Primary Aldosteronism (PAL)

Dr Prashant Bansal

Primary Aldosteronism

Dr. Jerome Conn first described primary aldosteronism in 1955 in a 34-year-old female presenting with hypertension and hypokalemia. Urine assays demonstrated a markedly elevated level of Mineralocorticoid activity. The patient’s condition greatly improved following the removal of a 4-cm unilateral adrenal tumour.

Prevalence: 5 - 13% of hypertensive patients

Pathophysiology RAAS is a key regulator of BP and ECF Volume Release of renin from JG cells is the rate-limiting step Under normal physiologic conditions, renin release is stimulated by

several conditions including low renal perfusion pressure, increased renal sympathetic nervous activity, and low sodium concentration sensed by the macula densa

Renin then cleaves angiotensinogen to angiotensin I, which in turn is cleaved by angiotensin-converting enzyme to angiotensin II.

Angiotensin II functions as both a potent vasoconstrictor and triggers the release of aldosterone from the zona glomerulosa. Additional regulators of aldosterone release include potassium and ACTH.

Primary aldosteronism Aldosterone secretion is independent of RAAS Plasma renin levels suppressed

Secondary hyperaldosteronism Elevated renin elevation of aldosterone

Following release from the adrenal cortex, aldosterone increases sodium reabsorption and potassium secretion in the distal nephron

Hypernatremia does not occur as sodium reabsorption is accompanied by water uptake, thereby maintaining isotonicity.

The resultant volume expansion is limited by Mineralocorticoid escape.

Mineralocorticoid escape is mediated by pressure-natriuresis, atrial natriuretic peptide secretion, and changes in electrolyte transporters in the distal nephron, which result in limiting volume expansion to approximately 1.5 kg or less

Increased plasma aldosterone and decreased plasma renin activity is common to all subtypes with primary aldosteronism

Subtypes

MC = Idiopathic hyperplasia and aldosterone-producing adenomas (95 %)

Although idiopathic hyperplasia is the most common subtype diagnosed

Prevalence of aldosterone-producing adenomas may be greater than previously thought, due to lack of routine lateralization studies

Idiopathic hyperplasia (bilateral adrenal hyperplasia) Pathophysiology unknown Both adrenal glands are responsible for increased aldosterone

production MC cause = Micronodular hyperplasia (Macronodular

hyperplasia is rare) Less severe hypertension and less likely to be Hypokalemic

compared with patients with aldosterone-producing adenomas Unilateral adrenalectomy is not therapeutic

Subtypes

Aldosterone-producing adenomas: A/w more profound hypertension and hypokalemia in

comparison with idiopathic hyperplasia, Unilateral adrenal hyperplasia

Uncommon Potentially curable with adrenalectomy following confirmation

of lateralizing aldosterone secretion

Less common causes of PAL: Adrenal cortical carcinomas

Rare <1% of cases of primary aldosteronism 2.5% to 5% of adrenal cortical carcinomas

Subtypes

Ectopic aldosterone-producing tumours Extremely rare Should raise suspicion for the presence of

Accessory adrenal tissue Adrenal heterotopia

Familial hyperaldosteronism (FH) Two types: type I and type II FH type I (Glucocorticoid-remediable aldosteronism)

Autosomal-dominant Chimeric fusion of the promoter region of the 11β-hydroxylase

gene (CYP11B1) and the coding region of the aldosterone synthase gene (CYP11B2)

Results in aldosterone synthase activity being controlled by ACTH. Thus aldosterone is secreted acc. to circadian rhythm of ACTH (not by RAAS)

Patients often have early-onset refractory hypertension and a F/H of early onset hypertension or cerebral vascular accidents

Subtypes

FH type II Genetically heterogeneous disease with Autosomal-dominant

inheritance Effected families will demonstrate either idiopathic

hyperplasia or aldosterone-producing adenomas that are clinically and morphologically indistinguishable from sporadic PAL

