Primary Chronic Adrenocortical Insufficiency Addison Disease

Slide 1 · Primary Chronic Adrenocortical

Insufficiency (Addison Disease)

Etiology • mechanisms • morphology • clinicopathologic interpretation

Pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish primary chronic adrenal failure from acute and secondary hypoadrenalism.

Explain autoimmune, infectious, metastatic, and genetic causes.

Recognize characteristic gland morphology and connect hormone loss with clinical findings.

Interpret adrenal crisis and the diagnostic value of corticotropin responses.

Slide 3 · Adrenal anatomy: Cortex and medulla

Capsule

Fibrous covering

Zona glomerulosa

Mineralocorticoids: Aldosterone

Zona fasciculata

Glucocorticoids: Cortisol

Zona reticularis

Adrenal sex steroids

Medulla

Catecholamines; Distinct from cortex

Slide 4 · The adrenal cortex synthesizes distinct hormone classes

Zona glomerulosa

Aldosterone

Sodium retention / potassium excretion

Zona fasciculata

Cortisol

Metabolic and stress adaptation

Zona reticularis

Sex steroids

Adrenal androgen contribution

Conceptual relationship, not a steroid-synthesis pathway

Slide 5 · Addison disease: Definition and basic lesion

Uncommon disorder caused by progressive destruction of the adrenal cortex.

Loss of steroidogenic cells compromises glucocorticoid and mineralocorticoid output.

Its manifestations appear insidiously as the functioning cortical reserve is depleted.

Slide 6 · The three patterns of adrenal insufficiency

Primary acute

Abrupt adrenal failure; Crisis

Primary chronic (Addison disease)

Progressive cortical destruction

Secondary

Insufficient pituitary corticotropin

Slide 7 · Large cortical reserve delays clinical recognition

Progressive cortical injury

Loss of functioning cortex

At least 90% compromised

Overt hormone deficiency

Symptoms generally emerge only after extensive cortical compromise.

The pace and morphology of destruction depend on etiology.

Schematic

Slide 8 · Etiologic groups: Several routes to cortical destruction

Autoimmune adrenalitis

Infections

Metastatic cancers

Genetic disorders

Additional infiltrative and hemorrhagic processes are described in the broader insufficiency differential.

All four principal groups can impair adrenal function, but their morphologic signatures differ.

Schematic

Slide 9 · Cause distribution depends on clinical setting

Autoimmune adrenalitis accounts for 80%–90% of primary insufficiency in high-income countries.

Tuberculosis remains important in low-resource settings and with active disease elsewhere.

The textbook attributes over 90% of cases to autoimmune adrenalitis, tuberculosis, AIDS, or metastatic cancer.

Interpret denominators

80%–90%:

Primary cases in high-income countries

Not a global estimate

Slide 10 · Autoimmune adrenalitis: Pathogenesis

Immune reactivity to adrenal antigens

Destruction of steroidogenic cells

Progressive cortical atrophy

Adrenocortical insufficiency

Autoimmune injury may occur alone or in autoimmune polyendocrinopathy.

Autoimmune inflammation is not necessarily prominent in every histologic section.

Schematic

Slide 11 · Autoantibodies implicate steroidogenic targets

Autoantibodies to 21-hydroxylase are detected in many patients with autoimmune adrenalitis.

The textbook also identifies reactivity against 17-hydroxylase.

These antibodies support the autoimmune nature of the disease; They do not themselves demonstrate functional reserve.

Slide 12 · Autoimmune adrenalitis: Isolated versus syndromic

Isolated adrenalitis

Polyendocrinopathy

Reported as 40% of autoimmune cases.

Clinical process is centered on adrenal insufficiency.

Evaluate the endocrine context rather than assuming other organs are affected.

Reported as 60% of autoimmune cases.

Adrenal disease coexists with other autoimmune disorders.

Patterns are grouped into APS-1, APS-2, and APS-4.

Slide 13 · APS-1: Autoimmune disease across multiple organs

Characterized by organ-specific autoimmunity affecting the adrenals and other endocrine targets.

Associated examples: Hypoparathyroidism, idiopathic hypogonadism, and pernicious anemia.

Mucocutaneous candidiasis and ectodermal abnormalities are distinctive additional features.

Slide 14 · APS-1: AIRE and loss of central immune tolerance

AIRE mutation

Reduced thymic display of tissue antigens

Impaired deletion of self-reactive T cells

Multiorgan autoimmunity

AIRE encodes an autoimmune regulator transcription factor.

The source locates AIRE on chromosome 21q22.

