Last edited: 4/7/2023

HYPERALDOSTERONISM
Hyperaldosteronism Medical Editor: Jude Loyola

OUTLINE
I) PATHOPHYSIOLOGY II) DIAGNOSTIC APPROACH III) TREATMENT
(A) ALDOSTERONE PATHWAY (A) PLASMA ALDOSTERONE AND RENIN IV) APPENDIX
(B) ALDOSTERONE TARGET ORGANS AND EFFECTS (B) SALT SUPPRESSION TEST
V) REVIEW
(C) SECONDARY VS PRIMARY VS PSEUDO- (C) ADRENAL CT/MRI & ADRENAL VENOUS
ALDOSTERONISM SAMPLING QUESTIONS
(D) RENAL ARTERY ULTRASOUND VI) REFERENCES
(E) APPROACH TO DIAGNOSIS OF
HYPERALDOSTERONISM OR MINERALOCORTICOID
EXCESS [HARRISON’S]

I) PATHOPHYSIOLOGY
(A) ALDOSTERONE PATHWAY

Figure 1. Pathway of aldosterone synthesis.

Juxtaglomerular (JG) cells are stimulated by the following:

o Low blood volume
o Low BP or effective arterial blood volume (EABV)
o Low renal perfusion from obstruction
Renin-angiotensin-aldosterone system (RAAS) Stimulators of aldosterone production:
o JG cells release renin RAAS activation from:
o Renin cuts angiotensinogen produced by the liver to o ↓blood volume
angiotensin I (AT-I) o ↓BP or EABV
o Angiotensin I goes to the capillary endothelium o ↓renal perfusion (obstruction)
(lungs) and is converted to angiotensin II (AT-II) by ↓↓Na
the angiotensin-converting enzyme (ACE) ↑↑K
o Angiotensin II then binds to receptors in the zona
glomerulosa (adrenal gland) to produce aldosterone
Abnormal electrolyte levels stimulate aldosterone
production = ↓↓Na and ↑↑K
o HypoNa or hyper K do NOT have a profound trigger
to produce massive aldosterone
Aldosterone: helps reabsorb Na and excrete K

Hyperaldosteronism ENDOCRINE PATHOLOGY: Note #8. 1 of 7

 (B) ALDOSTERONE TARGET ORGANS AND EFFECTS

Figure 2. Effects of hyperaldosteronism in the different systems.

Hyperaldosteronism comes from either of the following:
o ↑adrenal function OR
o ↑renin-ATII activity
(1) Renal (3) CVS
Aldosterone is lipophilic → binds to intracellular receptors Theoretically, hyper NA should ↑H2O retention → ↑blood
in the DCT (principal cell and intercalated cell) volume → ↑blood pressure
o ↑BV → ↑preload → ↑SV and CO → ↑BP
(i) Principal Cells
↑BP may be seen as secondary hypertension
↑Na-K ATPase activity = ↑K into the cell AND ↑Na out of o Hypertension that is resistant to multiple
the cell antihypertensives
↑Na pump into the apical membrane = ↑Na into the cell  Similar to Cushing’s disease
AND ↑K excretion out of the cell
Overall effect:
o ↑↑↑Na in the serum (hypernatremia) → polydipsia Feature of hyperaldosteronism:
(see CNS) Polydipsia
o ↑↑↑K excreted into the urine = ↓↓↓K in the serum o ↑↑Na → (+) ADH → ↑thirst
(hypokalemia) → polyuria (see CNS) Polyuria
o ↓↓K → (-) ADH to V2-R → (-) aquaporin synthesis
(ii) Intercalated Cells
→ ↑H2O excretion
↑H+ excretion and ↑HCO3- reabsorption = ↓serum H+ Secondary hypertension
and ↑serum HCO3- → metabolic alkalosis o ↑↑Na → ↑H2O retention → ↑BV → ↑BP
o Modified Henderson-Hasselbach: pH =
Metabolic alkalosis
[HCO3-]/[pCO2]
o ↑HCO3- reabsorption in the intercalated cells of
 ↑HCO3- → ↑pH
the DCT
(2) CNS
Hypernatremia induced by aldosterone

Hypokalemia → (-) ADH effect at the V2-receptors

o Recall: ADH binds to V2-receptors

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 (C) SECONDARY VS PRIMARY VS PSEUDO-ALDOSTERONISM
(1) Secondary Hyperaldosteronism
↓renin, ↓AT-II, ↑aldosterone
Tumor or hyperplasia of the adrenal gland, particularly the
zona glomerulosa → ↑↑↑aldosterone
Causes:
o Adenoma (unilateral)
 Only found on one kidney
 AKA Conn syndrome
o Hyperplasia (bilateral)
o Carcinoma (>4 cm)
 Least likely
↑↑↑aldosterone → negative feedback to the JG cells →
↓↓renin

(3) Pseudo-hyperaldosteronism

Figure 3. Causes of secondary hyperaldosteronism.

