Primary Hyperaldosteronism

Slide 1 · Primary Hyperaldosteronism

Adrenal pathology • mechanisms, morphology, and clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish autonomous aldosterone secretion from renin-driven excess.

Recognize the major causes and characteristic adrenal morphology.

Link mineralocorticoid action to hypertension and variable hypokalemia.

Expla diagnostic sequence and cause-directed management.

Slide 3 · Adrenal cortex: Functional zones

Capsule

Zona glomerulosa — aldosterone

Zona fasciculata — cortisol

Zona reticularis — sex steroids

Medulla — catecholamines

Slide 4 · Zona glomerulosa is the normal aldosterone source

The narrow subcapsular zona glomerulosa generates mineralocorticoids.

The wider zona fasciculata produces mainly glucocorticoids.

Zona reticularis contributes to adrenal sex steroid production.

Different cortical disorders reflect excessive secretion of different hormone classes.

Slide 5 · Hyperaldosteronism: The unifying definition

Chronic excess secretion of the mineralocorticoid aldosterone.

The category includes primary adrenal and secondary extra-adrenal causes.

Interpretation requires considering aldosterone together with the renin response.

Slide 6 · Primary versus secondary excess

Primary (adrenal autonomous)

Secondary (renin driven)

Aldosterone production escapes normal regulation.

Renin–angiotensin activity is suppressed.

Hypertension is a typical downstream result.

Aldosterone is secreted after RAAS stimulation.

Plasma renin is increased.

Renal perfusion or effective volume often provides the trigger.

Slide 7 · Normal renin-driven aldosterone response

Reduced renal perfusion / effective volume

Renin–angiotensin activation

Increased aldosterone release

Renal Na⁺ retention

Physiologic compensation is initiated outside the adrenal gland.

Slide 8 · Autonomous secretion breaks feedback control

Primary adrenal aldosterone excess

Renal Na⁺ and water retention

Expanded extracellular volume

Suppressed plasma renin

An elevated aldosterone-to-renin relationship follows from excess hormone despite renin suppression.

Slide 9 · Three major causes of primary disease

Cause

Approximate textbook share

Key lesion

Bilateral idiopathic hyperaldosteronism

~60%

Bilateral glomerulosa hyperplasia

Aldosterone-producing adenoma

~35%

Solitary functioning cortical neoplasm

Familial hyperaldosteronism

<5%

Inherited regulatory abnormalities

Adrenocortical carcinoma

Rare

Malignant cortical neoplasm

Slide 10 · Bilateral idiopathic disease predominates

About 60% of primary hyperaldosteronism in the cited textbook.

Usually sporadic rather than familial.

Involves hyperplasia of aldosterone-secreting zona glomerulosa cells.

Both adrenal glands are affected.

Slide 11 · Bilateral disease is not a single adenoma

Bilateral zona glomerulosa hyperplasia

Diffuse + focal glomerulosa expansion

Simplified schematic — not actual gross or microscopic pathology

Slide 12 · Clinical tendency in bilateral disease

Affected individuals tend to be older than patients with adenomas.

Hypertension may be less severe than in primary adrenal neoplasms.

These are group-level tendencies, not reliable individual diagnostic criteria.

Slide 13 · Hyperplasia: Diffuse and focal expansion

Proliferating cells resemble those of normal zona glomerulosa.

Both diffuse and focal cortical hyperplasia may be present.

The degree of gland enlargement can be subtle.

Slide 14 · Wedge-shaped cortical hyperplasia

Subcapsular zona glomerulosa

Wedge-shaped expansion toward cortex center

May create only subtle enlargement

Pathology must exclude a discrete aldosterone-producing adenoma before labeling hyperplasia.

Slide 15 · Aldosterone-producing adenoma: Conn syndrome

A solitary aldosterone-secreting adrenocortical adenoma causes Conn syndrome.

It accounts for approximately 35% of primary cases in the source.

Adrenocortical carcinoma is an uncommon alternative neoplastic cause.

