deficiency type 1 (ACTH resistance) with isolated glucocorticoid deficiency and preserved mineralocorticoid function.
  notes: A monogenic cause of CPAI in children; aldosterone is preserved so electrolyte abnormalities are usually absent.
  gene_term:
    preferred_term: MC2R
    term:
      id: hgnc:6930
      label: MC2R
- name: CTLA4
  association: Risk variants in this immune checkpoint regulator increase susceptibility to autoimmune CPAI by reducing T-cell inhibition.
  notes: Pharmacological CTLA-4 blockade (ipilimumab and related checkpoint inhibitors) can also precipitate immune-related adrenalitis.
  gene_term:
    preferred_term: CTLA4
    term:
      id: hgnc:2505
      label: CTLA4
  evidence:
  - reference: PMID:26204230
    reference_title: "CTLA-4 as a genetic determinant in autoimmune Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The G-allele of SNP rs231775 in CTLA-4 is associated with AAD in Norwegian patients (odds ratio (OR)=1.35 (confidence interval (CI) 1.10-1.66), P=0.004)"
    explanation: Demonstrates CTLA4 as a genetic susceptibility locus for autoimmune CPAI.
- name: HLA-DR3-DQ2 / HLA-DR4-DQ8
  association: Major histocompatibility complex class II haplotypes are the strongest non-monogenic genetic risk factor for autoimmune CPAI.
  notes: Altered peptide presentation to CD4+ T cells underlies the autoimmune susceptibility shared with type 1 diabetes and other organ-specific autoimmunity.
  evidence:
  - reference: PMID:26204230
    reference_title: "CTLA-4 as a genetic determinant in autoimmune Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the strongest genomic association with AAD has been with alleles at the HLA locus, DR3-DQ2 and DR4"
    explanation: Confirms the HLA class II haplotypes DR3-DQ2 and DR4 as the strongest genomic risk association in autoimmune Addison disease.
environmental:
- name: Tuberculosis and other adrenal infections
  notes: Adrenal tuberculosis was historically the leading worldwide cause of CPAI and remains important in high-incidence regions; disseminated fungal infections (histoplasmosis, paracoccidioidomycosis) and HIV-related opportunistic infections also cause adrenal destruction.
  evidence:
  - reference: PMID:27210825
    reference_title: "Is Adrenal Insufficiency a Rare Disease?"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In industrialized countries, autoimmune adrenalitis accounts for the majority of cases of PAI."
    explanation: Sets the geographic context — autoimmunity dominates in industrialized settings, infectious causes elsewhere remain important.
  exposure_term:
    preferred_term: Infectious agent exposure
    term:
      id: ECTO:3000000
      label: exposure to organism
- name: Glucocorticoid Therapy Withdrawal (precipitant of crisis)
  notes: Iatrogenic suppression of the HPA axis by chronic glucocorticoid therapy is a major cause of central adrenal insufficiency; in patients with established CPAI, abrupt withdrawal or failure to stress-dose precipitates adrenal crisis.
treatments:
- name: Glucocorticoid Replacement
  description: Lifelong glucocorticoid replacement with hydrocortisone (preferred) or other glucocorticoids, divided across the day to approximate physiological cortisol secretion.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cortisol
      term:
        id: CHEBI:17650
        label: cortisol
  evidence:
  - reference: PMID:24755997
    reference_title: "Current and emerging therapies for Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone."
    explanation: Documents hydrocortisone (cortisol) as the standard glucocorticoid for CPAI replacement therapy.
- name: Mineralocorticoid Replacement
  description: Lifelong fludrocortisone to replace aldosterone, titrated to blood pressure, electrolytes, and plasma renin activity.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: fludrocortisone
      term:
        id: CHEBI:50885
        label: fludrocortisone
  evidence:
  - reference: PMID:24755997
    reference_title: "Current and emerging therapies for Addison's disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Conventional steroid replacement for Addison's disease consists of twice or three-times daily oral hydrocortisone and once-daily fludrocortisone."
    explanation: Documents fludrocortisone as the standard mineralocorticoid replacement in CPAI.
- name: Stress-Dose Glucocorticoid Adjustment
  description: Two- to three-fold increase in glucocorticoid dose during intercurrent illness, surgery, or trauma to prevent adrenal crisis; parenteral hydrocortisone for severe stress, inability to take oral medication, or impending crisis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cortisol
      term:
        id: CHEBI:17650
        label: cortisol
- name: Patient Education and Emergency Identification
  description: Patient and family education on stress dosing, injectable emergency hydrocortisone kits, and medical alert identification are core to preventing fatal adrenal crisis.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  evidence:
  - reference: PMID:31321757
    reference_title: "Epidemiology, pathogenesis, and diagnosis of Addison's disease in adults."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD"
    explanation: Reinforces ongoing patient education as a lifesaving non-pharmacological intervention in CPAI.
notes: >-
  CPAI (Addison disease, when chronic) requires lifelong hormone replacement
  and stress-dose adjustments. Adrenal crisis remains a major cause of
  preventable mortality. Etiology should be defined at diagnosis
  (21-hydroxylase antibodies; very long chain fatty acids in males; imaging
  for infectious or infiltrative disease; APS-1/APS-2 evaluation) because it
  governs surveillance for additional autoimmune disease, cerebral X-ALD
  monitoring, and reproductive planning.
datasets: []