Schematic

Slide 15 · Why candidiasis accompanies APS-1

AIRE dysfunction

Autoantibodies to IL-17 / IL-22

Impaired Th17-linked antifungal defense

Mucocutaneous candidiasis

IL-17 and IL-22 are effector cytokines important in protection from fungal infection.

This phenotype illustrates that autoimmunity may compromise host defense.

Schematic

Slide 16 · APS-2: Adrenalitis with thyroid and pancreatic autoimmunity

Usually presents in the fourth decade of life in the source description.

Combines adrenal insufficiency with autoimmune thyroiditis, with or without type 1 diabetes.

Unlike APS-1, mucocutaneous candidiasis, ectodermal dysplasia, and autoimmune hypoparathyroidism do not develop.

Slide 17 · APS-1 versus APS-2: Clinically discriminating pattern

Feature

APS-1

APS-2

Underlying basis

AIRE mutation

Pathogenesis not understood in source

Typical cluster

Adrenal and other autoimmune targets

Adrenalitis + thyroiditis ± type 1 diabetes

Candidiasis

Characteristic

Absent as APS feature

Ectodermal change

Can occur

Not typical

Frequency

Less prevalent

More prevalent

Slide 18 · APS-4: Autoimmune overlap outside APS-1 and APS-2

Rare syndrome characterized by adrenalitis with other autoimmune manifestations.

Examples include gastritis, vitiligo, alopecia, and pernicious anemia.

By definition here, associated thyroiditis and type 1 diabetes are absent.

Slide 19 · Polyendocrinopathy syndromes: Rapid classification

Syndrome

Characteristic association

Important separator

APS-1

AIRE-related organ-specific autoimmunity

Candidiasis / ectodermal changes

APS-2

Addison disease + autoimmune thyroiditis ± T1D

No APS-1 ectodermal / candidal pattern

APS-4

Adrenalitis + other autoimmunity

Neither thyroiditis nor T1D

Slide 20 · Cancer immunotherapy can induce adrenalitis

Immune checkpoint blockade may cause primary adrenal insufficiency through autoimmune adrenalitis.

It can also cause secondary insufficiency through hypophysitis.

This distinction matters because primary and secondary states differ in aldosterone function and corticotropin levels.

Slide 21 · Tuberculous adrenalitis remains an important etiology

Tuberculosis was historically a major cause of Addison disease.

Its contribution declined with antimycobacterial therapy but remains relevant in certain settings.

Granulomatous inflammation may destroy enough cortex to cause chronic deficiency.

Slide 22 · Tuberculous Addison disease often has an extraglandular clue

Active tuberculosis elsewhere

Adrenal infection / inflammation

Granulomatous cortical destruction

Primary adrenal insufficiency

When present, adrenal tuberculosis is usually associated with infection in lungs or genitourinary tract.

Interpret adrenal findings in conjunction with the broader infectious context.

Schematic

Slide 23 · Disseminated fungi can cause adrenal insufficiency

Histoplasma capsulatum can involve the adrenal glands in disseminated fungal disease.

Coccidioides immitis is another source-listed cause.

Fungal adrenalitis may efface normal architecture through granulomatous inflammation.

Slide 24 · AIDS broadens the adrenal disease differential

Patients with AIDS may develop adrenal insufficiency through opportunistic infections.

Examples named: Cytomegalovirus and Mycobacterium avium-intracellulare.

Kaposi sarcoma is a noninfectious AIDS-associated adrenal lesion implicated in insufficiency.

Slide 25 · Infectious causes: Associate organism with context

Category

Representative causes

Pathologic implication

Tuberculosis

Mycobacterium tuberculosis

Granulomatous effacement

Systemic fungi

Histoplasma; Coccidioides

Granulomatous adrenalitis

AIDS-related infection

CMV; M. Avium-intracellulare

Infectious cortical injury

Slide 26 · Adrenal metastases: Frequent deposits, unusual failure

The adrenal glands are relatively common metastatic sites in disseminated cancer.

Adrenal hormone function is preserved in most patients despite metastatic deposits.

Clinical Addison disease develops only when enough cortex is replaced or destroyed.

Slide 27 · Primary tumors commonly implicated in adrenal metastases

Lung and breast carcinomas account for most adrenal metastases discussion.

Gastrointestinal carcinomas and malignant melanoma may also involve the adrenals.

Hematopoietic neoplasms are additional potential adrenal infiltrators.

Slide 28 · Metastasis does not automatically mean Addison disease

Tumor deposits in adrenal

Residual functioning cortex persists

Usually preserved adrenal function

Failure only with extensive loss

Distinguish radiologic adrenal involvement from physiologic adrenocortical insufficiency.