Slide 16 · Adenoma: Who typically presents?

Most often observed in mid-adult life.

The morphology discussion places most patients in their 30s and 40s.

The source describes a female-to-male ratio of approximately 2:1.

Demographic clues support context but do not establish a diagnosis.

Slide 17 · Gross appearance of aldosterone-producing adenoma

Usually solitary and well circumscribed.

Typically small, with a diameter under 2 cm.

Bright yellow cut surface corresponds to lipid-rich cortical cells.

Slide 18 · Small lesions can be hard to localize

Adenomas may be buried within adrenal parenchyma.

The gland may not be visibly enlarged.

Small dimensions and intraglandular position complicate imaging localization.

The source reports a left-sided predominance.

Slide 19 · Focal adenoma versus bilateral cortical change

Aldosterone-producing adenoma

Bilateral zona glomerulosa hyperplasia

Simplified schematic — not actual gross or microscopic pathology

Slide 20 · Adenoma cells are lipid rich

Microscopy typically shows uniform cortical cells with abundant lipid.

Their morphology resembles zona fasciculata cells.

This is noteworthy because normal aldosterone arises from zona glomerulosa.

Slide 21 · Nuclear atypia in a benign adenoma

Most neoplastic cells are uniform in size and shape.

Modest nuclear or cellular pleomorphism can occur.

These limited cytologic changes should not be interpreted as carcinoma on their own.

Slide 22 · Spironolactone bodies: Treatment-related finding

Aldosterone-producing adenoma

Exposure to spironolactone

Eosinophilic laminated cytoplasmic inclusions

Spironolactone bodies are described in treated adenomas; They are not an untreated-lesion requirement.

Slide 23 · Adjacent cortex is generally preserved

Aldosterone-producing adenomas usually do not suppress corticotropin secretion.

Therefore, the nearby adrenal cortex is not characteristically atrophic.

The opposite adrenal cortex also is not typically atrophic.

Slide 24 · Functional reason for preserved adrenal cortex

Autonomous aldosterone secretion

No usual suppression of pituitary corticotropin

Continuing trophic input to non-neoplastic cortex

No expected cortical atrophy

Contrast conceptually with ACTH suppression in cortisol-producing cortical lesions.

Slide 25 · Morphology-based differential

Feature

Adenoma / Conn syndrome

Bilateral idiopathic hyperplasia

Distribution

Solitary focal lesion

Bilateral diffuse/focal change

Gross pattern

Small, circumscribed, yellow nodule

Often only subtly enlarged

Dominant cells

Lipid-rich cells resembling fasciculata

Cells resembling glomerulosa

Surrounding cortex

No typical atrophy

Hyperplastic glomerulosa

Slide 26 · Neoplasia is not always benign

Most neoplastic primary hyperaldosteronism reflects an adenoma.

Rare cases arise from adrenocortical carcinoma.

Neoplasia and bilateral idiopathic hyperplasia are distinct etiologic categories.

Slide 27 · Genetic findings in aldosterone-producing adenomas

Somatic mutations define a molecular subset of aldosterone-producing adenomas.

KCNJ5 mutations in up to 50% of adenomas.

The mechanism links ion-channel dysfunction to autonomous hormone synthesis.

Slide 28 · KCNJ5 encodes the GIRK4 channel

KCNJ5 codes for a potassium ion-channel protein known as GIRK4.

The channel is expressed in cells of the zona glomerulosa.

Mutations can alter channel ion selectivity.

Slide 29 · Normal channel versus mutated channel

Normal GIRK4/KCNJ5 channel

Mutated GIRK4/KCNJ5

Potassium-selective channel

Maintains normal ionic selectivity

Loss of K⁺ selectivity

Na⁺ influx → persistent depolarization

Slide 30 · Mutation permits abnormal sodium influx

KCNJ5 mutation

Loss of K⁺ channel selectivity

Nonspecific Na⁺ influx

Chronic cell depolarization

Abnormal cation flux provides a cell-autonomous stimulus in the aldosterone-producing neoplasm.