↑Renin and ↑AT-II from:
o Obstruction of blood flow
o Low BP or low EABV
o Hypovolemic state

(i) Obstruction of blood flow

Renal artery stenosis: a most common cause of
secondary hyperaldosteronism
Figure 5. Causes of pseudo-hyperaldosteronism.
(ii) ↓BP or EABV
Not perfusing the renal artery properly → ↑renin → ↑AT-II ↑androgens (CAH) or ↑cortisol (Cushing’s) acting like
→ ↑↑aldosterone aldosterone → hyper NA, hypoK, ↑BP, metabolic
Causes: alkalosis
o CHF = poor CO o CAH: congenital adrenal hyperplasia
o Cirrhosis = drop in CO in low albumin levels o Both androgens and cortisol have some
o Nephrotic syndrome = low albumin → can’t keep an mineralocorticoid properties
adequate amount of water in the blood Licorice-induced hypermineralocorticoidism
(iii) Hypovolemic state (↓BP) o Glycyrrhetic acid from the licorice acts like
aldosterone because it inhibits 11-β-hydroxysteroid
↓BV to perfuse the kidney → ↑renin → ↑AT-II → dehydrogenase enzyme type 2 [Omar et al., 2012]
↑↑aldosterone
Due to mineralocorticoid activity = ↓renin, ↓AT-II,
Causes:
↓aldosterone
o GI losses: vomiting, diarrhea
o Renal losses: diuretic use
(2) Primary Hyperaldosteronism

Figure 4. Causes of primary hyperaldosteronism.

Hyperaldosteronism ENDOCRINE PATHOLOGY: Note #8. 3 of 7

 II) DIAGNOSTIC APPROACH
(A) PLASMA ALDOSTERONE AND RENIN (B) SALT SUPPRESSION TEST

Figure 7. Salt suppression test for confirmation of primary

hyperaldosteronism.
Confirmatory test
Administer IV NaCl or PO NaCl tablets = ↑Na and check
Figure 6. Levels of renin, AT-II, aldosterone, and ARR in whether aldosterone will be suppressed
differentiating types of hyperaldosteronism.
Results
↑↑renin and ↑aldosterone = secondary
hyperaldosteronism ↓serum/urine aldosterone: normal response
o Aldosterone-renin ratio (ARR) < 10-15 ↑serum/urine aldosterone: primary hyperaldosteronism
↓renin and ↑↑aldosterone = primary hyperaldosteronism o PO NaCl → ↑urine aldosterone
o IV NaCl → ↑serum aldosterone
o ARR > 40
↓renin and ↓aldosterone = pseudo-hyperaldosteronism
o CAH, Cushing’s or ↑↑licorice

(C) ADRENAL CT/MRI & ADRENAL VENOUS SAMPLING

(1) Adrenal CT/MRI (2) Adrenal Vein Sampling
Confirms the lesion for primary hyperaldosteronism

(i) Interpretation
Bilateral lesions → Adrenal hyperplasia
Unilateral lesion → adenoma
o It’s possible for adenomas to be bilateral, but it is
RARE

Figure 10. Interpretation of results in adrenal vein sampling.

Drainage of adrenal venous blood to determine the levels
of aldosterone

(i) Interpretation
If there is bilateral ↑aldosterone = hyperplasia
If there is unilateral ↑aldosterone = adenoma
Figure 8. Bilateral adrenal lesion indicating adrenal hyperplasia.

Adrenal carcinomas:
(+) calcifications
Irregular
Size > 4 cm

Figure 9. Unilateral adrenal lesion indicating adenoma.

Figure 11. Adrenocortical carcinoma. Case courtesy of

Hani Makky Al Salam, Radiopaedia.org, rID 9449.

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 (E) APPROACH TO DIAGNOSIS OF
(D) RENAL ARTERY ULTRASOUND HYPERALDOSTERONISM OR
MINERALOCORTICOID EXCESS [HARRISON’S]

Figure 12. Renal artery US to confirm the presence of stenosis.

