Primary Hyperaldosteronism (Conn's disease) Flashcards
Primary aldosteronism is a group of disorders characterised by ____ aldosterone secretion by ____.
Aldosterone secretion is __ of RAS, plasma ACTH and serum potassium concentration, and is __ by sodium loading.
This results in __ - hypertension and hypokalaemia due to plasma renin activity (PRA) suppression
Excessive and autonomous aldosterone secretion by one or both adrenal glands
Independent of RAS / ACTH / potassium
Non-suppressible by sodium loading
Mineralocorticoid hypertension
Aldosterone regulation in zona glomerulosa
Chromosome 8 - CYP11B1 and B2
- B1 converts 11-deoxycortisol to cortisol (timulated by ACTH)
- B2 converts corticosterone to aldosterone (stimulated by AT2 or hypokalaemia)
Classification of primary aldosteronism (5)
- Idiopathic bilateral hyperplasia of zona glomerulosa (commonest - 60-70%)
- Aldosterone producing adenoma (Conn syndrome) (30-40%)
- Primary adrenal hyperplasia (unilateral hyperplasia)
- Adrenocortical carcinoma (ACC)
- Glucocorticoid-remediable aldosteronism (GRA) - familial hyperaldosteronism type 1
> Fusion gene CYP11B1+B2 - FH-2 and FH-3 (familial hyperaldosteronism)
Prevalence of hyperaldosteronism
5 - 13% of patients with hypertension
Pathophysiology of primary aldosteronism
Normal: aldosterone acts at various sites at the kidneys
- Distal convoluted tubules: stimulates resorption of Na+ , excretion of K+ and H+
- Cortex and medulla: excretion of H+
- Excessive aldosterone action
- Hypertension: excessive Na+ -> water resorption
- Hypokalaemia: increased K+ excretion
- Metabolic alkalosis: incerased H+ excretion
- Hypomagnesaemia - RAAS negative feedback disruption
- Plasma renin suppressed
- Autonomous aldosterone production independent of stimulation - End organ damage
- Cerebral infarct/haemorrhage
- Cardiomegaly, cardiomyopathy, myocardial infarct
- Arrhythmias
- Kidney disease
Differential diagnoses of mineralocorticoid hypertension
A. Deoxycorticosterone defect
1. Congenital adrenal hyperplasia - 11B-hydroxylase deficiency, 17A-hydroxylase deficiency
2. Deoxycorticosterone-secreting adrenocortical tumours
3. Glucocorticoid receptor resistance (receptor mutations, mifepristone)
B. Hypercortisolism spillover to mineralocorticoid receptor
- Apparent mineralocorticoid excess
- Licorice and carbenoxolone ingestion
- Ectopic ACTH syndrome
C. Beta/delta subunit sodium channel mutation in collecting tubules
- Liddle’s syndrome
Clinical features of Primary Aldosteronism
- Resistant hypertension
- On multiple antihypertensives, resistant to treatment
- End organ damage: heart failure, CKD, retinopathy - Hypokalaemia
- Muscle weakness and spasms
- Easy fatigability
- Constipation (paralytic ileus)
- Paresthesia
- Diluted urine, polyuria, polydipsia, nocturia
- Ascending paralysis, respiratory distress (K < 2) - Metabolic alkalosis
- Altered mental status: confusion, headache
- Lethargy
- Seizures and coma - Peripheral oedema (more in 2’ hyperaldosteronism)
Examination
1. Focus on fasciculations and muscle weakness
2. Cardiomyopathy, arrhythmias
3. Bowel sounds and abdominal distention
4. Peripheral oedema
5. Ophthalmology examiantion - hypertensive retinopathy
Who should be investigated for hyperaldosteronism?