Metastatic lesions often enlarge the gland and obscure its native architecture.

Schematic

Slide 29 · Genetic categories of primary adrenal insufficiency

Congenital adrenal hypoplasia

Adrenoleukodystrophy

Rare X-linked disorder.

Mutations of NR0B1.

DAX1 transcription factor is implicated in adrenal development.

Caused by ABCD1 mutations.

Listed among genetic causes of primary insufficiency.

Neurologic details are outside this textbook unit.

Slide 30 · NR0B1-related adrenal hypoplasia: Developmental mechanism

NR0B1 mutation

DAX1 dysfunction

Abnormal adrenal development

Primary cortical insufficiency

Congenital adrenal hypoplasia differs mechanistically from acquired destruction by inflammation.

Schematic

Slide 31 · ABCD1-associated adrenoleukodystrophy

Adrenoleukodystrophy is identified as a genetic cause of adrenal insufficiency.

It is associated with mutations in the ABCD1 gene.

The disorder further in the nervous-system chapter; The present unit establishes its adrenal association.

Slide 32 · Less common destructive and infiltrative causes

Lymphoma and amyloidosis are among additional processes involving the adrenal cortex.

Sarcoidosis and hemochromatosis can also compromise adrenal tissue.

Adrenal hemorrhage is included in the broader etiology, especially for acute presentations.

Slide 33 · Etiologic reasoning starts with the type of gland lesion

Cortical destruction established

Assess autoimmune associations

Consider infection / malignancy

Account for genetic / infiltrative causes

The sequence is an educational checklist, not a validated diagnostic guideline.

Clinical setting and morphology direct the differential.

Schematic

Slide 34 · Autoimmune adrenalitis: Gross appearance

Glands are irregularly shrunken.

Atrophy may make them difficult to identify in suprarenal adipose tissue.

The gross pattern reflects extensive, long-standing loss of cortical parenchyma.

Slide 35 · Autoimmune adrenalitis: Architectural loss

Normal adrenal cortex

Autoimmune adrenalitis

Intact cortex above medulla

Collapsed, fibrotic cortex; Medulla spared

Schematic, not a histologic specimen

Slide 36 · Autoimmune adrenalitis: Microscopic pattern

Only scattered residual cortical cells remain.

Cortical architecture is replaced by a collapsed connective-tissue network.

Variable lymphoid infiltrates may be present.

Slide 37 · Medulla sparing helps localize autoimmune injury

Lymphocytes may extend from the cortex into adjacent medulla.

Despite this, the medulla is otherwise generally preserved.

Loss of cortical steroid secretion is the defining functional consequence.

Slide 38 · Different lesions produce different adrenal anatomy

Infectious granulomatous adrenalitis

Metastatic carcinoma

Tuberculous or fungal inflammation.

Granulomatous reaction obscures normal gland architecture.

Appearance reflects infection-driven inflammatory injury.

Adrenals may be enlarged.

Tumor infiltrates and replaces native architecture.

Appearance reflects space-occupying neoplastic infiltration.

Slide 39 · Morphology by etiology: Gross and microscopic distinctions

Cause

Gross pattern

Microscopic explanation

Autoimmune

Irregularly shrunken glands

Atrophic cortex; Connective tissue; Variable lymphocytes

Tuberculous / fungal

Architecture effaced

Granulomatous inflammatory destruction

Metastatic carcinoma

Often enlarged glands

Infiltrating tumor obscures cortex

Slide 40 · Morphology is a clue to the mechanism

Autoimmunity

Cortical atrophy / fibrosis

Cortical hormone deficit

Infection and neoplasia produce other distinct morphologies.

Recognize the lesion before inferring its likely cause.

Schematic

Slide 41 · Addison disease usually evolves insidiously

Long asymptomatic period reflects substantial adrenal functional reserve.

Symptoms emerge once glucocorticoid and mineralocorticoid concentrations decline substantially.

Early manifestations may be mistaken for nonspecific constitutional illness.

Slide 42 · Weakness and easy fatigability are common early complaints

Progressive weakness is a characteristic first manifestation.

Easy fatigability can initially be dismissed as nonspecific.

The clinical significance increases when accompanied by pigmentation or signs of salt loss.

Slide 43 · Gastrointestinal symptoms broaden the presentation

Anorexia and weight loss are frequent components of the syndrome.

Nausea and vomiting are also common.

Diarrhea can occur and may contribute to symptomatic volume depletion.

