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What is Primary Hyperaldosteronsim?

Posted Oct 30 2008 12:00am
There are many definitions of this disease which can be confusing. This is one I found at emedicine.com http:// emedicine.medscape.com/article/127080-overview
It describes primary hyperaldosteronism in medical detail that's easy to understand. I think it's better than the first description I posted.

Background

Although initially considered a rarity, primary hyperaldosteronism (PH) 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 PH secondary to an adrenal aldosteronoma.

While older data suggested that PH is rare, with an estimated prevalence of less than 1% of all patients with HTN, subsequent data indicated that it may actually occur in as many as 5-15% of patients with HTN. It may occur in an even greater percentage of patients with treatment-resistant HTN. Although still a considerable diagnostic challenge, recognizing this condition is critical because PH-associated HTN can often be cured with the proper surgical intervention. The diagnosis is generally 3-tiered, involving an initial screening, a confirmation of the diagnosis, and a determination of the specific subtype of PH.

Although prior studies suggested that aldosteronomas are the most common causes of PH (70-80% of cases), later epidemiologic work indicated that the prevalence of PH due to bilateral idiopathic adrenal hyperplasia (IAH) is higher than was previously believed. These reports suggested that IAH may be responsible for as many as 75% of PH cases. Moreover, reports have described a rare syndrome of PH characterized by histologic features intermediate between adrenal adenoma and adrenal hyperplasia. Clinically, the distinction between the 2 major causes of PH is vital because the treatment of choice for each is different. While the treatment of choice for aldosteronomas is surgical extirpation, the treatment of choice for IAH is medical therapy with aldosterone antagonists.

The complete list of entities known to cause PH includes aldosterone-producing adenomas (APAs), aldosterone-producing renin-responsive adenomas (AP-RAs), bilateral adrenal (glomerulosa) hyperplasia or IAH, primary adrenal hyperplasia (PAH), and familial forms of PH. (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.)

Two distinct genetic-familial varieties of PH exist. Sutherland and colleagues first described the type 1 variety of familial PH, glucocorticoid-remediable aldosteronism (GRA), in 1966. In GRA, HTN responds clinically to small doses of glucocorticoids in addition to other antihypertensive agents (see Image 2).1 The type 1 form of familial PH is due to a chimeric gene product that combines the promoter of the 11beta-hydroxylase gene with the coding region of the aldosterone synthetase gene. The type 2 variant of familial PH (which is not glucocorticoid sensitive) was first described in 1991. Although the exact genetic abnormality for type 2 PH has not been identified, data suggest that this type may be associated or closely linked with the MEN1 gene locus on band 11q13.2

Related eMedicine topics:
Adrenal Adenoma
Hyperaldosteronism [Pediatrics: General Medicine]
Hyperaldosteronism [Radiology]
Hypertension [ Nephrology ]
Hypertension [Pediatrics: Cardiac Disease and Critical Care Medicine]
Hypertensive Heart Disease

Physical

The cardinal pathophysiologic anomaly causing primary hyperaldosteronism (PH) syndrome is autonomous aldosterone production. In addition to nonsuppressible aldosterone production, suppressed and poorly stimulative levels of plasma renin are in the presence of only mildly expanded intravascular and extravascular fluid volume. Normal regulation of aldosterone secretion is mediated to varying degrees by renin, serum potassium and sodium levels, intravascular volume status, and adrenocorticotropic hormone (ACTH). Regulation of aldosterone production by these factors may be altered in a variable fashion, depending on the subtype of PH. Generally, APAs and PAH (see Image 1) remain ACTH responsive, while IAH and AP-RAs maintain responsiveness to the renin-angiotensin system (RAS).

In GRA, the RAS is suppressed, and aldosterone is regulated by ACTH because of the chimeric genetic combination of an ACTH-sensitive promoter with the coding regions of the aldosterone synthetase gene (which normally does not have such a promoter). Thus, ambient ACTH levels pathologically overstimulate aldosterone synthesis inappropriately.3 In patients with GRA, the administration of dexamethasone (or any other glucocorticoid) at doses sufficient to suppress ACTH production results in a reduction in aldosterone synthesis and natriuresis and in the correction of the biochemical anomalies of PH.4 Histologic studies in this disease have shown specific hyperplasia of the zona fasciculata, with concomitant atrophy of the zona glomerulosa.

Frequency
United States


The exact prevalence of primary hyperaldosteronism (PH) is unclear. PH appears to contribute more significantly than was previously thought to the prevalence of essential hypertension (HTN). Estimates suggest that 5-15% of essential HTN cases may be due to PH. The prevalence of PH is probably higher in patients who have a low serum potassium level, in patients who are elderly, and in patients who have HTN that is resistant to single medication use.

International

No evidence demonstrates that primary hyperaldosteronism, in its more common forms, occurs in relative excess in any part of the world.

Race

Primary hyperaldosteronism occurs worldwide. Several reports suggest a higher prevalence in African Americans, persons of African origin, and, potentially, other blacks. This appears particularly true of the IAH variant of the disease.

