B H
UTTERWORTH EINEMANN
Primary aldosteronism-some genetic, morphological, and biochemical aspects of subtypes
Richard D. Gordon, Michael Stowasser, Shelley A. Klemm, and Terry J. Tunny
Hypertension Unit, Greenslopes Hospital, Brisbane, Australia
Primary aldosteronism is the commonest cause of potentially curable hypertension when diagnosed in both florid and less florid forms. Genetic screening, so far available only for glucocorticoid-suppressible hyperaldosteron- ism, permits diagnosis from birth, before any biochemical or clinical abnormalities appear. Biochemical screen- ing using the aldosterone-to-renin ratio permits diagnosis in the absence of raised aldosterone or of hypokale- mia. Primary aldosteronism occurs in several familial forms. As well as the variety described in 1966 which is ACTH-dependent and glucocorticoid-suppressible, and not so far associated with tumors, another variety de- scribed in 1991 is not glucocorticoid-suppressible and is frequently associated with aldosterone-producing adenomas (APAs). Primary aldosteronism due to adrenocortical hyperplasia, adenoma, or carcinoma can also occur as part of the multiple endocrine neoplasia syndromes, where normoplasia, hyperplasia, benign neoplasia, and malignant neoplasia can exist in the same patient in the same endocrine gland(s) at the same time. The morphology of adrenocortical hyperplasia causing primary aldosteronism ranges from glomerulosa-like (idio- pathic hyperplasia of the adrenals) to fasciculata-like (glucocorticoid-suppressible hyperaldosteronism). The morphology of adrenocortical neoplasia causing primary aldosteronism can also be either predominantly glom- erulosa-like or fasciculata-like, in our experience equally often. Varying morphology of APAs is associated with varying responses of aldosterone to angiotensin II. Tumors predominantly fasciculata-like are unresponsive to angiotensin II, whereas those predominantly glomerulosa-like are responsive to angiotensin II. Both subtypes can be seen in a single family. Primary aldosteronism represents a spectrum of genetic disorders resulting in hyperplasia or neoplasia, but all are associated with some degree of autonomy of aldosterone production, independent of the renin-angiotensin system. (Steroids 60:35-41, 1995)
Keywords: primary aldosteronism; genetics, familial; autonomous; neoplasia
Introduction
The main thrust of this paper is to explore the hypothesis that the clinical, biochemical, and morphological character- istics of what has been termed primary aldosteronism are largely predetermined by genetic inheritance. Thus the clas- sically described subtypes represent a spectrum or a contin- uum in genetic terms. Bilateral and unilateral hyperplasia, diffuse or nodular, unilateral or bilateral adenoma, and car- cinoma can be viewed as differing manifestations of the same underlying genetic defect rather than as distinct and distinctive causes of primary aldosteronism (Table 1). They have in common autonomous production of aldosterone, independent of its normal chronic regulator, the renin-
angiotensin system. This autonomy of aldosterone produc- tion disrupts the normal relationship between renin and al- dosterone, leading to early, diagnostic changes in the aldosterone/renin ratio, and permitting biochemical screen- ing for primary aldosteronism relatively early in the evolu- tion of the disease process. Exploitation of this greater fa- cility in diagnosis has led to a redefinition of the incidence of primary aldosteronism which is the basis of the new and important place of primary aldosteronism in hypertension.
Incidence
Fortunately, when adrenocortical cells are genetically driven to secrete aldosterone autonomously, with the result that the renin-angiotensin system is either not activated or is frankly suppressed, the relationship of aldosterone to its normal regulator, angiotensin, becomes disturbed and a raised aldosterone-to-renin ratio results. When so-called
Address reprint requests to Professor Richard D. Gordon, University De- partment of Medicine, Greenslopes Hospital, Brisbane, Australia 4120.
