**2.1 Symptoms and signs**

The most common findings in PAL, moderate or severe hypertension and hypokalemia. PAL patients are often resistant hypertension, hypertension in these patients usually need to take control of multiple drug use. In recent studies, only a minority of patients with PAL (9– 37%) had hypokalemia.23 Although hypokalemia is considered the hallmark of hyperaldosteronism, the majority of patients with PAL have normal serum potassium levels. Hypokalemia is believed to be a late manifestation of PAL and many patients with PAL may present with HTN well before they develop hypokalemia. 6,23 Most symptoms of PAL are attributed to hypokalemia, which include muscle weakness, cramping, transient paralysis, palpitations, headache, or polyuria.22

Half the patients with an APA and 17% of those with idiopathic hyperaldosteronism (IHA) had serum potassium concentrations less than 3.5 mmol/liter.24 Thus, the presence of hypokalemia has low sensitivity and specificity and a low positive predictive value for the diagnosis of PAL. Separation of IHA and APA, IHA to be treated medically, surgically corrected if the APA is very important because of an illness.

#### **2.2 Laboratory findings**

The recently published Guidelines for diagnosis and treatment of PAL outlined for the first time the categoriesof hypertensive patients with relatively high prevalence of PAL who should undergo a screening test. 1 The screening test should be performed in all

on PAI-1 levels. In recent years, clinical trials have demonstrated an additive effect of combined ACEI and aldosterone receptor antagonism on cardiovascular morbidity and mortality.12,13 The mechanism, named aldosterone escape, referring to chronic ACEI that leads aldosterone to return to baseline concentrations, might clarify the additional effects of aldosterone on PAI-1 levels.14,15 We study, administration of an ACEI (fosinopril) and an ACEI plus aldosterone antagonist (spironolactone) both caused a significant decrease in

Several studies have shown that patients with either aldosterone-producing adenoma (APA) or idiopathic hyperaldosteronism (IHA) appear to have increased cardiovascular morbidity compared with age-, sex-, and systolic and diastolic BP-matched patients with essential hypertension.17,18 Patients with PAL, stroke, MI and significantly increased risk of atrial fibrillation.19 Optimal BP control and specific management of aldosterone excess by either adrenalectomy or medical treatment with mineralocorticoid receptor (MR) antagonists is

The adverse effects of aldosterone excess stress the importance of establishing the diagnosis of PAL and its underlying cause. The most common subtypes of PAL are APA (35% of cases) and IHA (60% of cases).21 Many other subtypes of PAL have also been described, including primary or unilateral adrenal hyperplasia (2%), pure aldosterone-secreting adrenocortical carcinoma (<1%) and ectopic aldosterone- secreting tumours (e.g. neoplasms

The most common findings in PAL, moderate or severe hypertension and hypokalemia. PAL patients are often resistant hypertension, hypertension in these patients usually need to take control of multiple drug use. In recent studies, only a minority of patients with PAL (9– 37%) had hypokalemia.23 Although hypokalemia is considered the hallmark of hyperaldosteronism, the majority of patients with PAL have normal serum potassium levels. Hypokalemia is believed to be a late manifestation of PAL and many patients with PAL may present with HTN well before they develop hypokalemia. 6,23 Most symptoms of PAL are attributed to hypokalemia, which include muscle weakness, cramping, transient paralysis,

Half the patients with an APA and 17% of those with idiopathic hyperaldosteronism (IHA) had serum potassium concentrations less than 3.5 mmol/liter.24 Thus, the presence of hypokalemia has low sensitivity and specificity and a low positive predictive value for the diagnosis of PAL. Separation of IHA and APA, IHA to be treated medically, surgically

The recently published Guidelines for diagnosis and treatment of PAL outlined for the first time the categoriesof hypertensive patients with relatively high prevalence of PAL who should undergo a screening test. 1 The screening test should be performed in all

fundamental for the prevention of cardiovascular events in patients with PA.20

PAI-1 levels, which might be attributed to aldosterone escape.16

in the ovary or kidney) (<0.1%).22

palpitations, headache, or polyuria.22

**2.2 Laboratory findings** 

corrected if the APA is very important because of an illness.

**2. Clinical findings** 

**2.1 Symptoms and signs** 

patients with: **1)** resistant hypertension; **2)** hypertension grade 2 or 3; **3)** hypertension and spontaneous or diuretic-induced hypokalaemia **4)** hypertension with adrenal incidentaloma; **5)**hypertension and a family history of early-onset hypertension or cerebrovascular accident at a young age (<40 year); **6)** all hypertensive first-degree relatives of patients with PAL.