Slide 31 · Depolarization activates aldosterone synthesis

Persistent depolarization

Calcium-dependent signaling

Activation of aldosterone synthase

Autonomous aldosterone output

The described calcium-linked mechanism explains secretion despite suppressed systemic renin.

Slide 32 · Integrating the adenoma molecular pathway

Mutant GIRK4 is not simply an overactive normal potassium channel.

The important defect is loss of potassium selectivity.

Ion influx and membrane voltage changes drive synthesis.

KCNJ5 / GIRK4 defect

Na⁺ influx

Depolarization

Aldosterone synthase activation

Slide 33 · Familial primary hyperaldosteronism is uncommon

Familial forms account for fewer than 5% of cases.

Four distinct subtypes, FH-I through FH-IV, are described.

FH-I is the most common familial subtype in this textbook.

Slide 34 · FH-I is glucocorticoid-remediable aldosteronism

FH-I reflects altered regulatory control of aldosterone synthesis.

Corticotropin becomes a major stimulus for aldosterone synthase expression.

The molecular defect differs from the somatic KCNJ5 mechanism.

Slide 35 · FH-I: A chimeric regulatory arrangement

CYP11B1 promoter

ACTH responsive

CYP11B2 gene

Aldosterone synthase

Chimeric regulatory unit

ACTH → aldosterone synthase

FH-I: Chromosome 8 rearrangement

Schematic gene regulatory arrangement; Not a genomic breakpoint map

Slide 36 · CYP11B1 and CYP11B2 have different roles

CYP11B1 promoter

CYP11B2 coding region

Provides a corticotropin-responsive regulatory element.

Abnormally controls CYP11B2 after the rearrangement.

Encodes aldosterone synthase.

Catalyzes the final step of aldosterone biosynthesis.

Slide 37 · FH-I mechanism links ACTH to aldosterone

Chromosome 8 rearrangement

CYP11B1 promoter drives CYP11B2

Corticotropin stimulation

Excess aldosterone synthase

The gene rearrangement changes regulation, not the identity of aldosterone as the secreted steroid.

Slide 38 · Sporadic adenoma versus FH-I

Dimension

Aldosterone-producing adenoma

Familial hyperaldosteronism I

Principal lesion

Solitary functional neoplasm

Hereditary regulatory disorder

Molecular model highlighted

Somatic KCNJ5 channel mutation in a subset

CYP11B1/CYP11B2 chimeric gene

Proximal signal

Abnormal cation flux / depolarization

Corticotropin-responsive promoter

Slide 39 · Secondary hyperaldosteronism: Renin rises

Adrenal secretion occurs after physiologic renin–angiotensin activation.

Plasma renin is elevated rather than suppressed.

The initiating problem is outside the adrenal gland.

Slide 40 · Reduced renal perfusion can stimulate RAAS

Renal artery stenosis or arteriolar nephrosclerosis

Reduced renal perfusion

RAAS activation

Secondary aldosterone excess

These are examples of secondary rather than autonomous adrenal hypersecretion.

Slide 41 · Edema states can increase aldosterone

Congestive heart failure is one textbook example.

Cirrhosis and nephrotic syndrome are additional examples.

The relevant signal is arterial underfilling or hypovolemia associated with edema.

Slide 42 · Pregnancy is another secondary setting

Pregnancy

Estrogen increases renin substrate

RAAS-related activation

Increased aldosterone secretion

A pregnancy-associated aldosterone rise does not itself imply primary adrenal autonomy.

Slide 43 · Primary versus secondary: Laboratory logic

Finding

Primary hyperaldosteronism

Secondary hyperaldosteronism

Aldosterone

Increased

Increased

Plasma renin

Suppressed / low

Increased

Dominant mechanism

Autonomous adrenal secretion

Physiologic RAAS drive

Illustrative source

Adenoma or bilateral hyperplasia

Renal hypoperfusion or effective volume loss

Slide 44 · Renal mineralocorticoid receptor mediates effects

Excess aldosterone acts on renal mineralocorticoid receptors.

