Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1382_Библиотеки_им_академика_М_И_Перельмана.pdf
360
ENDOCRINE SURGERY
Primary Hyperaldosteronism
PHA is due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa.
This leads to suppressed renin, hypertension,
and in more severe forms, hypokalemia. The
most common types of PHA are
aldosterone-producing adenomas (Conn’s
syndrome), accounting for approximately a
third of cases;
idiopathic bilateral adrenal hyperplasia,
accounting for about two thirds of cases;
primary adrenal hyperplasia, a rare condition
defined as angiotensin-II resistant tumors or
multinodular adenomas on a background of
adrenal hyperplasia;
familial forms of PHA (very rare):
Glucocorticoid-remediable aldosteronism
(familial hyperaldosteronism type I) is an
autosomal dominant disorder caused by a
hybrid gene mutation formed by a cross
over between the ACTH-responsive regulatory portion of the 11b-hydroxylase
(CYP11B1) gene and the coding region of
the aldosterone synthase (CYP11B2) gene.
High levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol
are produced under the control of ACTH
and are suppressible by physiological doses
of exogenous glucocorticoids.
Familial hyperaldosteronism type II is a
very rare condition with autosomal dominant inheritance whose precise genetic
cause remains to be elucidated. Such
patients have autonomous aldosterone
hypersecretion which is not suppressible
by dexamethasone [2].
There is a clear need to differentiate between
patients with aldosterone-producing adenomas
(i.e., Conn’s syndrome) and patients with bilateral adrenal hyperplasia. The first group can be
cured by unilateral adrenalectomy. In the second group, surgery is not indicated and patients
should receive targeted medical treatment with
mineralocorticoid receptor antagonists [3, 4].
Incidence of Hyperaldosteronism in Unselected
Hypertensive Patients
A lack of a universally accepted definition
means the exact prevalence of PHA cannot be
determined. Additionally, there is a failure to
identify patients during the normotensive and/
or normokalemic phases in the evolutionary
development of a disease eventually characterized by hypertension and hypokalemia.
Formerly, fewer than 1% of patients with
hypertension were believed to have PHA, and
hypokalemia was considered a prerequisite for
pursuing diagnostic tests for PHA. The ‘‘rediscovery’’ in the last decade of the normokalemic
phase of PHA (originally described by Jerome
Conn) and the wide application of screening
with aldosterone/renin ratio in all hypertensive
patients have triggered a potential ‘‘epidemic’’ of
PHA in recent years.
Currently, PHA is regarded as the commonest potentially curable form of hypertension
identified in at least 5–10% of unselected hypertensive patients (up to 30% in some series).
Such findings could translate into many millions of patients.
To illustrate this, in a retrospective review of
practice in centers in five continents, the application of screening with aldosterone/renin
ration led to a 5- to 15-fold increase in the
identification of PHA and up to sixfold increase
in the annual detection rate of aldosterone-producing adenomas [5]. Similarly, one Australian
Unit reported that the decision to screen all (not
just hypokalemic or resistant) hypertensives by
aldosterone/renin ratio testing led to a 10-fold
increase in detection rate of PHA and fourfold
increase in removal rate of aldosterone-producing adenomas [6].
A very high incidence of PHA (19%) was
detected in 420 hypertensive patients from Central Europe (Czech Republic) [7]. In an analysis
of 305 Italian hypertensive patients, 10% were
found to have PHA, a much higher incidence
than in a control group ofnormotensives (1.5%)
[8]. A proven (minimum) incidence for PHA of
8.5% was demonstrated in a study of 199 normokalemic hypertensives demonstrating that
restricting investigations only to hypokalemic
hypertensives will lead to an underestimation
of the true incidence of PHA [9].
Similarly, in a study of 1,180 consecutive
hypertensive patients presenting in 14 centers,
an average of 4.8% had aldosterone-producing
adenomas, with a higher incidence in centers
were adrenal sampling was available [10].
Similar figures have been reproduced in
studies on hypertensive Chinese patients [11].
361
ADRENAL VENOUS SAMPLING
Interestingly, a PHA incidence of 5.5% was also
found in a group of 125 normokalemic patients
with solid adrenal incidentalomas [12].
Despite this growing enthusiasm, some clinicians have raised concerns regarding widespread use of aldosterone/rennin ratio as a routine part of assessment of all hypertensives. Such
authors highlight the risk that suchprotocolswill
lead to massive increases in costs, both in money
and in morbidity, while providing benefit to only
a very small number of patients [13].