Linkage analysis mutations in 7p22 region

Subtypes

Subtypes of Primary AldosteronismSURGICALLY CORRECTABLE NOT CORRECTABLE BY SURGERY

• Aldosterone-producing adenoma • B/l adrenal hyperplasia

• Primary u/l adrenal hyperplasia • Familial hyperaldosteronism type I

• Ovarian aldosterone-secreting tumour

• Familial hyperaldosteronism type II

• Aldosterone-producing carcinoma

Clinical Characteristics

Third to sixth decades of life No specific symptoms in most patients when evaluated for HTN The degree of hypertension is typically graded as moderate to

severe with the mean blood pressure of 184/112 with primary aldosteronism

Mean B.P. = significantly higher in HTN with PAL than in patients without PAL

The association between primary aldosteronism and the severity of hypertension Demonstrated by Mosso and colleagues (2003) Prevalence of primary aldosteronism in hypertensives

Stage 1 (140 to 159/90 to 99) = 2 % Stage 2 (160 to 179/100 to 109) = 8 % Stage 3 (>180/>110) = 13 %

63% and 91% of newly diagnosed patients are normokalemic @ diagnosis

In minority of patients, hypokalemia is a/w headache, polydipsia, palpitations, polyuria, nocturia, and muscle weakness.

Due to Mineralocorticoid escape, Hypernatremia is uncommon Sodium levels are similar to other forms of Hypertension Cardiovascular and renal damage is a concern The incidence and severity of target organ damage > in PAL as

compared to other forms of HTN Cardiac abnormalities

Left ventricular filling and diastolic dysfunction Increased left ventricular mass measurement Prolonged QP interval

Clinical Characteristics

As compared to patients with essential hypertension: 4 times more likely to be diagnosed with a stroke 6.5 times more likely to be diagnosed with a myocardial

infarction 12 times more likely to be diagnosed with atrial fibrillation Increased proteinuria

The increased risk of CVS disease may be a/w the increased prevalence of metabolic syndrome in these patients

Clinical Characteristics

Diagnosis

Involves screening, confirmatory testing, and subtype differentiation.

Indications for Primary Aldosterone Screening (SHARE-USE) Severe hypertension (≥160/≥110) Hypertension with hypokalemia Adrenal Incidentaloma with hypertension Resistant hypertension (three or more oral agents with poor

control) Early-onset hypertension (<20) or stroke (<50 years) Unexplained hypokalemia (spontaneous or diuretic induced) Whenever considering Secondary causes of hypertension (i.e.,

pheochromocytoma or renovascular disease) Evidence of target organ damage disproportionate to degree of

hypertension

Screening Prior to screening

Hypokalemia should be corrected All contraindicated medications to be discontinued

Can continue majority of antihypertensive agents Potassium-sparing diuretics and Mineralocorticoid

receptor blockers greatly alter the RAA axis and should be stopped at least 6 weeks prior to aldosterone renin ratio (ARR) testing.

Patients requiring MC Receptor blockers for control of severe hypertension should be transitioned to agents such as α1-receptor blockers or long-acting CCBs

Other antihypertensive agents can alter screening values, but not to the extent that mandates their discontinuation

Diagnosis

Effect Of Antihypertensiv

es On Screening For

PAL

Screening for primary aldosteronism begins by obtaining a morning (between 8 and 10 AM) plasma aldosterone concentration (PAC) and plasma renin activity (PRA)

PAC and ARR are used to screen for autonomous aldosterone secretion

ARR is dependent on PRA It is recommended that the lowest PRA value be set at 0.2 ng/mL/hr

to avoid falsely elevated ratios PAC and ARR that define a positive screen and suggest the diagnosis

of PAL are not standardised. The National Institutes of Health (NIH) Consensus Statement (2002)

on the management of the clinically inapparent adrenal mass suggests cut-offs of > 30 for ARR > 20 ng/dL for PAC