Steroids 60:35-41, 1995 @ Elsevier Science Inc., 1995 655 Avenue of the Americas, New York, NY 10010
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| normoplasia hyperplasia - unilateral | |
|---|---|
| - bilateral diffuse - bilateral micronodular - bilateral macronodular | |
| neoplasia | - benign (adenoma), single or multiple - malignant (carcinoma) |
“essential hypertensives” are screened by measuring this ratio, normokalemic primary aldosteronism is common, 1-6 making up more than 50% of cases currently diagnosed by us. Such screening methods were not available in the 1960s when an incidence for primary aldosteronism of around 1% of the hypertensive population was estimated and became widely accepted.7-
Diagnosis utilizing a recognizable genetic mutation can antedate by many years (from birth onwards) a diagnosis based on recognizable biochemical abnormalities. The ab- normal, hybrid gene responsible for the familial variety of primary aldosteronism described by Sutherland et al. in 1966 (familial hyperaldosteronism type I [FH-I])10 was de- scribed in 199211 and can now be looked for as part of clinical screening. As yet no similar readily detected genetic defect has been recognized in the variety of primary aldo- steronism associated with tumors which we described in 1991 (familial hyperaldosteronism type II [FH-II]).1 Since the homeostatically determined gradual reduction of renin occurs long before aldosterone rises out of the normal range, and the marked suppression of renin which is so suggestive of primary aldosteronism occurs even later (Fig- ure 1), the aldosterone-renin ratio described by Hiramatsu in 198112 is the most sensitive biochemical screening test so far available. 1-6,13.14 We initially applied this test to all our patients with resistant hypertension, and found that a high proportion of those who were normokalemic had primary aldosteronism. This prompted application to all hyperten- sives, enabling us to diagnose at a rate of 50 new cases of primary aldosteronism per year for the last three years, more than half being normokalemic (Figure 2). In excess of 20 aldosterone-producing tumors per year have been re- moved in this unit during the last three years, after lateral- ization by adrenal venous steroid measurement. 1-6.15
The appearance of hypertension and hypokalemia, per- mitting a strong clinical suspicion of primary aldosteron- ism, is a relatively late development (Figure 1). Whether hypertension appears earlier than hypokalemia will depend on a variety of environmental and genetic factors such as dietary salt and the presence or absence of other genes pre- disposing to or protecting from hypertension (for example the second X chromosome presumably acting via the ovary and estrogens to protect from hypertension).
The evidence for a genetic basis for primary aldosteronism
Familial hyperaldosteronism
With a defined genetic basis and no tumors (FH-I). Ge- netic screening, already possible in the glucocorticoid-
PLASMA ALDOSTERONE (PA)
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PLASMA RENIN ACTIVITY (PRA)
PA/PRA RATIO (log scale)
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suppressible variety of primary aldosteronism, permits identification of those family members carrying the abnor- mal gene at birth, and at a time when they have normal aldosterone, normal renin, normal potassium, and normal blood pressure levels. This absence of clues is of enormous clinical importance, since affected individuals, and even whole families, can escape diagnosis and effective treat- ment for extended periods simply because they do not dis- play the currently accepted classical signs of primary aldo- steronism. Affected females protected by female gender and an independently inherited constellation of genes tending to lower blood pressure are more likely than males to transmit the unsuspected and undetected genetic abnormality to sub- sequent generations before dying from other causes. Thus 21 of 76 members of a family with FH-I so far assessed by us have the hybrid gene, but only two are hypokalemic,
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only two have raised aldosterone levels but 18 have raised aldosterone/renin ratios. An affected female aged 37 years has normal renin, aldosterone, aldosterone/renin ratio, po- tassium and blood pressure. One of her four children aged 7 to 11 years is affected, and, like her, may develop bio- chemical and clinical features of the disease only much later in life (Figure 3).
With genetic basis not yet defined, but with tumors (FH- II). Nineteen of the 325 patients with primary aldosteron- ism diagnosed and treated by us came from eight families containing 2-5 affected members. No affected patients had glucocorticoid-suppressible aldosterone secretion and the hybrid gene was not demonstrable in peripheral blood DNA digests. In six families at least one affected family member had an APA removed. APAs removed from an affected mother aged 78 years and an affected daughter aged 42 years showed different angiotensin responsiveness in vivo and the expected difference in morphology after removal. Clearly, the gene predisposing to primary aldosteronism did not also preselect the tumor type, and a second gene may be involved. The mother’s brother, now aged 67 years, had a craniopharyngioma removed aged 54 years. This is not a recognized association (see below) but could be a reflection of familial inheritance of a mutated tumor-suppressor gene predisposing to formation of endocrine tumors.