Diagnostic Tests Performed Before Proceeding
to AVS
Aldosterone/renin ratio is the screening test of
choice for PHA. The cutoff levels vary between
laboratories (range 20:1 to 50:1 if PAC is
expressed as ng/dl and PRA in ng/ml/h). Posture
and time of sampling should be standardized
both within and between centers to minimize
variability in cutoff levels [14]. An alternative
screening test is the measurement of aldosterone/renin ratio after 50 mg Captopril [15].
Antihypertensive therapy can interfere with
the interpretation of aldosterone/renin ratio.
False-positive results can be obtained in
patients on beta-blockers, clonidine, nonsteroidal antiinflammatories, and the contraceptive
pill. False-negative results can be obtained in
patients on diuretics, ACE inhibitors, calcium
channel blockers, patients with reno-vascular
hypertension or malignant hypertension, and
patients on very-low sodium diets. However, a
positive screening result is not diagnostic and
requires a confirmatory test.
Aldosterone suppression test after oral salt
loading. The diagnosis of PHA is further sug-
gested by an inability to suppress aldosterone
production (estimated from urine aldosterone
concentration) with a high sodium diet. Similarly, PHA is confirmed by the failure to suppress plasma aldosterone concentration to
below 10 ng/dl after intravenous salt loading
with 2 l of N-saline during 2–4 h, even though
the test is positive in only 3/10 patients with
Conn’s syndrome.
Once the diagnosis of PHA has been established, it is necessary to exclude glucocorticoidremediable aldosteronism. Subsequently there
is a need to differentiate unilateral versus bilateral disease and then proceed to localization
studies.
Posture test. The bedside posture test was originally promoted as a means of identifying
patients with aldosterone-producing adenomas.
In patients with idiopathic PHA (i.e., bilateral
adrenal hyperplasia) plasma aldosterone concentration usually increases after standing for 4 h,
whereas a postural decrease in aldosterone levels
is seen in patients with unilateral disease (i.e.,
Conn’s syndrome). This phenomenon is due to
the fact that aldosterone-producing adenomas are
unresponsive to angiotensin but still follow the
circadian rhythm of ACTH/cortisol axis. The test
can produce false-negative results and the overall
accuracy was calculated to be 85% in a series of
246 patients pooled from 16 studies [16]. A report
from the National Institutes of Health on 48
patients with PHA found that the posture test
could identify as many as 30% with a unilateral
source and the authors concluded that the posture
test was an important step in the decision-making
tree leading to surgical intervention.
Adrenal Imaging. CT scan is the initial localization procedure. If a solitary unilateral
macroadenoma larger than 1 cm is found in
the presence of a normal contralateral adrenal
gland, some authors would argue that no other
localization studies are necessary and unilateral
adrenalectomy can be considered.
This view is supported by a series of 50 patients
where adrenalectomy was performed in 35
patients (70%) solely on the information offered
by CT scans, and all these patients were cured
[17]. Similarly, in a series of 60 patients from
San Francisco 80% of patients had their adrenal
tumours lateralized based on CT scans, MRI, or
both. All patients achieved biochemical cure [18].
In contrast, in a series of 203 PHA patients the
Mayo Clinic reported that based on CT findings
alone, 42 patients (22%) would have been incorrectly excluded as candidates for adrenalectomy,
and 48 (25%) might have had unnecessary or
inappropriate adrenalectomy [19]. In a further
study of 62 patients, CT imaging was either inaccurate or provided no additional information in
68% of the patients with primary aldosteronism,
suggesting that adrenal CT imaging alone is not a
reliable method to differentiate between different
causes of primary aldosteronism [20].
Adrenal Venous Sampling
Formerly, AVS was usually reserved for patients
in whom both CT and isotope scanning of the
362
ENDOCRINE SURGERY
adrenals were inconclusive and not able to reliably distinguish between unilateral and bilateral
adrenal aldosterone hypersecretion. For this subgroup of patients adrenal vein sampling is essential to establish the correct diagnosis of PHA
[21]. For example, in one study the results of
AVS altered the management in 14 of 18 patients,
suggesting AVS is essential in patients with equivocal CT scans to avoid unnecessary and inappropriate adrenalectomy [22]. Functional adrenal isotope scanning has largely been abandoned
and indeed isno longer available inthe UK. More
recently AVS has become an integral part of the
preoperative work up of patients with Conn’s
tumor in many large centers.
Protocol for AVS
Patients are maintained recumbent overnight,
prior, and during the procedure. Relaxation
techniques may be used to eliminate stress
response.
CT is useful in planning adrenal vein sampling
by demonstrating the anatomy and positions of
the adrenal veins. A small amount of contrast
material is injected gently and slowly into the
adrenal vein; it is not necessary to perform formal
venography to outline the entire gland.
Simultaneous blood samples from each adrenal vein, renal veins, inferior vena cava, and
peripheral (antecubital) vein are drawn for
plasma aldosterone and cortisol measurement.