Diagnosis

However, other institutions have recommended lowering the cut-offs to greater than 20 and greater than 15 ng/dL, respectively

All positive tests must be confirmed with further testing Measurement of PRA can be time consuming and varies between

different laboratories. For this reason, plasma renin concentration has been evaluated as a possible replacement for PRA in screening for primary aldosteronism (not yet validated)

Diagnosis

CONFIRMATORY TESTING Of the patients with positive screening tests, only 50% to 70% will

be diagnosed with PAL on confirmatory testing Patient preparation is required

Correction of hypokalemia Discontinuation of Mineralocorticoid receptor antagonists

Of the confirmatory tests available 3 evaluate suppression of aldosterone following sodium loading 1 evaluates suppression of ARR following administration of an

ACE inhibitor. The selection of the confirmatory test used depends on individual

patient characteristics and physician preferences. Blood pressure should be monitored closely in all patients during confirmatory testing.

Diagnosis

Sodium loading tests: loading will decrease plasma renin and aldosterone production in patients without autonomous aldosterone secretion

Fludrocortisone suppression test Administration of Fludrocortisone (0.1 mg every 6 hours) and

NaCl (2 g every 8 hours) for 4 days. Following 4 days loading, PAC measured in upright position. Failure to suppress PAC to <6 ng/dL is diagnostic Once considered the gold standard Supplanted by oral sodium loading test and intravenous

infusion test due to risks of severe hypertension and hypokalemia

Diagnosis

Oral sodium loading test Administering a high-sodium diet for 3 days followed by 24-hour urine measurements of aldosterone,

sodium, and creatinine. Supplemental sodium chloride can be given to ensure the

intake of at least 12.8 g of sodium per day. Twenty-four-hour sodium should be greater than 200 mmol to

ensure adequate sodium loading. The diagnosis of primary aldosteronism is then made when the

24-hour aldosterone is greater than 12 μg per day

Diagnosis

Intravenous saline infusion test Spares the patient from several days of sodium loading Administration of 2 L of 0.9% NaCl intravenously over 4 hours. Infusion is performed in the morning after an overnight fast,

while the patient is in a recumbent position. Following infusion, PAC are measured Level > 5 ng/dl = diagnostic of PAL Levels > 10 ng/dl = suggestive of aldosterone-producing

adenomas

Diagnosis

Captopril suppression test Administer 25 to 50 mg of Captopril Followed by the measurement of PAC while the patient remains

recumbent Suppression of the RAAS should be noted in patients without

PAL Those with autonomous aldosterone secretion will have

persistently elevated PAC > 15 ng/dL Further standardization and validation is needed At this time, captopril suppression is recommended for

patients with cardiac and renal disease, which prohibits sodium loading

Diagnosis

SUBTYPE DIFFERENTIATION Subtype differentiation of PAL is essential in selecting appropriate

therapy, because surgical therapy is only successful for select subtypes

In patients who are not surgical candidates, subtype differentiation is of little consequence

Given the rarity of FH type I, genetic screening should not be performed in all patients

However, patients with a family history of primary aldosteronism, early age of onset (<20 years), or patients with a family history of cerebral vascular accidents at a young age should be considered for genetic testing

An adrenal CT scan should be obtained in all patients with primary aldosteronism who are potential surgical candidates

Diagnosis

Adrenal CT scan Imperfect in delineating the subtype Obtained to evaluate presence of adrenal nodules Radiographic characteristics of aldosterone-producing adenomas

unilateral low-density non-enhancing lesion of less than 10 Hounsfield units (HU)

Average size of 1.6 to 1.8 cm Normal appearing contralateral adrenal gland. ~ 20% of aldosterone-producing adenomas = < 1 cm in size. Therefore

lateralization is not based on CT findings alone Radiographic characteristics of idiopathic hyperplasia can include

Multiple unilateral or bilateral adrenal nodules Bilateral adrenal enlargement with increased limb size Or presence of normal-appearing glands.

