Hyperaldosteronism

Primary aldosteronism (PA) is a clinical syndrome of hypertension, suppressed renin activity and increased aldosterone secretion. The two most common causes of PA are aldosterone producing adrenal adenoma (APA), seen in ~35% of cases, a unilateral adrenal cortical tumour resulting in autonomous secretion of aldosterone, or bilateral adrenal hyperplasia (IHA), seen in ~60% of cases, where both adrenal glands secrete excessive amounts of aldosterone in response to angiotensin-II. Less common causes include primary unilateral adrenal hyperplasia (PAH), glucocorticoid remediable aldosteronism (GRA), and very rarely adrenal carcinoma. Some 15-25% of patients with PA have glucose intolerance, and diabetes is twice as common as in control populations. The prevalence of PA is increased in people with resistant hypertension associated with diabetes, with rates of 13% and 14% in two separate studies.Early detection and treatment can prevent long-term micro- and macrovascular complications in a significant proportion of patients. Impaired glucose metabolism is a frequent finding in patients with PA but the mechanism that leads to dysglycaemia requires further study.

Historical perspective

This syndrome was first described by Dr. Jerome W Conn in 1954, who described a 34 year-old woman with hypertension, hypokalaemia and muscle weakness. At operation in 1955 she was found to have a right sided adrenal tumour with normal left adrenal gland. Removal of the adrenal tumour resulted in near complete resolution of her clinical and metabolic symptoms.

Clinical relevance

PA is the most common cause of mineralocorticoid hypertension. Studies using plasma aldosterone concentration (PAC)-to plasma renin activity (PRA) ratio as a screening test have reported a prevalence of 10-32% among patients with essential hypertension [1][2][3][4], much higher than initially thought; the prevalence is particularly high among patients with resistant hypertension.

Diabetes and hypertension

Approximately 40–60% of type 2 diabetic patients are hypertensive [5][6], half of them being hypertensive at diagnosis [7]. The co-existence of these two conditions is associated with a significantly higher risk of micro- and macro-vascular complications [5][8].

Randomized clinical trials have shown that optimum blood pressure control in patients with diabetes significantly reduces the risk of vascular complications, cardiovascular events, and death [9][10][11]. The risk reduction seen with hypertension control in patients with diabetes is more marked than that seen in the non-diabetic population with similar blood pressure values [12].

Based on these findings, the Professional Practice Committee of the American Diabetes Association recommended a blood pressure goal of 130/80 mmHg for adult patients with diabetes [6][11]. In contrast, the recent Eighth Joint National Committee (JNC 8) recommendation suggests the less rigorous blood pressure goal of < 140/90. Achieving blood pressure control in subjects with diabetes is however difficult. Fewer than 50% of people with diabetes achieve their blood pressure goals [8], and many require three or more antihypertensive agents [13][1].

Resistant hypertension, defined as a failure of concomitant use of 3 or more different classes of antihypertensive agents (diuretics being one) to control blood pressure to <140/90 mmHg, is a common problem. 10–30% of patients with essential hypertension have resistant hypertension. Patients with resistant hypertension tend to have more severe hypertension at diagnosis, develop more end-organ damage, and are more likely to have a secondary cause of hypertension [14][15].

Primary Aldosteronism (PA) is the most common endocrine cause of secondary hypertension. Its prevalence was previously thought to be about 1% among hypertensive patients, but with increased awareness and screening, the prevalence has been noted in recent years to be much higher; it may account for 5–32% of the population with resistant hypertension [1][2][3][4][16][17]

Primary aldosteronism and diabetes

Despite the high prevalence of resistant hypertension among diabetic patients, the prevalence of PA in the diabetic population was not known until recently.

In 1964, Conn et al. observed that out of 145 cases of PA, 39 had an oral glucose tolerance performed, of whom 21 (54%) were detected to have impaired glucose tolerance (IGT) [17]. Over the last few decades, several reviews of large number of cases of PA have suggested an incidence of glucose intolerance between 15-25%.

In a retrospective case-control study of the German Conn's Register, 638 patients with PA were compared with 897 hypertensive control subjects. Diabetes mellitus was found to be more prevalent in patients with PA than in controls (23% vs. 10%) [18].

In a study by Umpierrez et al., out of 100 diabetic patients with resistant hypertension, 34 were noted to have PAC-to-PRA ratio >30; 14 (14%) had a confirmed diagnosis of PA [19].

Mukherjee et al. screened 100 consecutive Asian type 2 diabetic patients with poorly controlled BP and reported a 13% prevalence of PA; all 13 had resistant hypertension. Of these, 8 had surgically correctable form of PA, whilst the other 5 were managed medically [20].