All aldosterone measurements are normalized
according to the cortisol concentration in the
sample.
The use of adrenocorticotropic hormone
(ACTH) stimulation during AVS remains debatable. Infusion of ACTH before and during the
procedure minimizes episodic changes in aldosterone secretion caused by stress-induced endogenous ACTH release.
Some physicians argue that defining contralateral suppression in patients with Conn’s syndrome is facilitated by ACTH stimulation. In
contrast, others found that lateralization of
aldosterone secretion side did not improve: in
a prospective study of 24 consecutive patients a
high-dose ACTH (250 mg intravenous) bolus
administered at the beginning and 30 min into
the procedure led to a significant increase of
aldosterone from contralateral adrenal vein
blood, but not from the APA gland. Such results
do not support the usefulness of high-dose
ACTH testing to improve the diagnostic accuracy of AVS [23].
This topic was explored further in a study of 31
patients. In half the procedures, simultaneous
bilateral adrenal venous catheterization and sampling was performed before and after intraprocedural ACTH administration. In the remaining
half, sequential catheterization of the left and
right adrenal veins was performed during continuous ACTH infusion 1 h before and throughout
AVS. Simultaneous bilateral AVS localized unilateral disease in seven of eight cases (88%) and was
nondiagnostic in one case (13%). Sequential bilateral AVS localized unilateral disease in four of
four cases (100%). Baseline (prestimulation) sampling did not contribute unique diagnostic information in any case and provided contradictory or
confounding information in 3 of 11 simultaneous
AVS procedures (27%). Both simultaneous and
sequential AVS are adequate studies; however,
obtaining baseline prestimulation samples during
simultaneous AVS is unnecessary and increases
the cost of the procedure [24].
Criteria for Positive
Localization
To confirm that the vein is draining the majority
of adrenal cortical blood, the adrenal vein sample should have a significantly higher level of
cortisol than a peripheral sample. Access to the
adrenal veins is considered successful if the
cortisol gradient (central to peripheral) exceeds
2.0. Success rate of cannulation varies between
centers and is likely to be increase with experience. Some achieved a 95% success rate [25],
while others reported success in only 75% [26].
Adrenal glands that are producing excess
aldosterone demonstrate an aldosterone/cortisol ratio that is higher than the peripheral value.
A central/peripheral aldosterone ratio more
than 3.0 was accepted as evidence of an ipsilateral (autonomous) lesion, whereas ratios less
than 2.0 were taken as evidence of contralateral
suppression (i.e., sampling from the uninvolved
gland) provided the cortisol central/peripheral
ratio exceeded 10.
The criteria used to establish unilateral
autonomy (dominance) differ. Doppman et al.
363
ADRENAL VENOUS SAMPLING
[27] emphasized the importance of identifying
contralateral adrenal suppression in localizing
the abnormal gland. Other reports have placed
more emphasis on the differential aldosterone
output from the two glands.
When bilateral access is not achieved, lateralization can still be demonstrated when only
one adrenal vein (the contralateral) is accessed.
Of 39 patients who underwent adrenalectomy for presumed unilateral disease, only 16
patients had ‘‘ideal’’ AVS, and 18 patients had
only unilateral cannulization on AVS. Despite
this, 11 appeared to lateralize and 7 had imaging
to support unilateral disease. Postoperatively,
15 (82%) had a significant reduction in their
blood pressure, and 7 (39%) of these were
cured. Surgery failed in two patients; both
were found to have bilateral hyperplasia. Bilaterally unsuccessful cannulization (n = 5) still
lateralized in three patients, and two patients
had nodules on computed tomography scan.
All five patients had significant reduction in
blood pressure, and two were cured. Following
‘‘less than ideal’’ AVS, clinical decisions can
still be made using anatomic and partial AVS
data [28].
Complications
The technique is technically demanding, invasive,
and is associated with a recognized morbidity
including bleeding (1–5%), rupture/thrombosis
of adrenal veins, and adrenal infarction (1%).
Despite the limitation and potential morbidity,
AVS should be performed in specialized endocrine centers for selected patients with PAH
when diagnostic difficulty arises with conventional imaging. This diagnostic tool can facilitate
the management strategy, especially with reference to the adoption of surgical treatment, in
patients with PHA.
References
1. Lau JH, Drake W, Matson M. The current role of venous
sampling in the localization of endocrine disease. Cardiovasc Intervent Radiol. 2007;30(4):555–70.
2. Jackson RV, Lafferty A, Torpy DJ, Stratakis C. New
genetic insights in familial hyperaldosteronism. Ann N
Y Acad Sci. 2002;970:77–88.