There is a general consensus that aldosterone:renin ratio (ARR) is the most reliable available means for PAL screening; however there is no agreement on either the ARR cut-off or whether the absolute aldosterone level should also be taken into account. Aldosterone renin ratios (ARRs) were calculated from these values using the following Formula (ARR): Plasma aldosterone (ng/dL)**/**Plasma renin (ng/mL-h) . Individuals with an ARR of ≥30 were suspected of having primary aldosteronism, while an ARR of <30 was considered normal.1 However, it is now recognized the prevalence is higher (5-13% of all patients with hypertension) when the PAC to PRA ratio (ARR) is used to screen for PAL. Measurements of PAC and PRA are recommended for the diagnosis of PAL.

Several factors affect ARR, the most important being antihypertensive therapy: mineralocorticoid receptor antagonists and diuretics lead to false-negative results and thus should always be withdrawn for at least 4–6 weeks (6– 8 for spironolactone); dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists can potentially, but infrequently, led to false-negative results25; in contrast, beta-blockers and central 2-agonists can cause false positives.26 The direct renin inhibitor aliskiren lowers PRA, resulting in false-positive ARR for renin measured as PRA and false negatives for renin measured.1

An increased ARR is not diagnostic by itself, and PAL must be confirmed by demonstrating over- production of aldosterone. The Endocrine Society guidelines recommend the following four confirmatory tests; an oral sodium test, saline infusion test, fludrocortisone test and captopril challenge test.1 Patients should receive 12.8 g sodium chloride for 3 days in the oral sodium loading test. The captopril challenge test shows excellent sensitivity despite relatively low specificity and due to its simplicity can be performed at the outpatient clinic.

**Oral sodium loading test:** This test is performed to evaluate the suppression of aldosterone by oral sodium loading. The oral sodium loading test is also not practical in hypertensive patients because of their high-salt intake, and the intravenous saline infusion test is not common as it is dangerous for elderly patients or those with left ventricular hypertrophy or a previous myocardial infarction, all of which are commonly complicated by PAL. The most commonly used test to verify the diagnosis oarl sodium loading test. Patients should increase their sodium intake to 200 mmol/d (6 g/d) for 3 day, verified by 24-h urine sodium content. Patients should receive adequate slow-release potassium chloride supplementation to maintain plasma potassium in the normal range. Urinary aldosterone is measured in the 24-h urine collection from the morning of d 3 to the morning of day 4. PAL is unlikely if urinary aldosterone is lower than 10 µg/24 h (27.7 nmol/ d) in the absence of renal disease where PAL may coexist with lower measured urinary aldosterone levels. Elevated urinary aldosterone excretion >12 µg/24 h (>33.3 nmol/d) at the Mayo Clinic, >14 µg/24 h (38.8 nmol/d) at the makes PAL highly likely.

Diagnosis and Treatment of Primary Aldosteronism 129

both should be performed in patients with primary aldosteronism to identify the rare but large aldosterone-producing carcinoma.32 However, as MRI is more expensive and has a lower spatial resolution than CT, MRI has no advantage over CT in subtype evaluation of

Half of APAs are <20 mm in diameter and up to 42% are <6 mm in diameter, therefore, most patients with primary aldosteronism attributable to an APA who can be cured with surgery have a small or very small tumor.33 Other surgically curable subtypes of primary aldosteronism, such as primary aldosteronism caused by primary unilateral adrenal hyperplasia or multinodular unilateral adrenocortical hyperplasia, have nodular lesions that are also most often very small (<10 mm in diameter), which makes them hardly detectable with CT or MRI. In addition, a nonfunctioning adrenal mass (incidentaloma) can also be present in a patient with primary aldosteronism either with a small APA or with unilateral adrenocortical hyperplasia, both of which are undetectable with CT. Moreover, in a patient with primary aldosteronism, an adrenal nodule can be an APA, a macronodule of hyperplasia attributable to idiopathic hyperaldosteronism,34 or a macronodule attributable to