- Hypertension > 140/90 despite on 3 antihypertensives (resistant hypertension)
- Controlled hypertension despite on 4 antihypertensives
- Hypertension with spontaneous or diuretics induced hypokalaemia
- Hypertension with adrenal incidentaloma
- Hypertension with sleep apnoea
- Hypertension in young age
- Strong family history (1st degree) of hypertension or young stroke
Definitive investigations for hyperaldosteronism
Screening Test
1. Aldosterone-renin ratio (ARR)
- Plasma aldosterone concentration (PAC)
- Plasma renin activity (PRA)
> Collected in the morning, out of bed for at least 2 hours, and seated 5-15 minutes
Preparations for collection:
- Hypokalaemia corrected (if any)
- Sodium unrestricted diet
- Withdrawal of MRA (spironolactone, eplerenone), renin inhibitors and amiloride for 4-6 weeks
Interpretation:
ARR > 20 + PAC > 15 ng/dL
(or ARR > 30)
- 10-40% patients have borderline PAC 10-15 ng/dL
Confirmatory Tests
2. Oral sodium loading test
- Take 200mmol (6g) of oral sodium for 3 days, then collect 24H urine sample for aldosterone, sodium, creatinine
- Validity: aldosterone spectrometry, urine sodium > 200mmol/day, hypertension and hypokalaemia controlled
- Normal: volume expansion suppresses aldosterone
- Abnormal: > 12 mcg/day aldosterone
3. Saline infusion test
- IV NS 2L over 4 hours in recumbent position
- Measure PAC at baseline and end of infusion
- Normal: PAC < 5ng/dL; indeterminate 5-10
- Abnormal: PAC > 10 ng/dL
4. Captopril challenge or fludrocortisone suppression test
- Captopril: 25-50mg once, seated up 1 hour
- Fludrocort: 0.1mg + span K Q6H + high sodium diet for 4 days
- Normal: suppression of PAC > 30%
- Abnormal: PAC elevated, PRA suppressed
When is confirmatory testing not needed?
All criterias are met:
1. Spontaneous hypokalaemia
2. PRA suppressed
3. PAC > 20
How does medication affect ARR?
What medications could cause false negative results?
Medications DO NOT cause false positive result; they cause false negative results
- Inappropriately high PRA, or PAC suppression
Thus screening can be done no matter what medications patient is taking
If test is borderline or negative and hyperaldosteronism is suspected, to discontinue meds and repeat tests
Medications with false negative results
1. MRA, amiloride: elevates PRA
2. ACEi, ARBs, diuretics: elevates PRA
3. Beta blockers, alpha-2 blockers (clonidine, methyldopa): suppress PRA
4. Dihydropyridine based CCB: elevates PRA
What alternative medications can be used for blood pressure control while awaiting for confirmatory tests?
- Verapamil
- Hydralazine
- Prazosin, doxazosin, terazosin
How do you differentiate adrenal hyperplasia vs aldosterone producing adenoma (Conn) clinically?
Conn produces higher aldosterone
- More severe hypertension and biochemical abnormalities (hypoK and PAC)
- Has partial response to ACTH stimulation -> parallels circadian rhythm and diurnal variation (highest AM, lowest PM)
Adrenal hyperplasia controlled by AT2
- Increases with upright posture
Conn is surgically curable
Idiopathic adrenal hyperplasia requires chronic medical management
Further investigations for confirmed PA (to classify subtypes)
- CT or MRI adrenal glands
- Adrenal venous sampling
- Catheter to both adrenal veins and IVC
- Plasma aldosterone and serum cortisol obtained at baseline
- Inject Synacthen then repeat aldosterone and cortisol
- Normal: adrenal to IVC cortisol ratio > 10:1
- Check cortisol-corrected ratio (divide right and left adrenal vein aldosterone by cortisol)
> Cortisol-corrected aldosterone ratio >4:1 is unilateral hypersecretion
> APA higher aldosterone (1000-10,000)
When is AVS not needed?
All crieterias are met:
1. Age < 35
2. PAC marked elevated
3. Unilateral adenoma on CT