3. Al Fehaily M, Duh QY. Clinical manifestation of aldosteronoma. Surg Clin North. Am 2004;84(3):887–905.
4. Mulatero P, Dluhy RG, Giacchetti G, Boscaro M, Veglio
F, Stewart PM.Diagnosis of primary aldosteronism:
from screening tosubtype differentiation.Trends Endocrinol Metab. 2005;16(3):114–9.
5. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon
RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF
Jr. Increased diagnosis of primary aldosteronism,
including surgically correctable forms, in centers from
five continents.J Clin Endocrinol Metab. 2004;89(3):
1045–50.
6. Stowasser M, Gordon RD. Primary aldosteronism –
careful investigation is essential and rewarding. Mol
Cell Endocrinol. 2004;217(1–2):33–9.
7. Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky
J Jr. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe
region. J Hum Hypertens. 2003;17(5):349–52.
8. Fardella CE, Mosso L, Gomez-Sanchez C, Cortes P, Soto
J, Gomez L, Pinto M, Huete A, OestreicherE, ForadoriA,
Montero J. Primary hyperaldosteronism in essential
hypertensives: prevalence, biochemical profile, and
molecular biology. J Clin Endocrinol Metab.
2000;85(5):1863–7.
9. Gordon RD, Stowasser M, Tunny TJ, Klemm SA,
Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp
Pharmacol Physiol. 1994;21(4):315–8.
10. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B,
Ferri C, Ganzaroli C, Giacchetti G, Letizia C, Maccario
M, Mallamaci F, Mannelli M, Mattarello MJ, Moretti A,
PHAumbo G, ParentiG, Porteri E,Semplicini A, Rizzoni
D, Rossi E, Boscaro M, Pessina AC, Mantero F. PAPY
Study Investigators. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive
patients. J Am Coll Cardiol. 2006;48(11):2293–300.
11. Loh KC, Koay ES, Khaw MC, Emmanuel SC, Young WF
Jr. Prevalence of primary aldosteronism among Asian
hypertensive patients in Singapore. J Clin Endocrinol
Metab. 2000;85(8):2854–9.
12. Bernini G, Moretti A, Argenio G, Salvetti A. Primary
aldosteronism in normokalemic patients with adrenal
incidentalomas. Eur J Endocrinol. 2002;146(4):523–9.
13. Kaplan NM. The current epidemic of primary aldosteronism: causes and consequences. J Hypertens.
2004;22(5):863–9.
14. Tiu SC, Choi CH, Shek CC, Ng YW, Chan FK, Ng CM,
Kong AP. The use of aldosterone-renin ratio as a
diagnostic test for primary hyperaldosteronism and
its test characteristics under different conditions of
blood sampling. J Clin Endocrinol Metab.
2005;90(1):72–8.
15. Rossi E, Regolisti G, Negro A, Sani C, Davoli S, Perazzoli
F. High prevalence of primary aldosteronism using
postcaptopril plasma aldosterone to renin ratio as a
screening test among Italianhypertensives. AmJ Hypertens. 2002;15(10 Pt 1):896–902.
16. Young WJ, Klee G. Primary aldosteronism – diagnostic
evaluation. Endocrinol Metab Clin North Am.
1988;14:367.
17. Lombardi CP, Raffaelli M, De Crea C, Rufini V, Treglia
G, Bellantone R. Noninvasive adrenal imaging in hyperaldosteronism: is it accurate for correctly identifying
patients who should be selected for surgery? Langenbecks Arch Surg. 2007;392(5):623–8.
364
ENDOCRINE SURGERY
18. Tan YY, Ogilvie JB, Triponez F, Caron NR, Kebebew EK,
Clark OH, Duh QY. Selective use of adrenal venous
sampling in the lateralization of aldosterone-producing
adenomas. World J Surg. 2006;30(5):879–85.
19. Young WF, Stanson AW, Thompson GB, Grant CS,
Farley DR, van Heerden JA. Role for adrenal venous
sampling in primary aldosteronism. Surgery.
2004;136(6):1227–35.
20. Magill SB, Raff H, aShaker JL, Brickner RC, Knechtges
TE, Kehoe ME, Findling JW.Comparison of adrenal vein
sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab.
2001;86(3):1066–71.
21. Magill SB, Raff H, Shaker JL, Brickner RC, Knechtges
TE, Kehoe ME, FindlingJW. Comparison of adrenal vein
sampling and computed tomography in the differentiation of primary aldosteronism. J Clin Endocrinol Metab.
2001;86(3):1066–71.
22. Toniato A, Bernante P,Rossi GP,Pelizzo MR.The role of
adrenal venous sampling in the surgical management of
primary aldosteronism. World J Surg. 2006;30(4):624–7.