There are an increasing number of reports that adenal vein sampling (AVS) is the gold standard test to differentiate unilateral from bilateral disease in patients with PAL. The Endocrine Society guidelines state that AVS is the "standard test to differentiate unilateral from bilateral causes of [primary aldosteronism]. 1 Adrenal venous sampling is a difficult procedure as the right adrenal vein is small, with the success rate depending on the proficiency of the angiographer. AVS is expensive, technically demanding and carries a tiny,

In a study where AVS was used as the gold standard for diagnosis, CT scans mistakenly suggested that one-quarter of patients had an APA; correctly identified a unilateral or bilateral excess of aldosterone only in half of all patients; falsely suggested a bilateral adrenal hyperplasia in one-fifth of patients with a unilateral source of aldosterone excess;

Rapid cortisol assays during AVS to monitor cortisol levels can reduce the failure rate of AVS. We have developed a new rapid cortisol assay using immunochromatography, in which cortisol concentrations can be measured within 6 min. (briefly explain false positive rates etc., in this method- should this be used in conjunction with CT?) Using this

At our institution, we support the recommendation from the Endocrine Society guidelines1 that a lateralized aldosterone secretion should be demonstrated before undertaking surgery in patients who are candidates for general anesthesia and wish to achieve long-term cure. The goal of treatment for PAL is focused on the normalization of circulating aldosterone or aldosterone receptor blockade to prevent the morbidity and mortality associated with HTN,

and in some patients identified an APA in the wrong adrenal gland.34

technique, the success rate of AVS has improved to 93% .37

primary aldosteronism.1

primary unilateral adrenal hyperplasia.35

but not negligible, risk of adrenal-vein rupture.36

**3.2 Adrenal venous sampling** 

**4. Treatment** 

Urinary aldosterone levels greater than 12 mcg/24 hours indicate failure to suppress the aldosterone production by high salt intake and is diagnostic of PAL with over 90% sensitivity and specificity. 22

**Saline loading test:** Patients stay in the recumbent position for at least 1 h before and during the infusion of 2 liters of 0.9% saline iv over 4 h, starting at 08:00–09:30 h. Blood samples for renin, aldosterone, cortisol, and plasma potassium are drawn at time zero and after 4 h, with blood pressure and heart rate monitored throughout the test. Post infusion plasma aldosterone < 5 ng/dl make the diagnosis of PAL unlikely, and levels >10 ng/ dl are a very probable sign of PAL. Values between 5 and 10 ng/dl are indeterminate.34 SLT is contraindicated in patients with severe HTN, chronic kidney failure, HF, cardiac dysrhythmias, or severe hypokalemia.

**Captopril challenge test:** Patients receive 25–50 mg captopril orally after sitting or standing for at least 1 h. Blood samples are drawn for measurement of PRA, plasma aldosterone, and cortisol at time zero and at 1 or 2 h after challenge, with the patient remaining seated during this period. Plasma aldosterone is normally suppressed by captopril (>30%). The test is considered positive if SA remains greater than 12 ng/dL or ARR is greater than 26.28 This test has a higher sensitivity (100% versus 95.4%) and specificity (67% to 91% versus 28.3%) over the baseline screening tests, and is easier to perform than the SLT.

**Fludrocortisone suppression test:** Fludrocortisone suppression is the standard test used to confirm the diagnosis of PAL. Fludrocortisone (Florinef) is given 0.1 mg every 6 hours orally together with high oral sodium of 200 mmol (6 g) per day for 4 days. Potassium supplement should be given to maintain a close to normal serum potassium level. Upright SA and PRA are obtained on day 4 of the test. SA greater than 6 ng/dL is indicative of failure to suppress the aldosterone production and is diagnostic of PAL; PRA should be suppressed to less than 1 ng/mL/hour. FST requires hospital admission because of hypokalemia associated with testing as well as the need for frequent blood samples to monitor serum potassium levels. This test is contraindicated in patients with severe HTN or heart failure (HF). 1,27

#### **3. Imaging studies**

#### **3.1 Adrenal computed tomography**

Imaging of adrenal glands by computed tomography (CT) and magnetic resonance imaging (MRI) is frequently used to detect an adrenal mass in patients with positive screening and confirmation tests. 29

APA may be visualized as small hypodense nodules (usually<2 cm in diameter) on CT. IHA adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are almost always more than 4 cm in diameter, but occasionally smaller, and like most adrenocortical carcinomas have a suspicious imaging phenotype on CT. 30