The combination of small-size, aldosterone-producing adenomas, and potential for presence of non-functional adrenal adenomas makes CT imaging flawed in delineating lateralization of aldosterone hypersecretion.

Diagnosis

Adrenal MRI MRI does not offer an advantage in delineating primary

aldosteronism subtypes, and is a/w increased cost Routine use is not currently recommended

Diagnosis

Lateralisation Studies To establish lateralization of aldosterone secretion in surgical

candidates, adrenal vein sampling should be performed. By establishing lateralization, one can differentiate between

subtypes of primary aldosteronism and identify patients in which adrenalectomy is potentially beneficial.

The value of adrenal vein sampling was illustrated by Young and colleagues (2004), who noted that 22% of patients would have been incorrectly excluded from adrenalectomy, and 25% would have been inappropriately recommended to undergo adrenalectomy based on CT findings instead of adrenal vein sampling studies.

Diagnosis

Proper patient selection, patient preparation, and an accurate interpretation of results are essential

AVS is performed in the morning after an overnight fast. Percutaneous access to the femoral vein is obtained, and catheter

tips are positioned to collect samples from three sites: the right adrenal vein, left adrenal vein, and inferior vena cava (IVC).

Samples are evaluated for aldosterone and cortisol concentrations.

Appropriateness of the specimen collection is determined by comparing cortisol concentrations from the adrenal vein samples to the cortisol concentration from the IVC sample, which should be less.

The ratio of adrenal vein cortisol to IVC cortisol should be greater than 1.1 : 1 to 5 : 1, depending upon the use of ACTH stimulation

If ACTH stimulation is used, a higher ratio is expected

Diagnosis

Adrenal vein to IVC ratios below the cut-off, on either side, should be considered “nonselective” and discarded.

Adrenal vein to IVC ratio above cut-off, bilaterally = “selective,” and comparisons between aldosterone concentrations can be made to determine the presence of lateralization.

Lateralization of aldosterone secretion is determined by comparing the aldosterone to cortisol ratios of the dominant to nondominant sides using the formula (Adominant/Cdominant)/(Anondominant/Cnondominant).

Aldosterone is considered to be lateralized if ratio is greater than 2-4 : 1, depending on the use of ACTH stimulation

Sensitivity of 95% and specificity of 100% in detecting lateralized autonomous aldosterone secretion

Diagnosis

Role of ACTH stimulation in lateralisation study The routine use of ACTH stimulation during adrenal vein sampling

is controversial Potential advantages of ACTH stimulation include

Minimizing stress-induced fluctuations in aldosterone secretion Maximizing the cortisol gradient Maximizing the aldosterone secretion from aldosterone-

producing adenomas Facilitate the ascertainment of proper specimen collection

Disadvantage Small risk (3% to 12%) of incorrectly assigning the side of

lateralization of aldosterone-producing adenomas Moderate risk (36% to 37%) of incorrectly classifying

aldosterone-producing adenomas as idiopathic hyperplasia

Diagnosis

Alternative studies when AVS is inconclusive due to sampling error Nuclear Scintigraphy Postural stimulation testing and Measurement of cortisol metabolites

Nuclear Scintigraphy Provides both functional and anatomic data (necessary when

considering surgical intervention) 131I-6β-iodomethyl-norcholesterol (NP59) is a cortisol analog

that can label adrenal cortical cells in order to evaluate for areas of hypersecretion

Prior to injection of the radiotracer, saturated potassium iodine (Lugol solution) is administered to protect the thyroid from uptake of free 131I.

Additionally suppression of ACTH with dexamethasone (1 mg every 6 hours for 7 days) is necessary.

Diagnosis

Evaluation of radiotracer uptake is begun 4 days after NP59 injection and may continue through day 10.