23. Rossi GP, Ganzaroli C, Miotto D, De Toni R, PHAumbo
G, Feltrin GP, Mantero F, Pessina AC. Dynamic testing
with high-dose adrenocorticotrophic hormone does not
improve lateralization of aldosterone oversecretion
in primary aldosteronism patients. J Hypertens.
2006;24(2):371–9.
24. Carr CE, Cope C, Cohen DL, Fraker DL, Trerotola SO.
Comparison of sequential versus simultaneous methods
of adrenal venous sampling. J Vasc Interv Radiol.
2004;15(11):1245–50.
25. Nwariaku FE, Miller BS, Auchus R, Holt S, Watumull L, Dolmatch B, Nesbitt S, Vongpatanasin W,
VictorR,WiansF,LivingstonE,SnyderWH3rd.
Primary hyperaldosteronism: effect of adrenal vein
sampling on surgical outcome. Arch Surg.
2006;141(5):497–502.
26. Sheaves R, Goldin J, Reznek RH, Chew SL, Dacie JE,
Lowe DG, Ross RJ, Wass JA, Besser GM, Grossman
AB. Relative value of computed tomography scanning
and venous sampling in establishing the cause of primary hyperaldosteronism. Eur J Endocrinol.
1996;134(3):308–13.
27. Doppman JL, Gill JR, Miller DL, Chang R, Gupta R,
Friedman TC, Choyke PL, Feuerstein IM, Dwyer AJ,
Jicha DL, Walther MM, Norton JA, Linehan WM. Distinction between hyperaldosteronism due to bilateral
hyperplasia and unilateral aldosteronoma: reliability of
CT. Radiology. 1992;184:677–682.
28. Harvey A, Kline G,Pasieka JL. Adrenal venous sampling
in primary hyperaldosteronism: comparison of radiographic with biochemical success and the clinical decision-making with "less than ideal" testing. Surgery.
2006;140(6):847–53.
27
Primary Hyperaldosteronism
Joseph DiNorcia and James A. Lee
Introduction
In 1955, Dr. Jerome Conn described a female
patient with signs of hypertension and hypokalemia and symptoms of weakness and polyuria [1].
Exploratory laparotomy led to the resection of an
adrenocortical adenoma. The patient’s blood
pressure and metabolic derangements normalized after the operation, leading Conn to hypothesize that these signs and symptoms were due to
the adenoma’s excessive secretion of aldosterone.
True Conn’s syndrome is hyperaldosteronism secondary to an aldosterone-producing
adenoma, though other causes of aldosterone
excess have been identified. This chapter
explores the causes of primary hyperaldosteronism. After a brief review of the relevant physiology, we will delineate the various subtypes of
primary hyperaldosteronism and then examine
the epidemiology, pathologic features, clinical
characteristics, diagnostic methods, localizing
studies, and ultimate treatment options for this
potentially curable cause of hypertension.
Physiology
Aldosterone also promotes sodium absorption by
other epithelia, including the salivary and sweat
glands and the gastrointestinal mucosa. The ultimate effect is increased salt load which increases
water retention. Hyperaldosteronism thus leads to
expansion of the intravascular volume at the
expense of potassium and hydrogen ions, resulting
in hypertension, hypokalemia, and alkalosis [4].
The renin–angiotensin system is a principal
regulator of aldosterone secretion (Fig. 27.1).
In response todecreased renal perfusion, decreased
plasma sodium concentration, or sympathetic nervous system stimulation, the juxtaglomerular cells
of the kidney release renin. Renin enzymatically
cleaves angiotensinogen (produced in the liver) to
angiotensin I. Angiotensin-converting enzyme
(ACE) in the lungs and endothelium then cleaves
angiotensinItoformangiotensinII.AngiotensinII
directly stimulates aldosterone biosynthesis and
release from the adrenal gland, increasing sodium
absorption and expanding the intravascular
volume in an effort to increase renal blood flow.
Potassium and to a lesser degree adrenocorticotropic hormone (ACTH) also regulate aldosterone
secretion, but their implications are less relevant
to this discussion [4, 5].
Aldosterone, the potent mineralocorticoid
secreted by the zona glomerulosa of the adrenal
cortex, regulates the body’s fluid and electrolyte
balance by stimulating sodium retention and
potassium and hydrogen ion secretion in the
distal convoluted tubules of the kidneys [2, 3].
J.G.H. Hubbard et al. (eds.), Endocrine Surgery, Springer Specialist Surgery Series,
DOI 10.1007/978-1-84628-881-4_27, Ó Springer-Verlag London Limited 2009
General Considerations
Hyperaldosteronism can be divided into primary
and secondary forms (Table 27.1). Primary hyperaldosteronism is characterized by autonomous
365
ENDOCRINE SURGERY
Fig. 27.1. A schematic diagram illustrates how the renin–angiotensin system regulates aldosterone production.
