⭐️Primary Hyperaldosteronism (Conn)

Question 1

What is Conn’s Syndrome?

Answer 1

Characterized by HPT, ↓K and metabolic alkalosis due to excessive aldosterone secretion from zona glomerulosa of adrenal cortex

Question 2

Classification of Hyperaldosteronism

Answer 2

Primary Hyperaldosteronism (PHA)

Excess aldosterone production by the adrenal gland independent of renin and angiotensin II and sodium status.

• Aldosterone-producing adenoma (APA) (30%)
• Bilateral idiopathic hyperplasia (IHA) (60%)
• Primary (unilateral) adrenal hyperplasia (2%)
• Aldosterone-producing adrenocortical carcinoma (<1%)
• Familial hyperaldosteronism - Glucocorticoid-remediable aldosteronism (FH type I - IV) <1%
• Ectopic aldosterone-producing adenoma
• Aldosterone-producing carcinoma <0.1%

Secondary Hyperaldosteronism (SHA)

Excess stimulation of the RAAS.

• Renin-producing tumor,
• Renal artery stenosis,
• Edematous disorders (left ventricular heart failure, pregnancy, cor-pulmonale, or cirrhosis with ascites).

Pseudo Hyperaldosteronism

• Genetic disorders (e.g. Apparent mineralocorticoid excess syndrome, Liddle’s syndrome, and types of Congenital adrenal hyperplasia),
• Acquired conditions (e.g. Cushing’s syndrome and mineralocorticoid-producing adrenal tumors),
• Metabolic disorders,
• Dietary imbalances - excessive consumption of licorice.

Question 3

Epidemiology

Answer 3

• Conn’s tumor : F:M = 2:1.
• 3rd – 5th decade (young)
• IHA : F:M = same. Occurs later.
• 70% unilateral
• Left > Right

Question 4

Pathophysiology of Conn’s Syndrome

Answer 4

Primary aldosteronism → ↑ aldosterone → DCT →

• ↑ Na+ absorption ↔ K+ (Hypokalemia) - Principle cells collecting duct.
• H2O reabsorption (Volume expansion & HTN)
• H+ ↔ HCO3 (metabolic alkalosis) - α intercalated cells collecting duct
• ↑ volume → stretch of cardiac muscle → release ANP → ↑ Na & H2O excretion (Se Na remain same). Also ↓ Renin production.

Question 5

Presentation of patient ( History)

Answer 5

History

• HTN (diastolic HTN, decreased pulse pressure). Usually resistant to treatment but rarely malignant HPT.
• ↓ K : Proximal muscle Weakness (squatting shows weakness thigh muscle), fatigue, intermittent paralysis, muscle cramps, arrhythmia, DM due to impaired insulin secretion, Abdominal distension, paralytic ileus, polyuria, polydipsia.
• Need TRO pheochromocytoma which also present with HPT.
• Need TRO familial disorder like NF (associated with RA stenosis), MEN2, VHL.

Question 6

Presentation of patient ( Physical examination)

Answer 6

Physical

• General examination : Dysmorphic features, NF, Cushing’s, Pheochromocytoma & MEN2
• Neck : Thyroid mass
• Abdomen : Adrenal mass, ascites
• Neurology : Signs of HPT complication (stroke, visual acuity), ↓K symptoms
• HTN related complications - CCF, Atrial Fibrillation, Stroke, HTN retinopathy

Question 7

Investigation for primary Hyperaldosteroninsm ( Conn)

Answer 7

Rule of thumb, all endocrine tumour investigation is divided into:

Screening test 1 test:
- Aldosterone : Renin Ratio (ARR)

Confirmation test (Suppression test) 5 test
- Saline Infusion test
- Oral Salt Loading test
- Postural Test
- Captopril Challenge test
- Fludrocortisone Challenge Test (FST)