Slide 44 · Hyperpigmentation reflects pituitary feedback response

Cortisol decreases

Corticotropin pathway increases

POMC-derived melanocortin activity rises

Skin hyperpigmentation

POMC is the shared precursor of corticotropin and melanocyte-stimulating hormone.

This association differentiates primary from pituitary or hypothalamic insufficiency.

Schematic

Slide 45 · Hyperpigmentation: Characteristic distribution

Pigmentation may be conspicuous in sun-exposed areas.

Pressure points such as neck, elbows, knees, and knuckles are emphasized.

Its absence does not by itself exclude primary disease, but its presence is a valuable discriminator.

Slide 46 · High versus low corticotropin: Why pigmentation differs

Primary adrenal disease

Pituitary / hypothalamic disease

Adrenal cortex cannot provide adequate cortisol.

Pituitary corticotropin increases.

POMC-related pigmentation can occur.

Corticotropin output is deficient.

The stimulus for the pigmentation pathway is lacking.

Characteristic Addison hyperpigmentation is absent.

Slide 47 · Mineralocorticoid deficiency produces salt loss

Aldosterone activity decreases

Renal sodium loss increases

Potassium retention increases

Volume depletion / hypotension

The predicted serum pattern includes hyponatremia and hyperkalemia.

Renin–angiotensin–aldosterone function is typically preserved in secondary disease.

Schematic

Slide 48 · Biochemical pattern: Trace abnormalities to hormone loss

Finding

Hormonal basis

Clinical implication

Hyponatremia

Reduced mineralocorticoid effect → sodium loss

Contributes to extracellular fluid depletion

Hyperkalemia

Reduced renal potassium excretion

Suggests primary over secondary failure

Hypotension

Salt / water depletion

Hemodynamic vulnerability

Occasional hypoglycemia

Deficient cortisol → reduced gluconeogenesis

Limited metabolic stress response

Slide 49 · Volume depletion and hypotension are central consequences

Aldosterone normally supports sodium retention and potassium excretion.

With mineralocorticoid failure, sodium and water losses reduce circulating volume.

Hypotension may worsen rapidly if a stressor precipitates crisis.

Slide 50 · Cortisol deficiency impairs glucose homeostasis

Cortisol participates in gluconeogenesis.

Deficiency diminishes this metabolic support.

Hypoglycemia may occasionally occur, particularly when metabolic demands rise.

Slide 51 · Match hormone deficiency to clinical phenotype

Hormone / pathway

Characteristic change

Observed phenotype

Cortisol

Reduced gluconeogenic / stress support

Weakness; Occasional hypoglycemia

Aldosterone

Sodium loss; Potassium retention

Hypotension; Hyponatremia; Hyperkalemia

Elevated POMC / ACTH

Increased melanocortin activity

Cutaneous hyperpigmentation

Slide 52 · Stress can reveal a critically limited adrenal reserve

Infection may precipitate acute decompensation.

Trauma and surgical procedures are other textbook examples.

The already damaged cortex cannot augment steroid secretion sufficiently for increased demand.

Slide 53 · Adrenal crisis: Recognize the high-risk phenotype

Intractable vomiting and abdominal pain may dominate the presentation.

Marked hypotension and circulatory collapse can follow.

Altered consciousness or coma may occur.

Prompt corticosteroid therapy is lifesaving; Untreated collapse can be rapidly fatal.

Slide 54 · Chronic Addison disease can deteriorate into acute crisis

Chronic cortical depletion

Acute infection / trauma / surgery

Stress demand exceeds steroid reserve

Severe circulatory collapse

A potentially compensated chronic state becomes a medical emergency.

The threshold for crisis is driven by limited adrenal reserve and increased demand.

Schematic

Slide 55 · Acute adrenal crisis is not synonymous with Addison disease

Addison-associated crisis

Hemorrhagic acute failure

Chronic, progressive loss of adrenal cortex.

An acute stressor precipitates decompensation.

Pre-existing pigmentation and salt-loss findings may be clues.

Massive bilateral adrenal hemorrhage.

May accompany sepsis or disseminated intravascular coagulation.

Waterhouse–Friderichsen is the classic infective syndrome.

Slide 56 · Primary versus secondary insufficiency: Core distinctions

Feature

Primary (Addison)

Secondary (pituitary)

Anatomic defect

Adrenal cortex

Deficient corticotropin

Cortisol

Low

Low

Aldosterone

Usually deficient

Preserved / near-normal

Corticotropin

Elevated

Low or inappropriately normal

Skin pigment

May increase

No Addison pattern

Hyperkalemia

Possible / characteristic

Generally absent

Slide 57 · Corticotropin provides a mechanistic diagnostic distinction

Low cortisol recognized

Measure corticotropin

High → primary deficiency

Low / normal → central cause

A normal corticotropin concentration can be inappropriate when cortisol is deficient.