Sex

APAs are more common in women than in men, with a female-to-male ratio of 2:1. IAH is more common in men than in women, with a male-to-female ratio of 4:1.

Age

The typical patient with APA is a woman aged 30-50 years. Accumulating data for IAH suggest different demographics. IAH is more prevalent in men than in women and peaks in the sixth decade of life.

Clinical
History


The clinical presentation of primary hyperaldosteronism (PH) is not distinctive, and the correct diagnosis requires a high index of suspicion on the part of the physician.

* The common clinical scenarios in which the possibility of PH should be considered include the following o Patients with spontaneous or unprovoked hypokalemia, especially if the patient is also hypertensive5
o Patients who develop severe and/or persistent hypokalemia in the setting of low to moderate doses of potassium-wasting diuretics
o Patients with refractory hypertension (HTN)
* The 2 major familial varieties of PH are GRA (type 1 familial PH) and a non – glucocorticoid-remediable type (type 2 familial hyperaldosteronism).
o The recognition of GRA is particularly important because of its implications for patients who are hypertensive and whose family members are apparently unaffected.
o HTN, strokes, and other significant cardiovascular events are described in young persons with this syndrome.
o Although the syndrome is uncommon, heightened levels of suspicion are essential for the diagnosis. Fewer than 150 well-validated cases exist in the literature. All patients with GRA should be treated medically with glucocorticoids and without surgery.
o Although uncommon, GRA may be more prevalent than was previously presumed. A significant subgroup of patients with the milder normokalemic variety of this syndrome is probably incorrectly presumed to have essential HTN.
o A family history of HTN (particularly with a young age of onset), HTN in children, low-renin HTN, and presumed IAH are the typical situations in which this diagnosis should be considered.

Patients with primary hyperaldosteronism do not present with distinctive clinical findings, and a high index of suspicion based on the patient's history is vital in making the diagnosis.

* The findings could include the following o Hypertension (HTN) - This condition almost invariably occurs, although a few rare cases of primary aldosteronism unassociated with hypertension have been described in the literature.
o Weakness
o Abdominal distension
o Ileus from hypokalemia
o Findings related to complications of HTN - These include cardiac failure, hemiparesis due to stroke, carotid bruits, abdominal bruits, proteinuria, renal insufficiency, hypertensive encephalopathy, and hypertensive retinal changes.

It is important to note that primary aldosteronism in and of itself is typically not associated with edema, despite the volume-expanded state associated with it. This is due to spontaneous natriuresis and diuresis (called the aldosterone escape) that occurs in patients with primary aldosteronism and that appears to be mediated by atrial natriuretic peptide (ANP).6, 7 Thus, the finding of significant edema in patients who are presumed to have primary aldosteronism suggests either that a wrong diagnosis has been made or that associated complications, such as renal or cardiac failure, are present.

Causes

The exact cause of sporadic primary hyperaldosteronism (PH) due to an adenoma or hyperplasia is unclear. The existence of trophic factors has been postulated in hyperplasia. Somatic mutations of genes leading to growth advantage in the adrenal adenomatous tissue are a possible, but unproven, cause.

* In familial forms of PH, the molecular basis of GRA is known. GRA is due to a mutation that results from a hybrid gene product.2 The 11beta-hydroxylase and aldosterone synthetase genes that are normally located closely to each other on chromosome 8 cross over to create a novel hybrid gene product. This hybrid gene consists of the regulatory ACTH-responsive sequence of the 11beta-hydroxylase gene, fused to the structural component of the aldosterone synthetase gene.1
* Most sporadic aldosteronomas arise from the zona fasciculata, and they often have surrounding glandular hyperplasia close to the adenoma. This suggests that a proliferative response of cells to some presently unidentified paracrine/autocrine factor occurs. Within this zone of hyperplasia, a clonal change in a single cell is believed to take place, thus providing the nidus for the developing adenoma.
* The genetic basis of type 2 familial hyperaldosteronism is unclear; however, several reports of patients with this condition have shown a loss of heterozygosity close to the MEN1 gene locus (band 11q13).2 Whether menin mutations exist in the adrenal tissue of these patients is currently unknown. This syndrome can histologically manifest as hyperplasia or adenomas.
* The existence of tertiary hyperaldosteronism as a separate entity remains controversial. The entity is presumed to result from chronic elevations in plasma renin levels and secondary hyperaldosteronism, which eventually establishes a state of autonomous, unregulated hyperaldosteronism with a histologic picture of mixed hyperplasia and adenomas in the affected adrenocortical tissue.
o Few well-described cases exist, but in most, the adrenal glands are hyperplastic, often with nodular hyperplasia (which can cause diagnostic confusion). Virtually all of the cases described are in the setting of renal artery stenosis.
o Initially, renin levels are elevated, which is typical of secondary hyperaldosteronism. When the tertiary (autonomous) phase develops, the biochemical profile changes to a low-renin/high-aldosterone state. The paradigm is analogous to the pathogenesis of tertiary hyperparathyroidism.
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