A high resolution CT scan with 2–3 mm cuts represents the best available technique for identifying adrenal nodules that can be an APA, primary unilateral adrenal hyperplasia or bilateral adrenal hyperplasia.31 According to the Endocrine Society guidelines, MRI, CT or

Urinary aldosterone levels greater than 12 mcg/24 hours indicate failure to suppress the aldosterone production by high salt intake and is diagnostic of PAL with over 90%

**Saline loading test:** Patients stay in the recumbent position for at least 1 h before and during the infusion of 2 liters of 0.9% saline iv over 4 h, starting at 08:00–09:30 h. Blood samples for renin, aldosterone, cortisol, and plasma potassium are drawn at time zero and after 4 h, with blood pressure and heart rate monitored throughout the test. Post infusion plasma aldosterone < 5 ng/dl make the diagnosis of PAL unlikely, and levels >10 ng/ dl are a very probable sign of PAL. Values between 5 and 10 ng/dl are indeterminate.34 SLT is contraindicated in patients with severe HTN, chronic kidney failure, HF, cardiac

**Captopril challenge test:** Patients receive 25–50 mg captopril orally after sitting or standing for at least 1 h. Blood samples are drawn for measurement of PRA, plasma aldosterone, and cortisol at time zero and at 1 or 2 h after challenge, with the patient remaining seated during this period. Plasma aldosterone is normally suppressed by captopril (>30%). The test is considered positive if SA remains greater than 12 ng/dL or ARR is greater than 26.28 This test has a higher sensitivity (100% versus 95.4%) and specificity (67% to 91% versus 28.3%)

**Fludrocortisone suppression test:** Fludrocortisone suppression is the standard test used to confirm the diagnosis of PAL. Fludrocortisone (Florinef) is given 0.1 mg every 6 hours orally together with high oral sodium of 200 mmol (6 g) per day for 4 days. Potassium supplement should be given to maintain a close to normal serum potassium level. Upright SA and PRA are obtained on day 4 of the test. SA greater than 6 ng/dL is indicative of failure to suppress the aldosterone production and is diagnostic of PAL; PRA should be suppressed to less than 1 ng/mL/hour. FST requires hospital admission because of hypokalemia associated with testing as well as the need for frequent blood samples to monitor serum potassium levels. This test is contraindicated in patients with severe HTN

Imaging of adrenal glands by computed tomography (CT) and magnetic resonance imaging (MRI) is frequently used to detect an adrenal mass in patients with positive screening and

APA may be visualized as small hypodense nodules (usually<2 cm in diameter) on CT. IHA adrenal glands may be normal on CT or show nodular changes. Aldosterone-producing adrenal carcinomas are almost always more than 4 cm in diameter, but occasionally smaller, and like most adrenocortical carcinomas have a suspicious imaging phenotype on CT. 30

A high resolution CT scan with 2–3 mm cuts represents the best available technique for identifying adrenal nodules that can be an APA, primary unilateral adrenal hyperplasia or bilateral adrenal hyperplasia.31 According to the Endocrine Society guidelines, MRI, CT or

over the baseline screening tests, and is easier to perform than the SLT.

sensitivity and specificity.

or heart failure (HF). 1,27

**3.1 Adrenal computed tomography** 

**3. Imaging studies** 

confirmation tests. 29

dysrhythmias, or severe hypokalemia.

22

both should be performed in patients with primary aldosteronism to identify the rare but large aldosterone-producing carcinoma.32 However, as MRI is more expensive and has a lower spatial resolution than CT, MRI has no advantage over CT in subtype evaluation of primary aldosteronism.1

Half of APAs are <20 mm in diameter and up to 42% are <6 mm in diameter, therefore, most patients with primary aldosteronism attributable to an APA who can be cured with surgery have a small or very small tumor.33 Other surgically curable subtypes of primary aldosteronism, such as primary aldosteronism caused by primary unilateral adrenal hyperplasia or multinodular unilateral adrenocortical hyperplasia, have nodular lesions that are also most often very small (<10 mm in diameter), which makes them hardly detectable with CT or MRI. In addition, a nonfunctioning adrenal mass (incidentaloma) can also be present in a patient with primary aldosteronism either with a small APA or with unilateral adrenocortical hyperplasia, both of which are undetectable with CT. Moreover, in a patient with primary aldosteronism, an adrenal nodule can be an APA, a macronodule of hyperplasia attributable to idiopathic hyperaldosteronism,34 or a macronodule attributable to primary unilateral adrenal hyperplasia.35