Mechanism of hyperglycaemia in PA

Following Conn's report in 1965 describing a higher prevalence of impaired glucose metabolism in patients with PA, many studies have been undertaken to look for the reason behind this finding. Several possibilities have been explored, including hypokalaemia-related insulin hypo-secretion and aldosterone-induced insulin resistance.

Closure of K-ATP channels causes depolarization of the pancreatic β-cell membrane, which is a key step in insulin secretion, and potassium is essential in maintaining the resting membrane potential. It has been shown in animal models that β-cell depolarization may differ when exposed to different serum potassium concentrations. Similar observations have been seen in human studies as well. Rowe et al. showed that glucose intolerance due to hypokalaemia was due to reduced insulin secretion but not due to reduced insulin sensitivity [21].

Although this hypothesis can explain insulin secretory defect in patients with hypokalaemic PA, it does not explain the presence of IGT in the normokalaemic PA population, who constitute two-thirds of all PA patients. Insulin resistance as a contributory factor in the pathogenesis of DM in PA has been described in a few studies. Sindelka et al., using a hyperinsulinaemic euglycaemic clamp study, demonstrated that PA patients are insulin resistant [22]. They observed significantly reduced glucose disposal rate, metabolic clearance rate of glucose, and insulin sensitivity in patients with PA, compared to controls. Catena et al., in a prospective study, compared the HOMA-IR in 47 PA patients with their normotensive-matched controls, and discovered that the PA patients were significantly more resistant to insulin [23]. Several studies have reported that aldosterone may induce insulin resistance through several cellular pathways. Kraus et al. suggested that the major insulin signaling elements (protein kinase B and mitogen-activated protein kinase) had diminished activation in cultured adipocytes that were pre-treated with aldosterone [24]. Hitomi et al. suggested that aldosterone may impair insulin signaling by down-regulating insulin receptor substrate-1 in vascular smooth muscle cells [25].

However, several other studies have disputed the suggestion that PA represents a special form of diabetes. Widimsky et al. found no difference in the level of blood glucose, insulin and OGTT in patients with PA, and in patients with essential hypertension [26]. Furthermore, Shamiss et al. observed higher insulin resistance in patients with essential hypertension when compared to those with PA [27].

Clinical features

Diabetes secondary to PA, tends to be milder. Patients do not develop ketoacidosis, and chronic complications are rare; however, untreated patients may have vascular complications due to uncontrolled blood pressure.

Diagnosis

Steps in the diagnosis of PA are essentially the same in diabetic and non-diabetic hypertensive patients. All diabetic patients who have not met their blood pressure goals despite treatment with three anti-hypertensive medications, including a diuretic, should be screened for PA [20]. Diabetic hypertensive patients with history of spontaneous or diuretic induced hypokalaemia or incidentally detected adrenal adenoma or severe hypertension at young age should also be considered for screening test. The PAC-to-PRA ratio is considered the screening test of choice for PA [29][28]. ACE inhibitors, ARBs, and diuretics have been reported to increase PRA, calcium channel blockers to suppress aldosterone release, and beta -blockers to suppress PRA, thereby potentially confounding the assessment of the PAC-to-PRA ratio [29][30][31]. Recent studies, however, have demonstrated that measurement of the PAC-to-PRA ratio to screen for PA is not significantly affected by concurrent use of antihypertensive agents [16][32][33][34]. In addition, if there is a confounding effect, it would most likely result in an underestimation of PAC-to- PRA ratio because the most commonly used antihypertensive agents (ACE inhibitors, ARBs, and diuretics) tend to increase PRA, resulting in an increased number of false negative results [15][26]. One must stop mineralocorticoid receptor antagonists (spironolactone, epleronone) for at least 4 – 6 weeks prior to measuring the PAC-to-PRA ratio.

There have been suggestions to add a threshold value of aldosterone (>15 ng/dL) as part of the screening criteria to improve the specificity of the ratio (decrease the number of false-positive results); however, this might decrease its sensitivity [16].

In most studies, an ARR > 20 ng/dL per ng/mL/hr is considered suspicious for PA. An ARR >30 ng/dL per ng/mL/hr, especially in the setting of a PAC > 15 ng/dL, has been shown to be 90% sensitive and 91% specific for the diagnosis of PA[34][35], whereas a ratio of >50 ng/dL per ng/mL/hr is virtually diagnostic of PA [36].