The principal relevant effects involve sodium reabsorption and potassium excretion.

Extracellular water follows retained sodium.

Slide 45 · Direction of renal ion transport

Blood / extracellular fluid

Renal tubular lumen

Na⁺ reabsorption

K⁺ secretion / urinary loss

Aldosterone → MR activation

Schematic transport directions — not a renal micrograph

Slide 46 · Sodium retention expands extracellular volume

Elevated aldosterone

Increased renal Na⁺ reabsorption

Secondary water retention

Extracellular volume expansion

The textbook links volume expansion to higher cardiac output and hypertension.

Slide 47 · Potassium is lost into urine

Elevated aldosterone

Renal potassium wasting

Reduced potassium in some patients

Potential neuromuscular symptoms

Hypokalemia is variable: Its absence must not be used to exclude primary hyperaldosteronism.

Slide 48 · One hormone, two renal consequences

Sodium / water axis

Potassium axis

Increased sodium reclamation.

Water retention expands extracellular volume.

Promotes raised blood pressure.

Increased potassium secretion into urine.

May cause hypokalemia.

Weakness and paresthesias are possible.

Slide 49 · Primary hyperaldosteronism and hypertension

Identified by Robbins as the most common cause of secondary hypertension.

Elevated blood pressure is a consequence of renal volume expansion.

The condition is potentially identifiable among patients with difficult hypertension.

Slide 50 · Resistant hypertension enriches prevalence

Prevalence increases with the severity of hypertension.

Some cited studies report 20% or more among treatment-resistant hypertension.

This is a context-specific textbook estimate, not a universal prevalence.

Slide 51 · Long-term pressure burden affects the heart

Chronic aldosterone-associated hypertension

Cardiovascular compromise

Left ventricular hypertrophy

Reduced diastolic volumes

The syndrome has consequences beyond a single abnormal blood pressure measurement.

Slide 52 · Clinical complications extend beyond the heart

Increased adverse cardiovascular events.

Stroke is among the associated adverse outcomes.

Myocardial infarction is another noted outcome.

Early recognition provides an opportunity to target the hormonal cause.

Slide 53 · Hypokalemia is not obligatory

Some patients have primary hyperaldosteronism without low serum potassium.

Renin suppression and inappropriate aldosterone are more fundamental to the syndrome.

Using hypokalemia as a mandatory entry criterion would miss cases.

Slide 54 · When potassium falls: Clinical effects

Neuromuscular weakness can occur.

Paresthesias are a characteristic reported manifestation.

Visual disturbances are also listed in the source.

Symptoms are not exclusive to this disorder.

Slide 55 · Clinical pattern: Connect the abnormalities

Autonomous adrenal production

Low renin + aldosterone excess

Hypertension ± hypokalemia

Cardiovascular / neuromuscular burden

A single laboratory measurement should be interpreted in its physiological and clinical setting.

Slide 56 · Aldosterone-to-renin ratio: Screening principle

Compare the plasma aldosterone concentration with plasma renin activity.

The ratio is elevated in typical primary hyperaldosteronism.

The relationship is informative because renin is suppressed despite excessive aldosterone.

Slide 57 · Why a positive ratio is not definitive

Other disorders and circumstances can alter aldosterone and renin measurements.

A positive screening ratio requires clinical interpretation.

Confirmatory suppression testing after positive screening.

Slide 58 · Aldosterone suppression as confirmation

Clinical suspicion

Elevated aldosterone-to-renin ratio

Aldosterone suppression test

Integrated etiologic assessment

Shown here is the textbook conceptual sequence; Assay-specific cutoffs and protocols are not provided.

Slide 59 · Etiology matters after biochemical recognition

Bilateral glomerulosa hyperplasia and a functional adenoma have different treatments.

A small, buried adenoma may not produce obvious adrenal enlargement.