Localization 3 test
- CT Scan
- Adrenal Venous Sampling
- SPECT/CT

Question 8

Who to screen for Primary Aldosteronism

Answer 8

• Patients with sustained blood pressure above 150/100 mmHg, grade 2 and grade 3 HTN
• Patients with resistant HTN (blood pressure not controlled by 3 conventional drugs including a diuretic) or controlled BP (<140/90 mmHg) on 4 or more antihypertensive drugs
• Patients with HTN and spontaneous or diuretic induced hypokalemia
• Patients with an adrenal incidentaloma
• Patients with sleep apnea or with a family history of early-onset HTN or CVA at a young age (<40 years)
• All 1st-degree relatives of patients with PA.

Question 9

Screening Tests for Conn’s Syndrome

Answer 9

Prerequisite:

• Normal salt intake, minimum 5g NaCl/day,
• Correct hypokalemia (key regulator of aldosterone production),
• Upright position for at least 2 hrs,
• To allow activation of the RAAS, blood samples withdrawn in morning when patients have been out of bed for ≥2 hrs.
• Stop anti HPT that do not interfere with the ARR (β-blockers, clonidine, methyldopa, NSAIDS, ACE i, ARB’s and calcium blockers) - 2 weeks before.
• Stop those that interfere with ARR – (spironolactone & diuretics, β - blockers) - 4 - 6 weeks before.▪

ARR (Aldosterone : Renin Ratio)

• > 20 - 40 = 1⁰ Aldosteronism
• < 30 = 2⁰ Aldosteronism

PAC (Plasma Aldosterone Concentration) / PRA (Plasma Renin Activity)

Question 10

Confirmation test for Conn’s Syndrome

Answer 10

Principle → lack of suppression of aldosterone excretion with intravascular expansion is indicative of aldosterone production. Correct K + K supplement during testing. Cortisol levels should be monitored during confirmatory testing → ↑ cortisol indicates inappropriate stress at the end of the test.

Saline Infusion Test

• Supine position for 1h, Infuse 2L 0.9% NS over 4 h. Measure Renin, Aldosterone, K at 0 & 4h.
• Serum aldosterone (Plasma Aldosterone concentrationn / PAC):
  
  • < 5 ng/dL - Conn’s unlikely;
  • 5 – 10 (140–280 pmol/L) - borderline,
  • > 10 - diagnostic of Conn’s.

Oral Salt Loading Test

• Oral Na loading 6g/day for 3 days. From 3rd day morning to 4th day morning take 24-hour urine Na & aldosterone.
• 24H urine Na >200mmol/day indicate adequate Na loading.
• 24H urine aldosterone < 10 mcg/d unlikely Conn’s.
• 24H urine aldosterone > 12 mcg/d diagnostic of Conn’s.

Postural Test

• After overnight recumbency. Baseline cortisol, aldosterone & PRA → walk 2 hrs → repeat bloods
• Result: Conn’s result same.
• Bilateral idiopathic hyperplasia (IHA) – walking ↑ renin & aldosterone.
• Cortisol confirm ↑ ACTH.

Captopril challenge test

• 25–50 mg PO after sitting or standing for >1 h, circumvents potential fluid overload.
• ↓ in PAC ≤ 30% (or ARR > 200 pg/mL/ng/mL/h)

Fludrocortisone Challenge test (FST)

• Fludrocortisone 0.1mg every 6h for 4 days, with sodium and potassium supplementation. Hospitalized to ensure control of Bp and to maintain urinary sodium excretion > 3mmol/kg.
• Upright PAC > 6 ng/dL (170 pmol/L) on day 4
• PRA < 1 ng/mL/h
• Plasma cortisol < than the value.

Question 11

Localization test for Conn’s syndrome

Answer 11

Only Unilateral Conn’s benefit from surgery.