366
Table 27.1. Causes of Hyperaldosteronism
Primary Hyperaldosteronism
Aldosterone-producing adrenocortical adenoma (2/3)
Idiopathic bilateral adrenal hyperplasia (1/3)
Aldosterone-producing adrenocortical carcinoma (<1%)
Unilateral adrenal hyperplasia (<1%)
Familial hyperaldosteronism, Types I and II (<1%)
Secondary Hyperaldosteronism
Renal artery stenosis
Congestive heart failure
Cirrhosis
Pregnancy
adrenal hypersecretion of aldosterone with consequent suppressed plasma renin levels.
Primary hyperaldosteronism has several subtypes. Aldosterone-producing adrenocortical
adenoma (aldosteronoma) and idiopathic
hyperaldosteronism (bilateral adrenal hyperplasia) are the most common causes and
account for 95% of all cases [6–10]. Uncommon
causes include aldosterone-producing adrenocortical carcinoma, unilateral adrenal hyperplasia, familial hyperaldosteronism type 1
(glucocorticoid-suppressible hyperaldosteronism), and familial hyperaldosteronism type 2
[11, 12]. Familial hyperaldosteronism type 1 is
an autosomal dominant genetic disorder that
results from the fusion of the ACTH-responsive
11-beta-hydroxylase gene promoter to the coding sequence of the aldosterone synthase gene.
Aldosterone synthesis thus is under ACTH stimulation resulting in excess aldosterone production [13, 14]. Patients have a family history of
early onset hypertension. Diagnosis can be made
by measuring 24 h urine samples for elevated 18hydroxycortisol and 18-oxocortisol levels or by
genetic testing [15, 16]. Exogenous glucocorticoid therapy with agents such as dexamethasone
suppresses ACTH and the overproduction of
aldosterone, normalizing both blood pressure
and potassium levels [12, 17]. Familial hyperaldosteronism type 2 is another rare cause and
refers to the familial occurrence of aldosteroneproducing adrenocortical adenoma, unilateral
adrenal hyperplasia, or both [18–21].
The appropriate surgical or medical treatment of primary hyperaldosteronism depends
on the correct differentiation of the various
subtypes. Aldosterone-producing adrenocortical adenoma, for example, is treated by
unilateral adrenalectomy. Idiopathic hyperaldosteronism, on the other hand, does not
respond to adrenalectomy and is treated with
aldosterone antagonists. From a treatment
standpoint, the subtypes of primary hyperaldosteronism thus can be divided into two
groups: (1) unilateral adrenal aldosterone
hypersecretion that is amenable to surgical
resection (e.g., aldosteronoma, unilateral hyperplasia, carcinoma, and familial hyperaldosteronism type 2) and (2) bilateral adrenal aldosterone hypersecretion that is managed medically
(e.g., idiopathic hyperaldosteronism and familial hyperaldosteronism type 1) [6, 7].
367
PRIMARY HYPERALDOSTERONISM
In secondary hyperaldosteronism, the adrenal glands function normally, and increased
plasma renin levels stimulate the hypersecretion
of aldosterone. Conditions associated with elevated plasma renin levels such as renal artery
stenosis, congestive heart failure, cirrhosis, and
normal pregnancy cause increased plasma
aldosterone levels [22, 23]. Renin-secreting
tumors are another rare cause of secondary
hyperaldosteronism [24]. Treatment of secondary hyperaldosteronism involves management
of the underlying condition.
Epidemiology
Primary hyperaldosteronism is twice as common in women as in men, usually occurring
between ages 30 and 50 [25, 26]. Early studies
indicated that primary hyperaldosteronism was
an uncommon cause of hypertension with a
prevalence of <1 to 2% [8, 27]. In these studies,
hypokalemia was thought to be a necessary
finding, and screening thus was limited to
patients with low potassium levels [28–30].
More recent studies have shown that the majority of patients with primary hyperaldosteronism
have normal potassium levels, indicating that
the early studies likely underestimated the true
prevalence [31–33]. In addition, with the more
widespread use of the plasma aldosterone
concentration (PAC) to plasma renin activity
(PRA) ratio as a screening test in patients
with resistant hypertension or who are on multiple medications, the detection of primary
hyperaldosteronism is increasing [33–41]. The
true prevalence is between 5 and 13% in general
hypertensive populations [8] and perhaps as
high as 20% in patients with resistant hypertension [42, 43].