Multiple endocrine neoplasia including primary aldosteronism
Primary aldosteronism due to either bilateral overproduc- tion or APA has been described as part of the multiple endocrine neoplasia type I (MEN I) syndrome, 16-19 includ- ing loss of heterozygosity for the MEN I locus on chromo- some 11.20 Presumably, when primary aldosteronism oc- curs as part of MEN I, where an association has been described with chromosome 11q13, there is an interaction of at least two genetic influences. The loss of heterozygos- ity for loci on 11q13 has been interpreted as loss of a tumor- suppressor gene. This might contribute to the development
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of hyperplasia or neoplasia in a variety of endocrine glands. A second mutation might need to occur in each endocrine gland which is affected in a particular individual before full activation of the pathological process occurs. Thus in a single family, with some individuals affected as described above, one or more of several endocrine glands in varying combinations can be involved in hormone overproduction recognizable during life,21 giving rise to great diversity of clinical phenotypes. Such observations have the capacity to significantly broaden our concepts of the syndrome of MEN I.
In our series of 325 patients with primary aldosteronism from whom 118 APAs have so far been removed, there have been four associations with hyperparathyroidism and one with pituitary adenoma. These could presumably be included in the syndrome of MEN I. We have sent DNA extracted from paired blood and tumor samples from 14 patients with aldosterone-producing tumors, who were not known to belong to families with MEN I, to Dr. Nakamura and Dr. Imai at the Cancer Institute, Tokyo, Japan. When restriction fragment length polymorphisms (RFLPs) which map in the region containing the MEN I locus were exam-
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ined, five of 11 tumors which were informative for at least one locus showed loss of heterozygosity. Two distinct re- gions of 11q13 involving a deletion were identified, sug- gesting that at least one gene responsible for aldosterone- producing tumors might also affect development of the kind of tumors associated with MEN I (unpublished observa- tions). Two of these patients had adrenal cancer and two came from families with FH-II.
Influence of the renin gene on the expression of primary aldosteronism
The conventional wisdom in the 1970s and early to mid- 1980s suggested that bilateral adrenal hyperplasia causing primary aldosteronism could be differentiated from APA because aldosterone was stimulated by upright posture and angiotensin infusion in the former but not in the latter. This was considered an important distinction, since unilateral adrenalectomy could often correct all abnormalities in the latter but was considered unhelpful in the former. Consid- eration of the results of postural and angiotensin infusion studies and adrenal vein sampling involving comparison of aldosterone/cortisol ratios in each adrenal vein, compared with a simultaneous ratio in a peripheral vein, suggested that several patients initially categorized as bilateral hyper- plasia had an APA. Cure of hypertension and hypokalemia after removal of an adrenal containing an adenoma was convincing, and in 1987 we reported the new entity of an- giotensin-responsive APAs.22.23 Subsequently we found that one third to one half of all the adenomas removed belonged in this category. Interestingly, these tumors did not produce the hybrid steroids described by Ulick and Chu (24) in excess and thus differed from the more commonly diagnosed angiotensin-unresponsive APAs.25 This distinc- tion was later to become clearer when it was seen that there were morphological differences. Unlike the classical an- giotensin-unresponsive APAs made up of 50-100% zona fasciculata type cells, these angiotensin-responsive APAs consisted of 0-20% zona fasciculata-type cells, the rest be- ing either glomerulosa-like, hybrid or reticularis-like.26
The intra-adrenal renin-angiotensin system (RAS) is ca- pable of stimulating aldosterone production independently of circulating renin, and the elements of the RAS have been shown to be present in some but not all APAs.27-30 We have therefore questioned whether, in the angiotensin-responsive subtype of APA, responsiveness of aldosterone to infused angiotensin despite depressed circulating levels might be a consequence of higher levels of RAS activity in the adeno- ma itself. We therefore measured levels of renin mRNA in adenomas which were angiotensin responsive and compared them with levels in unresponsive adenomas and in normal adrenal cortices. We also examined levels in the non- tumorous adrenal cortex in the adrenals containing the APAs. Levels in angiotensin-responsive APAs were signif- icantly higher than in unresponsive-APAs or in normal adrenal cortex.31,32 Furthermore, levels in the non- tumorous cortex from some adrenals containing the an- giotensin-responsive (but not angiotensin unresponsive) APAs were higher than in normal adrenals. This suggested that the overexpression of renin mRNA in the angiotensin- responsive tumors may lead to overactivity of the intra-
adrenal renin-angiotensin-aldosterone system, so that when further stimulation occurs this already active system re- sponds with increases in aldosterone.