To confirm the presence of renal artery stenosis
o If ↓ARR + ↑↑renin + ↑aldosterone = secondary
hyperaldosteronism
May show high-velocity blood flow
Angiogram may confirm

Figure 13. Approach to diagnosis and management of

mineralocorticoid excess [Harrison's, 2018].

III) TREATMENT
Table 1. Treatment modalities in primary hyperaldosteronism.
ETIOLOGY TREATMENT

Adrenalectomy
Adrenal adenoma or carcinoma
Can be bridged with aldosterone antagonists

Aldosterone antagonist (e.g. spironolactone

and eplerenone)
Adrenal hyperplasia Blocks effects of ↑↑aldosterone

� Do NOT do adrenalectomy �

Figure 14. Treatment of primary hyperaldosteronism.

Hyperaldosteronism ENDOCRINE PATHOLOGY: Note #8. 5 of 7

 IV) APPENDIX
Table 2. Primary vs. secondary vs. pseudo-hyperaldosteronism.
Renin AT-II Aldosterone ARR Causes

Obstruction of blood flow = renal artery

stenosis
Secondary Low BP or EABV = CHF, cirrhosis, or
Hyperaldosteronism ↑↑ ↑ ↑ ↓ nephrotic syndrome
Low BV = GI losses (diarrhea or vomiting) or
renal losses (diuretics)

Adenoma = unilateral
Primary
Hyperaldosteronism ↓ ↓ ↑↑ ↑ Hyperplasia = bilateral
Carcinoma

Congenital adrenal hyperplasia (↑androgens)

Pseudo-
hyperaldosteronism ↓ ↓ ↓ = Cushing’s syndrome (↑cortisol)
Licorice-induced

Table 3. Summary of tests in hyperaldosteronism.

TEST RESULTS AND INTERPRETATION

Plasma Aldosterone and Differentiates primary, secondary and

See Table 2
Renin pseudo-hyperaldosteronism

Confirmatory test for primary ↑serum/urine aldosterone = primary

Salt Suppression Test
hyperaldosteronism hyperaldosteronism

(+) bilateral lesions = adrenal hyperplasia

Adrenal CT/MRI
(+) unilateral lesion = adenoma
Determines the etiology of primary
hyperaldosteronism
↑aldosterone bilateral = adrenal hyperplasia
Adrenal vein sampling
↑aldosterone unilateral = adenoma

(+) high-velocity blood flow; angiogram for

Renal artery ultrasound Confirmation of renal artery stenosis
confirmation

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 V) REVIEW QUESTIONS
1) Which of the following matched pairs is correct?
a) Renin: liver
b) AT-I: adrenal gland
c) ACE: lungs
d) All of the above
2) The following are potent stimulators of aldosterone
production EXCEPT:
a) Hypokalemia
b) Hypotension
c) Hypovolemia
d) Decreased perfusion to the kidneys
3) What are the effects of aldosterone in the principal
cells of the DCT?
a) ↓H+ excretion
b) ↑HCO3- reabsorption
c) ↑Na out of the apical membrane
d) ↓Na-K ATPase activity
4) The following conditions are caused by aldosterone-
induced hyponatremia EXCEPT:
a) Polydipsia
b) Polyuria
c) Hypertension
d) Metabolic alkalosis
5) What are the four features of hyperaldosteronism?
A ________________________
B ________________________
C ________________________
D ________________________
6) Fill in the blanks with either (↑ or ↓):
Renin AT-II Aldosterone
Secondary
Primary
Pseudo-
7) What type of hyperaldosteronism has a low ARR?
8) Differentiate adenoma and adrenal hyperplasia
based on the lesions in imaging.
9) What test is used to confirm primary
hyperaldosteronism?
10) Treatment for adrenal hyperplasia? Give one
example.

VI) REFERENCES
● Omar, H. R., Komarova, I., El-Ghonemi, M., Fathy, A., Rashad,
R., Abdelmalak, H. D., Yerramadha, M. R., Ali, Y., Helal, E., &
Camporesi, E. M. (2012). Licorice abuse: time to send a warning
message. Therapeutic Advances in Endocrinology and Metabolism,
3(4), 125–138. https://doi.org/10.1177/2042018812454322

● Silverstone, L. (2023, January 3). Adrenal cortical carcinoma.

Radiology Reference Article | Radiopaedia.org.
https://radiopaedia.org/articles/adrenal-cortical-carcinoma-
1?lang=us

● Loscalzo, J., Fauci, A. S., Kasper, D. L., Hauser, S. L., Longo,

D. L., &amp; Jameson, J. L. (2022). Harrison's Principles of Internal
Medicine. McGraw Hill.

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