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ENDOCRINE SURGERY
Fig. 27.3. A CT scan with thin cuts through the adrenal glands shows an aldosterone-producing adenoma on the left.
370
presence of a unilateral lesion measuring 1–2 cm
with a normal contralateral adrenal gland on CT
scan is strong evidence for an adenoma and
further localization is likely unnecessary [96].
Small aldosteronomas (<0.5cm),however,can
be missed by CT scan, leading to a misdiagnosis
of adrenal hyperplasia in a patient with clinical
hyperaldosteronism. Moreover, aldosteronomas
can reside amid nonfunctional adenomas in one
or both glands, appear as multinodularity or bilateral lesions on CT, and thus may be mistaken for
hyperplasia [97, 98]. Conversely, hyperplasia can
appear as a small lesion on CT and be mistaken for
an aldosteronoma. Theradiographic diagnosis and
localization of an aldosterone-producing adenoma, therefore, cannot be definitive unless the
CT scan clearly demonstrates a unilateral 1- to
2-cm lesion with a normal contralateral adrenal
gland. CT findings of a unilateral lesion less than
1 cm or greater than 2 cm, unilateral adrenal thickening, bilateral adrenal nodularity, or bilateral
normal adrenal glands warrant additional testing
to differentiate between possible aldosteroneproducing adenomas and hyperplasia [96, 99, 100].
Magnetic resonance imaging (MRI) is another
imaging option. While costly, it is useful for
imaging the adrenal glands in pregnant patients,
iodine allergicpatients,or when CT scan isotherwise contraindicated [101, 102] (Fig. 27 4). Adre-
nal scintigraphy with
131
I-6beta-iodomethyl-19norcholesterol (NP-59) in conjunction with dexamethasone suppression has been used to
diagnose and locate overactive adrenal glands
when CT results are equivocal. Lateralization of
NP-59 uptake is primarily dependent on tumor
size, however, and is less accurate for small
lesions. Additionally, NP-59 scanning requires
an involved set up and significant time to block
thyroid uptake of radioiodine, prohibiting its
widespread use [103]. At the time of this publication, NP-59 is no longer available in the USA.
When successful, adrenal venous sampling
remains the most accurate method for differentiating between unilateral aldosteronoma and
idiopathic hyperaldosteronism [93, 98, 104].
Fig. 27.4. An MRI demonstrates a left aldosterone-producing
adrenocortical adenoma.
371
PRIMARY HYPERALDOSTERONISM
While some authors consider it a routine part of
the workup for primary hyperaldosteronism,
others feel it should be reserved for patients in
whom imaging is inconclusive [72, 105–107].
Arguments for its routine use cite that as many
as one third of patients thought to have a unilateral lesion on imaging studies will have bilateral
adrenal hyperplasia on adrenal venous sampling.
Against its routine use are the facts that it is
invasive and has resulted in complications such
as thrombosis and rupture of the adrenal veins,
bleeding, and adrenal infarction. Moreover, it is
technically difficult and failure to cannulate the
adrenal veins, especially on the right, is common
[106]. In the hands of an experienced angiographer, however, the successful cannulation rate is
approximately 90% [93, 100, 108, 109].
Selective venous sampling involves obtaining
plasma levels of cortisol and aldosterone from
both adrenal veins and the inferior vena cava.
Cortisol and aldosterone levels are measured at
each of these points before and after administration of ACTH. ACTH infusion minimizes any
fluctuations due to episodic changes in aldosterone secretion that might be caused by stressinduced endogenous ACTH release [100, 106].
When performing selective venous sampling,
the two main goals are to (1) confirm successful
cannulation of the adrenal veins and (2) determine if there is lateralization of aldosterone
hypersecretion. To confirm proper cannulation
of the adrenal veins, cortisol levels from the
adrenal vein samples are compared to the vena
cava sample on the theory that the cortisol levels
will dilute and thus decrease at locations further
from the adrenal gland. If there is a twofold
greater concentration of cortisol in each adrenal
vein when compared to the vena cava, then
successful cannulation is assured and determination of laterality can be conducted. In addition, measuring cortisol levels helps to assure
that specimens have not been mislabeled since
cortisol levels should be lower in the left adrenal
vein when compared with the right adrenal vein
due to dilution from the phrenic vein. The comparison of the aldosterone-to-cortisol ratio
between the right and the left adrenal vein
samples determines whether unilateral or bilateral hypersecretion of aldosterone is present.