We then went on to question whether variations in the constitutive renin gene might explain differences in the be- havior of angiotensin II-responsive APAs compared with angiotensin-unresponsive APAs. Genomic DNA extracted from peripheral blood was digested by four restriction en- zymes seeking associations between allelic frequencies of the RFLP sites and aldosterone responsiveness to angioten- sin II in patients with APAs. With the Taql (located in the 5’ untranslated region), Hinfl and BglI (located in intron A) RFLPS, a significant difference in allelic frequencies was found between angiotensin-responsive and angiotensin- unresponsive APAs, suggesting that variations at these RFLP sites are in linkage disequilibrium with a site in the region of exon 1/intron A of the renin gene which is asso- ciated with aldosterone responsiveness. This was possibly the first description of an association between allelic vari- ation in the renin gene and a cause of human hypertension (33,34).
Other observed, but so far unexplained associations of primary aldosteronism
In 325 patients with primary aldosteronism we have found two associations of primary aldosteronism with adrenaline- secreting pheochromocytoma and six with fibromuscular hyperplasia of the renal artery. Both these conditions are also known to occur in families, and either chance or some form of genetic linkage may explain the association.
Unilaterality versus bilaterality of expression of hyperaldosteronism
Examples in our series of 325 patients with primary aldo- steronism of (1) apparent cure following removal of appar- ently solitary adenomas by unilateral adrenalectomy fol- lowed by relapse many years later, with overproduction of aldosterone by the remaining adrenal; (2) bilateral solitary APAs; (3) more than one APA >1.5 cm in diameter in the same gland; (4) solitary APA, plus micronodular hyperpla- sia throughout the remaining cortex of that (and presumably the contralateral) gland; and (5) bilateral disease causing primary aldosteronism in one member of a family and a solitary adenoma removed with apparent cure in another member of the family, led us to postulate that primary al- dosteronism is always a bilateral disease with a genetic basis. One of the first reports of bilateral hyperplasia caus- ing primary aldosteronism35 includes an illustration of bi- lateral hyperplasia affecting both glands. In fact, both glands contained multiple nodules, with at least one in each gland large enough and circumscribed enough to be defined as an adenoma. The factors which determine the develop- ment of an apparently solitary adenoma in one patient, mul- tiple adenomas or nodules in a second, and bilateral hyper- plasia in a third appear unknown.
Incidentally discovered adrenal masses (incidentalomas)
With the advent of CT scanning, it is becoming increasingly common for previously unsuspected adrenal masses to be
detected, and this raises difficult questions of identity and appropriate management. On retrospective analysis of 17 consecutive incidentalomas studied over a two-year period by Corsello et al.36 diagnoses of APA (one), FH-I with bilateral nodular hyperplasia (one), cortisol secreting ade- nomas (one), pheochromocytoma (three, two benign, one malignant), and ganglioneuromas (two) were made. A fur- ther five had suppressed PRA and normal plasma aldoste- rone. The authors pointed out how important it is to diag- nose hyperfunctioning or malignant tumors.
Adrenal medullary and adrenal cortical products for which clinical assays are readily available are few in num- ber. If levels of all those readily measurable are normal, the questions of identity and appropriate management remain unanswered. Undoubtably, such adrenal tumors can already be cancerous, or have the capacity to become cancerous given time. Undoubtably, too such apparently non-secreting tumors can be autonomously secreting but achieving levels still within the normal range and therefore clinically inap- parent. Histochemically and immunohistochemically they may have demonstrable capacity to secrete specific hor- mones. It has been pointed out by Shepherd21 that small neoplasms, which are usually benign, can exist undetected for many years in patients with the MEN syndromes. Only 21 of 130 patients with MEN I were diagnosed before the MEN I kinship was recognized.21
With the advent of laparoscopic adrenalectomy, inci- dentally discovered adrenal masses are increasingly likely to have removal as the preferred option, in order to avoid later hyperfunction or malignancy. The possibility that in- cidentalomas are part of an MEN syndrome should always be considered. Excessive production of a currently identi- fiable hormone may not be an inevitable, or even a com- mon, consequence of glandular hyperplasia or neoplasia which is genetically determined.
Regulation of aldosterone in primary aldosteronism
Since this paper forms part of a discussion of normal and abnormal regulation of aldosterone, it is appropriate to con- sider the role of regulators of aldosterone in determining aldosterone levels in primary aldosteronism.