Aldosterone-producing adenomas U/l uptake of radiotracer less than 5 days after injection

Idiopathic hyperplasia B/l uptake The ability to detect a hyper-functioning adenoma using NP59

is directly proportional to tumour size and function, with a diminished ability to detect lesions less than 1.5 cm in size

Diagnosis

Posture stimulation test To distinguish between aldosterone-producing adenomas and

idiopathic hyperplasia based on changes in PAC levels in response to changes in posture.

By comparing PAC levels after patient has been recumbent overnight, and again after 4 hours of being upright.

In theory, increase of angiotensin induced when upright leads to an increase of plasma aldosterone concentration in normal patients that is two- to fourfold greater when compared with recumbent levels.

In comparison, patients with idiopathic hyperplasia will demonstrate an increase of at least 33% over baseline

Patients with aldosterone-producing adenomas or FH type I will not demonstrate an increase

Although the test can be helpful in distinguishing between aldosterone-producing adenomas and idiopathic hyperplasia, it does not provide information regarding the location

Diagnosis

Reliability of the posture stimulation test is limited by the observation that 30% to 50% of aldosterone-producing adenomas demonstrate an increase of plasma aldosterone concentration, while 20% of idiopathic hyperplasia patients do not demonstrate any elevation with postural changes

Measurement of 18-Hydroxycortisone (18-OH-B) Another potential method for differentiating aldosterone-

producing adenomas from idiopathic hyperplasia Formed by 8-hydroxylation of corticosterone May be immediate precursor of aldosterone >100 ng/dL s/o aldosterone-producing adenoma <100 ng/dL s/o idiopathic hyperplasia However, accuracy < 80% Additionally, the test does not provide information about

tumour location (Right vs. Left)

Diagnosis

Treatment

Goal of treatment in primary aldosteronism is to control and prevent the morbidity associated with Mineralocorticoid excess.

Treatment strategies aim to Remove the source of Mineralocorticoid excess or Block the effect of aldosterone on target organs

Treatment strategies are primarily dependent on subtype classification and surgical candidacy U/l adrenalectomy Medical therapy

Surgery Aldosterone-producing adenomas:

Usually small sized Offer laparoscopic adrenalectomy

Adrenal cortical carcinoma Open procedure recommended

Improvement in blood pressure 33 - 73% of patients do not require antihypertensives postoperatively Predictors of persistent hypertension following

adrenalectomy for PAL Age > 50 Use of two or more antihypertensive agents preoperatively Having a 1st degree relative with hypertension Prolonged duration of hypertension prior to adrenalectomy Renal insufficiency

Treatment

In patients < 40 yr with u/l adenoma > 1 cm u/l adrenalectomy can be performed without AVS (rarity of incidental adenomas in this population)

In the immediate postoperative period PAC and ARR should be evaluated to ensure biochemical cure.

Additionally, patients should maintain a high-sodium diet and be monitored for hyperkalemia for several weeks following surgery

Treatment

Medical treatment in patients with nonsurgically correctable subtypes and those who

are not surgical candidates Aldosterone receptor antagonists (Spironolactone and

Eplerenone) are successful in lowering BP and are the antihypertensive agents of choice

Spironolactone Initiated at doses of 25 to 50 mg/day Can be titrated up to 400 mg/day, depending on blood

pressure, serum potassium levels, and side effects. Side effects:

Gynecomastia, impotence, and menstrual disturbances.

Treatment

Eplerenone More favorable side-effect profile Increased selectivity for aldosterone receptor Initiated with 25 mg twice per day Titrated up to 100 mg per day

Other antihypertensive agents will often be needed. Lifestyle modifications: weight loss, low- sodium diet, and regular

exercise FH type I can be treated with oral Glucocorticoids.

Glucocorticoid reduce ACTH release decreased aldosterone production

When BP is not controlled with Glucocorticoids alone Development of Iatrogenic Cushing’s

Treatment

Add aldosterone receptor

antagonist