Although the limit is controversial, an aldosterone-to-cortisol ratio in one adrenal vein that is
four times greater than that obtained from the
contralateral vein is considered indicative of a
unilateral aldosterone-producing tumor. This
fourfold greater ratio is predictive of a unilateral
lesion in more than 90% of cases [100]. Minimal
difference in the ratios between the two sides
suggests bilateral aldosterone hypersecretion.
Treatment
The goal of treatment, whether medical or surgical, is to prevent the morbidity and mortality of
the hypertension, hypokalemia, and cardiometabolic alterations associated with aldosterone
excess [9]. Patients with clinical primary hyperaldosteronism and a unilateral source of excess
aldosterone secretion should be considered for
unilateral adrenalectomy. Patients with bilateral
sources of excess aldosterone secretion or those
who are poor surgical candidates should undergo
medical therapy [110–112] (Table 27.2).
Surgical
Causes of hyperaldosteronism that respond to
adrenalectomy include unilateral adrenocortical
adenoma, unilateral adrenal hyperplasia, unilateral adrenocortical carcinoma, and familial
hyperaldosteronism type 2. Adrenalectomy for
idiopathic hyperaldosteronism seldom corrects
the hypertension and is not indicated [50, 79,
113, 114]. Adrenalectomy for bilateral aldosterone-producing tumors also is not indicated.
Bilateral aldosterone-producing tumors are
rare, and the resultant adrenal insufficiency
from adrenalectomy may be more difficult to
manage medically than the hypertension [115].
The traditional approach for adrenalectomy is
via an open flank or posterior incision. Most
Table 27.2. Treatment for primary hyperaldosteronism
Surgical
Aldosterone-producing adrenocortical adenoma
Aldosterone-producing adrenocortical carcinoma
Unilateral adrenal hyperplasia
Familial hyperaldosteronism, Type II
Medical
Idiopathic bilateral adrenal hyperplasia
Familial hyperaldosteronism, Type I
372
ENDOCRINE SURGERY
authors still recommend open adrenalectomy for
suspected adrenocortical carcinoma as these
cancers usually are large and advanced when
discovered [116–119]. Laparoscopic unilateral
adrenalectomy, however, has emerged as a safe,
effective, and optimal surgical treatment for the
aforementionedsubtypesof primary hyperaldosteronism [120–124]. Although operative time
and complications may not be significantly different from open adrenalectomy, advantages
include smaller wounds, less postoperative
pain, and shorter hospital stays [125, 126]. Most
patients are able to leave the hospital within 48 h
of a laparoscopic adrenalectomy [127, 128].
Preoperative treatment with spironolactone,
a competitive aldosterone antagonist, reduces
surgical risks by helping to control blood pressure and correct hypokalemia. Studies have
shown that control of blood pressure by spironolactone before surgery is a good predictor
of successful treatment of hypertension after
surgery [25, 129, 130]. Preoperative aldosterone
receptor blockade also reduces the risk of postoperative hypoaldosteronism by reactivating
the aldosterone-suppressed renin–angiotensin–
aldosterone system and allowing the contralateral
adrenal gland to begin functioning normally
again [8]. Postoperative postural hypotension
and hyperkalemia may be signs of postoperative
hypoaldosteronism. Treatment involves adequate
sodium intake and/or short-term fludrocortisone
replacement.
Medical
The indications formedical therapy include idiopathic hyperaldosteronism, glucocorticoid-suppressible hyperaldosteronism, and primary
hyperaldosteronism of whatever etiology in
patients who are poor surgical candidates. Idiopathic hyperaldosteronism and hyperaldosteronism in high-risk surgical candidates both
respond to management with an aldosterone
antagonist, whereas glucocorticoid-suppressible
hyperaldosteronism responds to exogenous steroid administration. Spironolactone is the mineralocorticoid receptor antagonist of choice and is
effective in controlling hypertension and hypokalemia,though it isnot without side effects [112,
131]. As a competitive mineralocorticoid receptor blocker, spironolactone binds androgen and
progesterone receptors as well as aldosterone
receptors and may cause generalized gastrointestinal upset, breast tenderness, and menstrual
irregularities in women, and decreased libido,
impotence, and gynecomastia in men [111, 112,
132]. Eplerenone, a highly selective mineralocorticoid receptor antagonist, has less binding affinity to androgen and progesterone receptors and
thus is associated with fewer side effects [133,
134]. It is more expensive, however, and randomized, placebo-controlled trials are needed to
evaluate its efficacy relative to spironolactone.
Dexamethasone is used to suppress ACTH production and control aldosterone excess in glucocorticoid-suppressible hyperaldosteronism. It is
administered in small doses to avoid signs and
symptoms of Cushing’s syndrome [12].