As shown in Table 2, autonomous secretion of aldoste- rone, genetically determined, is the hallmark of primary aldosteronism, and is therefore the essential contributor to aldosterone excess in this condition. Since we may define autonomous secretion as that which is independent of the normal regulator, renin-angiotensin, we can include with the presently genetically undefined biosynthetic defects which cause non-glucocorticoid-suppressible forms of pri-
Table 2 Regulation of aldosterone secretion in primary aldo- steronism
1. Autonomous secretion (genetically determined)
2. Angiotensin II - circulating
- intra-adrenal
3. ACTH
4. Potassium
5. Atrial natriuretic peptide
mary aldosteronism, FH-II and MEN I, the glucocorticoid- suppressible (ACTH-driven) forms, of which FH-I is the only currently recognized example.
In FH-I where the tissue hyperresponsive to ACTH is probably zona fasciculata (ZF), and in the variety of APA which is composed ≥50% of ZF cells, there is hypersensi- tivity to ACTH but resistance to angiotensin II. This is the reason why plasma aldosterone falls despite morning as- sumption of upright posture in these two conditions. In the case of FH-I, there are normal genes present in addition to the hybrid gene, but they have been dormant because en- dogenous renin-angiotensin has been chronically sup- pressed by hypervolemia and hypertension.37,38 When oversecretion of aldosterone has been corrected by partial or complete suppression of endogenous ACTH, the resultant hypovolemia stimulates endogenous angiotensin II produc- tion, the normal aldosterone synthase genes are stimulated, and aldosterone then becomes responsive to angiotensin II and more or less normally regulated.37,38 It is our impres- sion, however, that the aldosterone/PRA ratio remains low for very long periods after initiation of treatment, and al- dosterone relatively hyporesponsive to angiotensin II.
In all varieties of primary aldosteronism, FH-I, APA (angiotensin responsive and unresponsive), bilateral hyper- plasia, and adrenocortical carcinoma, aldosterone secretion is stimulated briefly but significantly by ACTH. However, if ACTH administration is continued for more than 24 h, significant, persistent suppression of aldosterone secretion occurs in all forms except FH-I. When endogenous ACTH secretion is suppressed by dexamethasone administration, aldosterone secretion falls to and remains at very low levels for at least 5 days in FH-I, and falls significantly in all other varieties but recovers to at least 25% (and sometimes 80%) of basal by day 3. In some of these other varieties, chronic partial suppression of ACTH by physiological doses of glu- cocorticoid might (theoretically at least) lower aldosterone levels sufficiently to be effective treatment. It is unlikely to become a popular option.
The renin-angiotensin system is the normal chronic reg- ulator of aldosterone, and in bilateral hyperplasia and in angiotensin-responsive APAs the tissue responsible for the aldosterone excess is responsive to infused angiotensin. In angiotensin-unresponsive APA and in FH-I there is no al- dosterone response to infused angiotensin. Findings in transgenic animals with an extra renin gene, with high intra- adrenal and low circulating levels of renin and angiotensin but raised aldosterone excretion,39 suggest that the intra- adrenal renin-angiotensin system can be very important in the regulation of aldosterone secretion. This appears to be so in the case of angiotensin-responsive APA, where there is evidence for over-expression of the renin gene in the tumors and, in at least some cases, in the surrounding non- tumorous cortex (see above).
Potassium is an important regulator of aldosterone in every situation, including primary aldosteronism of all types. Here it is usually reduced potassium levels which have a significant impact on prevailing aldosterone levels, and low potassium levels should always be raised to 4.0 mmol/L before the influence of other regulators is assessed.
Atrial natriuretic peptide (ANP) inhibits aldosterone se- cretion directly, as well as also inhibiting renin secre-
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tion.40,41 In primary aldosteronism, ANP levels are ele- vated,42,43 and presumably act to reduce aldosterone secretion, but clearly not enough to fully correct the excess. It is reasonable to suggest, however, that hyperaldosteron- ism would be more severe if ANP was not secreted in re- sponse to the volume expansion44,45 and raised blood pres- sure46,47 which accompany it.
Acknowledgments
We gratefully acknowledge the support of the National Health and Medical Research Council of Australia, and the Australian Government Department of Veterans’ Affairs Central Health and Medical Research Committee.
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