Morphology and hormone physiology should be interpreted together.

Slide 60 · Management of aldosterone-producing adenoma

Aldosterone-producing adenoma

Local adrenal source of secretion

Surgical excision

The therapeutic approach targets a discrete functional cortical lesion.

Slide 61 · Management of bilateral hyperplasia

Surgical removal of a single focal adenoma does not address bilateral hyperplasia.

The source favors medical treatment with mineralocorticoid receptor antagonists.

Spironolactone and eplerenone are named examples.

Potassium-sparing diuretics have also been used.

Slide 62 · Treat the underlying cause in secondary disease

Secondary hyperaldosteronism reflects heightened RAAS activity.

Management therefore targets the driving disorder rather than an autonomous adrenal lesion.

Examples include renal perfusion deficits and edematous systemic states.

Slide 63 · Treatment follows etiologic classification

Etiology

Pathologic mechanism

Textbook treatment principle

Solitary aldosterone-producing adenoma

Autonomous focal cortical secretion

Surgical excision

Bilateral idiopathic hyperplasia

Bilateral aldosterone-secreting hyperplasia

Mineralocorticoid receptor blockade

Secondary hyperaldosteronism

Extra-adrenal RAAS activation

Treat underlying disorder

Slide 64 · Case 1: Hypertension without hypokalemia

A patient has persistent hypertension and a non-low potassium concentration. Plasma aldosterone is inappropriately elevated while plasma renin is suppressed. Does normal potassium exclude primary hyperaldosteronism?

Explain the likely pathological mechanism.

Slide 65 · Case 1: Interpretation

No: The source explicitly states that hypokalemia is not mandatory.

The renin-suppressed hormonal pattern supports autonomous aldosterone excess.

Aldosterone-to-renin screening and appropriate subsequent evaluation are indicated conceptually.

Slide 66 · Case 2: Small yellow adrenal nodule

A solitary, small, well-circumscribed yellow cortical lesion is found in a patient with autonomous aldosterone excess. Microscopy shows uniform lipid-rich cells resembling fasciculata. Which primary etiologic subtype best fits?

Explain the likely pathological mechanism.

Slide 67 · Case 2: Interpretation

Aldosterone-producing adenoma (Conn syndrome) fits the combined morphology and hormonal setting.

Gross yellow color reflects abundant cortical cell lipid.

Nearby cortical atrophy is not a typical expectation for this adenoma.

Slide 68 · Case 3: Aldosterone and renin both rise

A patient with decreased renal perfusion has increased plasma renin activity and increased aldosterone secretion. Is the abnormality consistent with primary adrenal autonomy?

Explain the likely pathological mechanism.

Slide 69 · Case 3: Interpretation

The pattern is more consistent with secondary hyperaldosteronism.

Renin–angiotensin stimulation is the proposed physiological driver.

The initiating cause is extra-adrenal and management targets that cause.

Slide 70 · Integrated diagnostic distinctions

Question

Typical primary answer

Typical secondary answer

What initiates aldosterone excess?

Adrenal autonomous secretion

Extra-adrenal renin stimulus

What happens to renin?

Suppressed

Increased

What lesion might be present?

Adenoma / bilateral hyperplasia

No necessary autonomous adrenal lesion

How is treatment directed?

Adrenal subtype

Underlying RAAS trigger

Slide 71 · Core messages to retain

Primary hyperaldosteronism couples aldosterone excess with suppressed renin.

Bilateral hyperplasia is more frequent than a solitary adenoma.

Adenomas and bilateral hyperplasia differ in morphology and treatment.

KCNJ5 and CYP11B1/CYP11B2 illustrate distinct molecular routes.

Hypertension is central; Hypokalemia is optional.

Slide 72 · Reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026) · Chapter 24, The Endocrine System

“Primary Hyperaldosteronism,” pp. 1015–1017

Lecture content follows the supplied textbook extraction; diagnostic protocols and current guideline-specific cutoffs are not reproduced.