Controversy persists, however, as some argue
that the PAC to PRA ratio lacks specificity to be
used as a screening test. They note that overreliance on the ratio asa screening test combined
with a selectionbias based on patients referred to
hypertension specialty clinics contribute to an
exaggeration of prevalence. Moreover, varying
thresholds for what is considered an elevated
ratio, considerable variation in laboratory assays,
and lack of standardization have resulted in a
broad range of prevalence estimates [44–46]. As
the incidence and prevalence of the disease
increase, some clinicians suggest screening all
hypertensive patients for primary hyperaldosteronism, although this subject also is under much
debate [47–49].
Pathologic Features
Aldosteronomas are usually solitary, unilateral,
and small (typically less than 2 cm in diameter)
[50]. Although adrenal tumors that hypersecrete aldosterone rarely are malignant, aldosterone-secreting adrenocortical carcinoma should
be suspected in a unilateral tumor larger than
4 cm [51]. Grossly, adenomas have a characteristic golden yellow appearance on cross section
due to the presence of intracytoplasmic lipid
[25, 52, 53] (Fig. 27 2). Microscopically, they
have large, lipid-rich clear cells. Idiopathic
hyperaldosteronism, on the other hand, usually
involves both adrenal glands and appears as
macronodular or micronodular hyperplasia on
gross and microscopic examination [54, 55].
These pathologic features, however, are not
absolute, but rather represent a spectrum of
Fig. 27.2. A section through the adrenal gland reveals an
aldosteronoma.
368
ENDOCRINE SURGERY
disease. Glands with adenomas, for example,
often have surrounding areas of macronodular
and micronodular hyperplasia [56–58]. Rare
reports of unilateral hyperplasia and bilateral
solitary adenomas further highlight the variable
pathologic presentations of primary hyperaldosteronism that must be differentiated prior
to developing a treatment strategy [59, 60].
Clinical Characteristics
Hypertension, with or without hypokalemia,
results from the effect of excess aldosterone in
the distal nephronas describedabove. The hypertension is moderate to severe and refractory to
medical therapy, though malignant hypertension
is rare [61–63]. Headache is common, likely secondary to hypertension. Symptoms that result
from hypokalemia are nonspecific and when present include malaise, muscle weakness, paresthesias, cramps,polyuria, andpolydipsia. Tetanyand
paralysis are rare occurrences [63]. Peripheral
edema also is rare despite expanded extracellular
fluid volume due to ‘‘aldosterone escape,’’ a phenomenon in which mechanisms involving atrial
natriuretic peptide and pressure natriuresiscounteract the sodium-retaining effects of excess
aldosterone and return the extracellular fluid
volume to a steady state [64–66]. Hyperaldosteronism also induces significant cardiac and
metabolic alterations including left ventricular
hypertrophy, which leads to an increased risk of
myocardial infarction and stroke, and insulin
resistance, which leads to glucose intolerance
and increased body mass index (BMI) [67–70].
These deleterious effects are mediated in part by
aldosterone receptors in the heart, brain, and
blood vessels throughout the body [71]. Normalization of circulating aldosterone levels in addition to control of hypertension and hypokalemia
thus is a vital part of the management plan for all
patients with primary hyperaldosteronism [8].
Diagnosis
Refractory hypertension and hypokalemia
should raise suspicion of hyperaldosteronism.
Hypokalemia, however, is not an obligatory
finding. Indeed, recent studies have consistently
found that hypokalemia occurs in a minority of
patients with primary hyperaldosteronism, and
many researchers now advocate screening for
primary hyperaldosteronism whether or not
hypokalemia is present [32, 37, 72, 73]. When
primary hyperaldosteronism is suspected, it is
necessary first to establish the presence of
hyperaldosteronism biochemically and then to
distinguish surgically correctable unilateral disease from medically treatable bilateral disease.
Biochemical Diagnosis
Elevated aldosterone levels with suppressed
renin levels are characteristic biochemical features of primary hyperaldosteronism. An initial
test that determines the PAC to PRA ratio by
measuring PAC (in ng/dL) and PRA (in ng/mL/
hr) has been recommended in several studies to
screen for patients with primary hyperaldosteronism [44, 74–76]. Elevated PAC levels in combination with an elevated PAC:PRA ratio further
improve the screening strategy [77]. While different authors report variable cutoff values for
both the PAC:PRA ratio and the PAC level, a
ratio greater than 20–30 in the setting of a
PAC level greater than 15–20 ng/dL generally
are reliable criteria to secure the diagnosis
[10, 78–80].
Certain medications that affect the reninangiotensin-aldosterone axis may confound
the results of the PAC:PRA screening test [26,
38, 39, 42]. Spironolactone, an aldosterone
antagonist, renders the test uninterpretable.
Estrogens likewise confuse the results as they
increase angiotensinogen and consequently
increase PACs [23]. Both should be discontinued 6 weeks before performing the workup.