Use hormone results in clinical context, not as isolated signs.

Schematic

Slide 58 · Cosyntropin tests adrenal cortical responsiveness

Synthetic corticotropin (1–24), or cosyntropin, stimulates the adrenal cortex.

In established primary failure, cortical destruction blunts cortisol response.

In long-standing secondary failure, chronically understimulated glands can also respond poorly.

Slide 59 · Cosyntropin: Interpret time course, not just response

Established primary failure

Secondary insufficiency

Cortex is destroyed.

Response to exogenous corticotropin is reduced.

Baseline endogenous corticotropin is elevated.

Long-standing disease can also blunt response.

Recent-onset secondary disease may retain a normal cortisol response.

Baseline corticotropin is low or inappropriately normal.

Slide 60 · Clinicopathologic synthesis of suspected Addison disease

Symptoms and examination

Electrolytes / cortisol context

ACTH and adrenal responsiveness

Identify underlying etiology

Primary failure is suggested by hyperpigmentation plus aldosterone-deficiency findings.

This is a teaching synthesis, not a formal diagnostic guideline or testing protocol.

Schematic

Slide 61 · Clinical exercise: Autoimmune polyendocrinopathy

Hypothetical teaching case

A patient with progressive weakness, weight loss, skin darkening, and hypotension also has a history of autoimmune thyroiditis.

Which adrenal compartment is failing?

Which autoimmune syndrome is suggested?

What electrolyte pattern would support primary failure?

Slide 62 · Case interpretation: Adrenalitis with thyroid autoimmunity

The combination is compatible with primary adrenal insufficiency in APS-2.

Aldosterone deficiency makes hyponatremia and hyperkalemia plausible.

Pigmentation supports an adrenal rather than pituitary source of cortisol deficiency.

Slide 63 · Clinical exercise: Granulomatous adrenal destruction

Hypothetical teaching case

A patient being treated for active pulmonary tuberculosis develops fatigue, weight loss, low blood pressure, and diffuse skin darkening.

Which disease process could link lung and adrenal findings?

What adrenal histologic reaction is expected?

Why would primary adrenal function fail?

Slide 64 · Case interpretation: Tuberculous Addison disease

Tuberculous adrenalitis can accompany infection at other sites, particularly lungs.

Granulomatous inflammation can efface adrenal architecture.

Functional failure requires sufficiently extensive destruction of cortex.

Slide 65 · Clinical exercise: Bilateral adrenal metastases

Hypothetical teaching case

A patient with disseminated lung carcinoma has bilateral adrenal masses on imaging but no clear evidence of hormone deficiency.

Does metastatic adrenal involvement establish Addison disease?

What functional threshold must be crossed?

What morphologic pattern would suggest metastasis?

Slide 66 · Case interpretation: Anatomy and function differ

The adrenal glands are common metastatic sites, but functional reserve is usually retained.

Addison disease develops only if adequate cortical tissue is lost.

Neoplastic infiltration typically enlarges glands and obscures native architecture.

Slide 67 · Integrated pathogenesis–morphology–clinical matrix

Etiology

Main mechanism

Morphology

Clinical clue

Autoimmune

Steroidogenic cell injury

Small, fibrotic cortex

Other autoimmune diseases

Tuberculous / fungal

Infectious granulomatous damage

Granulomatous effacement

Infection at another site

Metastatic neoplasm

Replacement by tumor

Often enlarged / infiltrated

Disseminated cancer

Genetic

Adrenal development or ABCD1-linked disease

Not specified for all variants

Relevant inherited context

Slide 68 · Most discriminating clinicopathologic lessons

Addison disease reflects extensive destruction of adrenal cortex with combined glucocorticoid and mineralocorticoid deficiency.

Autoimmune adrenalitis predominates among primary cases in high-income countries; Infections and metastases remain important alternatives.

Cortical atrophy, granulomatous effacement, and tumor infiltration point toward different causes.

Hyperpigmentation, salt loss, elevated corticotropin, and impaired stress response localize disease to the adrenal cortex.

Slide 69 · Primary reference

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th edition (2026).

The Endocrine System: adrenal glands, adrenocortical insufficiency, and Addison disease.

Figures and diagnostic tissue photographs from the textbook are not reproduced; conceptual mechanisms and morphology are redrawn as editable schematics.