Postoperative Outcomes
Excision of an aldosterone-producing adenoma normalizes potassium levels in more
than 95% of patients almost immediately and
improves hypertension in over 75% within 1
month of surgery [50, 79, 109, 135]. Of those
patients with improvement in hypertension,
approximately one third will require no antihypertensive medications and two thirds will
require fewer antihypertensive medications
than before surgery. Long-term cure of hypertension, however, ranges from 30 to 60% in
reported series possibly due to concurrent
underlying essential hypertension and/or
atherosclerosis and end-organ damage from
the prior long-standing presence of hypertension and aldosterone excess [9, 129, 130, 136,
137]. The association between increasing age
and longer duration of hypertension with persistent postoperative hypertension further
supports the idea that persistent hypertension
is likely the result of the reduced ability to
reverse chronic pathologic vascular changes
[56, 138, 139]. Early diagnosis and treatment
thus may result in better outcomes.
Conclusion
Primary hyperaldosteronism is a potentially
curable cause of hypertension. Refractory
hypertension with or without hypokalemia
373
PRIMARY HYPERALDOSTERONISM
Fig. 27.5. General algorithm for diagnosing and treating primary hyperaldosteronism.
should prompt a workup for primary hyperaldosteronism. Once the diagnosis is made, it is
crucial to differentiate between unilateral and
bilateral sources of aldosterone excess. This
distinction is important for selecting patients
who may benefit from surgical versus medical
therapy (Fig. 27.5). Laparoscopic unilateral
adrenalectomy is the recommended surgical
approach for aldosteronoma while aldosterone
receptor antagonist therapy is the recommended medical treatment for idiopathic
hyperaldosteronism. Adrenalectomy normalizes
hypokalemia in virtually all patients and significantly improves hypertension in about 60%
of patients while also protecting against the
harmful cardiometabolic effects associated
with aldosterone excess.
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28
Cushing’s Disease and Syndrome
Brian Hung-Hin Lang and Chung-Yau Lo
Introduction
In 1932, Harvey W. Cushing first described a
disease entity characterized by muscular weakness, obesity, abdominal striae, diabetes, and
arterial hypertension from a specific pituitary
cause of hypercortisolism, which is known as
Cushing’s disease nowadays. With an increased
understanding of the different etiological causes
of hypercortisolism, Cushing’s syndrome is
recognized or represents as a distinct disease
entity with a complex of symptoms and signs
caused by prolonged and inappropriate exposure to excess glucocorticoids.
Epidemiology and Etiology
Cushing’s syndrome is considered a rare disease
as its incidence ranges from 0.7 to 2.4 per million
peryear[1].Although thediagnosis can be readily
madeforpatients presentingwithclassical clinical
features (i.e., overt Cushing’s syndrome), it isnow
realized that majority of patients suffer from a
more subtle or subclinical form of Cushing’s syndrome [2]. Patients with subclinical Cushing’s
syndrome have at least two biochemical abnormalities in the hypothalamo–pituitary–adrenal axis
but lack the classic clinical symptoms and signs of
hypercortisolism [2, 3]. However, the prevalence
of obesity, hypertension, and type II diabetes are
high,and surgical intervention has been shown to
improve these metabolic abnormalities [2, 3]. If
obese patients with poorly controlled type II diabetes mellitus and hypertension are screened for
Cushing’s syndrome, the reported prevalence
ranges from 2 to 5% [4, 5].
Cushing’s syndrome can cause significant
long-term morbidity and mortality. In the
early 1950s, a study on natural history of Cushing’s syndrome showed that untreated patients
had a 5-year survival of only 50% [6]. A more
recent study confirmed that those with incompletely controlled Cushing’s syndrome had up
to 11-fold increase in mortality when compared
to the national average over the long term [1].
Despite these findings, long-term prospective
studies evaluating the outcome of patients with
subclinical Cushing’s syndrome are lacking and
the overall benefit of surgical intervention for
adrenal incidentaloma with subclinical Cushing’s syndrome remains somewhat controversial [2, 3, 7]. In addition, Cushing’s syndrome is
a rare condition that resembles many of the
phenotypic features of modern life such as obesity, hypertension and depression, the cost
effectiveness of screening for these high-risk
groups alone based on phenotypic features or
the wider population remains doubtful [8–12].
By far, the most common cause of Cushing’s
syndrome is the prolonged exogenous administration of excess amount of glucocorticoids during the treatment of various diseases. Therefore,
by taking a detailed medication history, the clinical suspicion can frequently be confirmed [11].
Endogenous causes of hypercortisolism are
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DOI 10.1007/978-1-84628-881-4_28, Ó Springer-Verlag London Limited 2009
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