• Bilateral or Bilateral idiopathic hyperplasia (IHA) treated with spironolactone (Mineralocorticoid receptor antagonists)

CT scan
- Unilateral – Conn’s, adenoma is functional thus the opposite gland and remaining cortex of ipsilateral cortex atrophies.
- Bilateral – Bilateral idiopathic hyperplasia (IHA).
- 10-15% incidence of non-functioning adenoma with increasing age
- Able to exclude adrenocortical carcinoma (mass > 4cm)

AVS (Adrenal Venous Sampling)
- Definitive test to differentiate Conn’s from Bilateral idiopathic hyperplasia (IHA). Prerequisite same as screening. Bilateral adrenal veins catheterized.
- Indication - elderly undergoing unilateral adrenalectomy, when imaging unable to lateralize, or bilateral hyperaldosteronism with normal CT.
- Successful cannulation - Selectivity Index (SI): Adrenal vein: IVC cortisol ratio > 3.
- Result: PAC/PCC (Plasma Cortisol Concentration) > 4 with ACTH & >2 without ACTH is positive.
- Complication: Adrenal vein rupture, infarction, thrombosis, adrenal hemorrhage.

SPECT/CT (NP59 (6b-131) iodo methyl 19 Nor cholesterol scan)

• Performed with dexamethasone suppression for 5 days. Detect > 90% tumors.
• Not useful in small adenomas.

Question 12

Management of Conn’s sydrome

Answer 12

Divided into:
Medical
Surgical

Medical

• Control HPT with Mineralocorticoid Receptor Antagonist (MRA) - Spironolactone. If contraindicated: Ca blocker, α blocker.
  
  • MRA - Spironolactone starting dose is 12.5 to 25 mg daily and titrated every 2 weeks upward.
• Correct hypokalemia
• Maintain ideal body weight
• Avoid alcohol
• Regular exercise

Operative

• Access: Laparoscopic vs. Open, Posterior vs. Anterior approach.
• Unilateral adenoma - unilateral adrenalectomy, preferably laparoscopic or retroperitoneal approach.
• Bilateral - treated medically.

Postoperative

• Risk of postoperative hypoaldosteronism
  
  • Avoid K replacement. Risk of ↑K
  • Low BP. May need supplement mineralocorticoids (fludrocortisone)

Question 13

HPE of Conn’s Tumour

Answer 13

Conn’s Tumor

• Macroscopic : Unilateral, < 2cm (rarely > 2cm), golden or canary yellow appearance (due to fat laden vacuoles). No hemorrhage, necrosis. Circumscribed capsule formed from compressed cortex of gland. Generally, but not always, demarcated from the adjacent cortex by a pseudo capsule.
• Cortex next to a non functional adenoma will be normal, one near a functional one will be atrophic.

Microscopic : Lipid laden clear cells with zona glomerulosa hyperplasia.

- Bilateral idiopathic hyperplasia (IHA)
- Macroscopic : Range from hyperplasia only to macro-nodules.
- Microscopic : Bands of thickened cells in zona glomerulosa either focal or diffuse.

Question 14

Prognosis / Outcome of Conn’s Syndrome

Answer 14

• Cure rate: 70% at 1 year, Recurrence is rare.
• Normotensive: 45-98%, > 75% will have improvement in HPT if not resolution within 1 month.
• The older the patients, less likely to become normotensive due to long standing HPT with vessels wall changes & delay diagnosis (essential HTN).
• Correction of hypokalemia: almost immediately in > 95%.
• Young & Female better prognosis possibly due to protective female hormone on blood vessels.

Question 15

What is Aldosterone escape phenomenon?

Answer 15

Aldosterone escape phenomenon:
edema is typically absent despite volume expansion in primary
aldosteronism due to aldosterone escape phenomenon – volume expansion leads to increased ANP and
subsequently natriuresis by inhibition of Na reabsorption in collecting ducts; and reduced Na
reabsorption in proximal tubules (due to volume expansion0 which leads to increased delivery of urinary
Na to distal tubules and overwhelming of aldosterone-mediated reabsorption in distal tubule.