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Conn's Syndrome Overview

Discussion in 'Endocrinology' started by Dr.Scorpiowoman, Jun 23, 2017.

  1. Dr.Scorpiowoman

    Dr.Scorpiowoman Golden Member

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    Although initially considered a rarity, primary aldosteronism now is considered one of the more common causes of secondary hypertension (HTN). Litynski reported the first cases, but Conn was the first to well characterize the disorder, in 1956. Conn syndrome, as originally described, refers specifically to primary aldosteronism due to the presence of an adrenal aldosteronoma (aldosterone-secreting benign adrenal neoplasm). (See Etiology.)

    Based on older data, it was originally estimated that primary aldosteronism accounted for less than 1% of all patients with HTN. Subsequent data, however, indicated that it may actually occur in as many as 5-15% of patients with HTN. Primary aldosteronism may occur in an even greater percentage of patients with treatment-resistant HTN and may be considerably underdiagnosed; this is especially true if patients with treatment-refractory HTN are not specifically referred for evaluation to an endocrinologist.

    Although primary aldosteronism is still a considerable diagnostic challenge, recognizing the condition is critical because primary aldosteronism–associated HTN can often be cured (or at least optimally controlled) with the proper surgical or medical intervention. The diagnosis is generally 3-tiered, involving an initial screening, a confirmation of the diagnosis, and a determination of the specific subtype of primary aldosteronism.

    Although prior studies suggested that aldosteronomas were the most common cause of primary aldosteronism (70-80% of cases), later epidemiologic work indicated that the prevalence of aldosteronism due to bilateral idiopathic adrenal hyperplasia (IAH; sometimes also abbreviated as BAH) is higher than had previously been believed. These reports suggested that IAH may be responsible for as many as 75% of primary aldosteronism cases. Moreover, reports have described a rare syndrome of primary aldosteronism characterized by histologic features intermediate between adrenal adenoma and adrenal hyperplasia, which often is unilaterally localized (also referred to earlier literature as “intermediate aldosteronism”)

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    Magnetic resonance imaging (MRI) scan in a patient with Conn syndrome showing a left adrenal adenoma.

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    Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

    Clinically, the distinction between the 2 major causes of primary aldosteronism is vital because the treatment of choice for each is markedly different. While the treatment of choice for aldosteronomas is surgical extirpation, the treatment of choice for IAH is medical therapy with aldosterone antagonists. (See Treatment and Medication.)

    Entities known to cause aldosteronism include the following (see the image below):

    · Aldosterone-producing adenomas (APAs) [1]

    · Aldosterone-producing renin-responsive adenomas (AP-RAs; also abbreviated as RRAs)

    · Bilateral idiopathic adrenal (glomerulosa) hyperplasia or IAH (also known as primary adrenal hyperplasia or PAH)

    · Familial forms of primary aldosteronism

    · Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs described in the literature that, in the setting of neoplastic disease, can be ectopic sources of aldosterone, but this is a rare occurrence.)

    · Pure aldosterone-producing adrenocortical carcinomas (very rare; physiologically behave as APAs)

    [​IMG]

    Scintigram obtained by using iodine-131-beta-iodomethyl-norcholesterol (NP-59) in a 59-year-old man with hypertension shows fairly intense radionuclide uptake in the right adrenal tumor. At surgery, a Conn tumor was confirmed.

    Aldosterone, by inducing renal reabsorption of sodium at the distal convoluted tubule (DCT), enhances secretion of potassium and hydrogen ions, causing hypernatremia, hypokalemia, and alkalosis. (See Prognosis, Workup, and Treatment.)

    Genetic-familial primary aldosteronism

    Three distinct genetic-familial varieties of primary aldosteronism exist. Sutherland and colleagues first described the type 1 variety of familial primary aldosteronism, glucocorticoid-remediable aldosteronism (GRA), in 1966. In GRA, HTN responds clinically to small doses of glucocorticoids in addition to other antihypertensive agents. [2] The type 1 form of familial primary aldosteronism is due to an aberrantly formed chimeric gene product that combines the glucocorticoid-responsive (inhibitable) promoter of the 11beta-hydroxylase gene (CYP11B1) with the coding region of the aldosterone synthetase gene (CYP11B2). Under ambient glucocorticoid levels, the promoter is not fully transcriptionally silenced, and this leads to overexpression of aldosterone synthetase, with subsequent increased synthesis and secretion of aldosterone.

    The type 2 variant of familial primary aldosteronism (which is not glucocorticoid sensitive) was first described in 1991. Although the exact genetic abnormality for type 2 primary aldosteronism has not been identified, data suggest that the locus for this disease is on band 7p22.

    The type 3 variant of familial primary aldosteronism is due to KCNJ5 (potassium inwardly rectifying channel, subfamily J, member 5) potassium channel mutations. This type was described by Lifton’s group in 2011.

    Workup

    Screening (first-tier) tests for primary aldosteronism include the following:

    · Serum potassium and bicarbonate levels

    · Sodium and magnesium levels

    · Plasma aldosterone/plasma renin activity ratio

    Confirmatory (second-tier) tests include the following:

    · Serum aldosterone level

    · 24-hour urinary aldosterone excretion test

    · Salt-loading test

    Tests for determining the primary aldosteronism subtype (third-tier tests) include the following:

    · Postural stimulation test

    · Furosemide (Lasix) stimulation test

    · Diurnal rhythm of aldosterone

    The initial radiologic investigation in the workup of primary aldosteronism is high-resolution, thin-sliced (2-2.5 mm) adrenal computed tomography (CT) scanning with contrast.

    Other tests include the following:

    · NP-59 iodo-methyl-norcholesterol scintigraphy: Although fairly difficult to set up and not routinely available, this test can be useful in select cases for distinguishing between adenomas and hyperplasia

    · Adrenal venous sampling: Adrenal venous sampling probably has its greatest utility when adrenal imaging findings are completely normal despite biochemical evidence for primary aldosteronism and in settings in which bilateral adrenal pathology is present on imaging and the biochemistry suggests the presence of a functional aldosteronoma

    · Dexamethasone suppression test: This test is relevant only in the setting of possible familial aldosteronism

    · Metoclopramide (Reglan) test: This is a noninvasive test for distinguishing between aldosteronomas and idiopathic adrenal hyperplasia (IAH)

    Management

    Pharmacologic therapy includes use of the following:

    · Calcium channel blockers

    · Mineralocorticoid antagonists

    · Glucocorticoids

    Surgery is the treatment of choice for the lateralizable variants of primary aldosteronism, including typical aldosteronomas, renin-responsive adenomas (RRAs), and primary adrenal hyperplasia (PAH). An adrenalectomy can be performed via a formal laparotomy or by using a laparoscopic technique (with performance of the latter becoming increasingly common).

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