Confirming the Diagnosis

In patients with a positive ARR, subsequent confirmation of autonomous aldosterone secretion is necessary. Most confirmatory tests aim to demonstrate autonomy of aldosterone production in spite of volume expansion. Options include oral sodium loading or intravenous saline infusion. Patients need to stay off aldosterone antagonists for at least 4-6 weeks before these tests. For oral sodium loading test, patients are instructed to consume a high sodium (~4-6g/day) diet for 3 days. On the third day of high dietary sodium intake, 24-hour urine for urinary aldosterone, creatinine, and sodium is collected. Aldosterone excretion > 12 ug/d, in the presence of a urinary sodium excretion > 200 mmol/24 hours, confirms the diagnosis of PA. The advantage of oral sodium loading is that it can be performed on an outpatient basis without using hospital resources. However, this test should not be performed in patients with uncontrolled blood pressure or moderate to severe, untreated hypokalaemia. Blood pressure and potassium levels should be monitored during the testing [35][37].

For the intravenous saline suppression test, 2 liters of isotonic saline are infused (500ml/hr) over 4 hours. This test should not be performed in patients with compromised cardiac function. In normal subjects, PAC decreases to below 5 ng/dL at the end of the saline infusion; levels greater than 10 ng/dL are considered diagnostic of autonomous aldosterone production. Values between 6 and 10 ng/dL are considered indeterminate [37][38].

The Fludrocortisone suppression test is advocated in few centres; it is a cumbersome test necessitating hospital admission for a few days.

Once the biochemical diagnosis of PA has been confirmed, further testing is required not only to determine the aetiology of the disorder but also to plan for potential surgical treatment.

Computed tomography (CT) scanning of the abdomen with thin 3mm slices through the adrenal region is the radiographic investigation of choice. Adrenal adenomas typically are solitary, hypodense, lipid-rich (<10 HU) nodules, less than 4 cm in size. However, only 30-50% of patients with biochemically confirmed PA have positive CT findings for a solitary adenoma [39][40]. Both adrenal glands may be radiologically abnormal. Moreover, non-functioning adrenal ‘incidentalomas’ are not rare, especially in patients above the age of 40; these are radiographically indistinguishable from an APA, and can co-exist with an APA in the same or the opposite adrenal gland. So, radiological finding can be misleading in a significant proportion of patients [39][41].

Adrenal venous sampling (AVS) is considered to be the ‘gold standard’ for distinguishing unilateral versus bilateral disease in PA [39][41]. AVS involves sampling from the right and left adrenal veins, and inferior vena cava (IVC) for aldosterone and cortisol. Cortisol-corrected aldosterone ratios, obtained by dividing aldosterone concentration by cortisol concentration from each location to correct for dilutional effects, are used to lateralize to the site of aldosterone over production. AVS is not necessary in a young patient (< 40 years) with confirmed PA with an unequivocal unilateral adrenal adenoma and a normal contralateral gland. In older patients (above 40 years), it might be prudent to consider AVS because the incidence of an ‘incidentaloma’ is fairly high in this age-group.

Treatment

Treatment for PA depends on the underlying aetiology. Surgery is the treatment of choice for a unilateral APA, and is often performed laparoscopically. Successful resection of APA results in either cure or a reduction in the number of anti-hypertensives necessary to control blood pressure, and normalises serum potassium. Resolution of hypertension after resection of an APA is less likely if there is family history of hypertension and if the patient had been on more than two antihypertensive agents for a prolonged period pre-operatively [42][43]. Blood pressure tends to show maximal improvement 1-6 months post-operatively. Improved insulin sensitivity after adrenalectomy has been documented in several reports [44][22].

Administration of a mineralocorticoid antagonist (Spironolactone or Epleronone) is the standard treatment for IHA, and in patients who refuse to or are unable to undergo a surgical procedure. Catena et al. [23] have reported that impaired insulin sensitivity in patients with PA is rapidly and persistently reversed following either adrenalectomy or administration of spironolactone, but further studies are needed.

Summary

In summary, PA is the most common endocrine cause of secondary hypertension. Its prevalence has been found to be between 13-14% amongst type 2 diabetic patients with resistant hypertension. Early detection and treatment can prevent long-term micro- and macrovascular complications in a significant proportion of patients. Impaired glucose metabolism is a frequent finding in patients with PA but the mechanism that leads to dysglycaemia needs further study.

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Comments

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    Praveen Jeyapathy added a compliment on 27 July 2015 at 03:00PM
    Very well written article, Dr Subir. Crisp and to the point. Definitely a must-know for most practicing clinicians in the field of diabetes.
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