Other medications including diuretics, ACE
inhibitors, and vasodilators also should be
stopped 4–6 weeks prior [81]. Control of hypertension still is necessary, however, and peripheral alpha-adrenergic blockers, beta-blockers,
and calcium-channel blockers are the preferred
agents during evaluation.
An increased PAC:PRA ratio alone does not
make the diagnosis of primary hyperaldosteronism. A suppression test should be performed
to demonstrate that the aldosterone secretion is
inappropriate for a high-sodium diet and not
normally suppressible. Between 30 and 50% of
patients with a positive PAC:PRA ratio will have
appropriate aldosterone levels that are normally
369
PRIMARY HYPERALDOSTERONISM
suppressed by confirmatory testing [82]. Failure
to suppress aldosterone production with a
sodium challenge (i.e., saline suppression test)
can confirm a suspected diagnosis of primary
hyperaldosteronism. The saline suppression
test can be performed with either intravenous
or oral sodium loading. For intravenous loading, 2 l of 0.9% normal saline are infused over
4 h in patients who have consumed a lowsodium diet for three days [26, 83]. For oral
loading, the patient consumes a high-sodium
diet for three days supplemented with sodium
chloride tablets. After the sodium challenge, a
plasma aldosterone level is measured and a 24-h
urine sample is collected for aldosterone and
sodium levels. Failure to suppress PAC below
10 ng/ml and urinary aldosterone secretion of
greater than 12 ug/24 h with urinary sodium
excretion greater than 200 mEq/24 h suggest
primary hyperaldosteronism [26, 82, 84].
Captopril, an ACE inhibitor, and fludrocortisone, a mineralocorticoid, also have been used
to test the suppressibility of aldosterone production [85, 86]. The usefulness of the captopril
suppression test is debatable [87]. While many
authors consider the fludrocortisone suppression test (FST) to be the most reliable confirmatory test, it is complex and costly. FST risks
severe hypokalemia that requires hospitalization for close monitoring, which is both timeconsuming and expensive, thus limiting its
usefulness [82].
Differentiating Unilateral
and Bilateral Disease
Once the diagnosis of primary hyperaldosteronism has been made, it is necessary to distinguish
between unilateral and bilateral adrenal disease
to guide treatment. Patients with aldosteronomas generally are younger, have more severe
hypertension, more profound hypokalemia,
and higher plasma and urinary aldosterone
levels than patients with idiopathic hyperaldosteronism [26, 79]. These clinical characteristics
are unreliable, however, and further testing is
necessary to predict unilateral versus bilateral
adrenal disease [8].
The postural stimulation test, based on the
differential regulatory mechanisms of the two
conditions, is one noninvasive method of predicting aldosterone-producing adenoma versus
idiopathic hyperaldosteronism [88, 89]. Aldosteronomas are unaffected by feedback from the
renin–angiotensin system, but remain sensitive
to ACTH. Plasma aldosterone levels, therefore,
fall with ACTH and cortisol levels as the
day progresses in patients in an upright position. PRA remains suppressed. In contrast,
idiopathic hyperaldosteronism demonstrates
enhanced sensitivity to small changes in the
renin–angiotensin system, butis relatively unaffected by ACTH. Plasma aldosterone levels in
these patients, therefore, rise with the relative
increase in PRA that occurs in the upright position. False-negative results of the postural stimulation test, however, are reported in the
literature [50, 56]. Stress during the test likely
can stimulate ACTH release and elevate PAC,
thus confounding the results.
Measurement of plasma 18-hydrocorticosterone (18-OHB) concentration also has been used
to differentiate between aldosterone-producing
adenoma and idiopathic hyperaldosteronism
[90]. An aldosterone-producing adenoma typically is associated with a plasma 18-OHB level
greater than 100 ng/dl. The assay to measure
18-OHB, however, is not commonly available,
and its reported accuracy of about 80% limits
its usefulness [50, 91].
Localization
Differentiation between the unilateral and the
bilateral forms of primary hyperaldosteronism
thus cannot be made convincingly with the currently available biochemicalstudies. Localization
studies usually are necessary and, in combination with the aforementioned tests, can greatly
improve diagnostic accuracy. Actually visualizing an adrenal tumor by radiography or detecting unilateral excess aldosterone production by
adrenal venous sampling helps separate patients
who may benefit from adrenalectomy from those
who should be managed medically.
High-resolution, thin-section computed tomography (CT) scan is the preferred initial imaging
modality for a suspected aldosterone-producing
adrenocortical adenoma. The sensitivity of modern scanners approaches 90% with thin cut (i.e.,
5 mm or less) adrenal protocols [92, 93]. Most
aldosterone-producing adenomas that cause
clinically significant hyperaldosteronism can be
seen on CT as hypodense lesions that measure
0.5–2.0 cm in diameter [94, 95] (Fig. 27.3). The