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19 Hypercortisolism
– A high-dose dexamethasone suppression test, in which 2mg dexamethasone
is administered orally every 6h for 48h, followed by a 24-h urine-free cortisol collection during the second day, can differentiate ACTH-secreting pituitary tumor (cortisol will suppress) from an ectopic ACTH syndrome (cortisol
will not suppress).
• Mild autonomous cortisol secretion (MACS) (previously termed “subclinical
Cushing syndrome”) often presents as an adrenal mass found incidentally on
imaging without overt signs or symptoms of cortisol excess.
– Patients with an adrenal mass should undergo biochemical screening for func-
tionality including a 1mg overnight dexamethasone suppression test.
– Cortisol levels ≥1.8–5pg/mL suggest failure of HPA axis suppression and are
diagnostic of MACS.
– Surgical management (unilateral adrenalectomy) in patients with MACS has
been shown to improve hypertension, dyslipidemia, and impaired glucose tolerance, particularly in younger patients.
177
Imaging
• Imaging studies should be guided by the results of biochemical studies.
– To identify an adrenal source:
“Adrenal protocol CT” scans the abdomen in 3 phases: non-contrast (no
delay); portal venous phase (60–70 s delay post-contrast); and delayed
phase (15-min delay post-contrast).
An adrenal lesion with density<10 HU on a non-contrast series indicates
a lipid-rich adenoma and does not require further imaging.
– To identify a pituitary source, obtain a pituitary MRI.Since lesions under
6mm may not be detected, bilateral inferior petrosal sinus sampling (IPSS)
may be required.
– To identify an ectopic ACTH source, obtain chest/abdomen/pelvis cross-
sectional imaging or functional imaging (DOTATATE/PET).
Medical Management [2, 5, 11]
• Pharmacologic steroidogenesis inhibition can be used to manage the effects of
cortisol excess as a bridge to surgery or in the setting of a non-localized or
uncontrollable primary source (e.g., metastatic or unresectable tumor).
• Medical therapies to treat Cushing syndrome include:
– Metyrapone (11βhydroxylase inhibitor).
178
L. A. Stewart and L. F. Morris-Wiseman
– Ketoconazole (blocks multiple adrenal enzymes involved in adrenal steroid
biosynthesis).
– Mitotane (used in the setting of adrenal cortical carcinoma (ACC); adreno-
lytic action in steroid-secreting adrenocortical cells).
– Osilodrostat (11βhydroxylase and aldosterone synthase inhibitor).
– Mifepristone (trade name: Korlym) is a competitive glucocorticoid receptor
antagonist that modulates the activity of cortisol at the receptor, thereby
reducing the symptoms of hypercortisolism.
– Etomidate (rapidly normalizes cortisol concentrations; used for acute control
of severe hypercortisolism only in an intensive care unit setting).
Surgical Management [5, 10–12]
• Standard surgical treatment for benign cortisol-secreting adrenal masses is minimally invasive (laparoscopy or robotic) due to benets of shorter hospitalization,
reduced postoperative pain, and decreased blood loss (Fig.19.2). There are two
main approaches (transabdominal and retroperitoneal), both with a conversion
rate of <5%. (See Chap. 23: Minimally Invasive Adrenalectomy: Techniques and
Potential Complications).
• A posterior (prone) retroperitoneal approach is favored by some for management
of adrenal masses <6cm in the setting of prior abdominal surgery or if bilateral
adrenalectomy is planned (to avoid need for repositioning or redraping).
• Bilateral adrenalectomy may be considered in cases of uncontrollable
Cushing syndrome (ex, if pituitary surgery fails or the patient has bilateral
adrenal hyperplasia or ectopic ACTH-producing tumor unresponsive to primary therapy).
Fig. 19.2 Gross specimen
after laparoscopic
adrenalectomy of a patient
with hypercortisolism. The
arrows delineate adrenal
cortical nodules in the
characteristic golden color
compared to the pale
yellow surrounding fat
19 Hypercortisolism
179
• Open adrenalectomy should be performed in patients with suspected ACC, particularly with tumors >6cm.
– Adrenal cancers are soft and any fracture of the capsule with tumor spillage
during laparoscopic manipulation can cause peritoneal carcinomatosis.
– Suspicion for ACC is raised in patients who have rapid growth of nodules,
hypersecretion of multiple steroid hormones, local/vascular invasion, or
regional adenopathy.
Perioperative Management [9, 11]
• Consider administering heparin 5000units subcutaneous within an hour prior to
incision for deep vein thrombosis (DVT) prophylaxis and Cefazolin for antibiotic prophylaxis.
• Given the longer half-life of steroids, there is no need to administer steroids in
the operating room.
• Patients with overt Cushing syndrome are initiated empirically on IV stress dose
steroids postoperatively with a rapid taper (hydrocortisone IV 25mg Q6h×24h,
then hydrocortisone PO 30mg Q8 am, 10 mg Q3 pm). They are typically discharged home on the 40 mg/day divided dosing with careful monitoring and
instructions to double the dose for sick days or if they develop signs of adrenal
insufciency:
– Adrenal insufciency is life-threatening and can present with fatigue, hypo-
tension, anorexia, abdominal pain, weakness, syncope, back pain, nausea,
vomiting, fever, or confusion (these may also be symptoms associated with
postoperative sepsis or hemorrhage).
– Any patient who has undergone adrenalectomy and presents with these signs
or symptoms should be administered empiric steroids as the diagnostic
workup is ongoing.
• Patients undergoing adrenalectomy for MACS have a 60% chance of requiring
postoperative steroids until recovery of the HPA axis; asymptomatic patients
should undergo testing the morning of postoperative day 1:
– Draw 8am serum cortisol level.
– Inject 250 mcg IV corticotropin.
– Draw 30–60min post-injection cortisol levels.
– If either the baseline cortisol is <10 mcg/dL or peak cortisol levels are
<16–20mcg/dL at 30–60min post-injection, begin steroids.
• HPA axis recovery is determined by an 8am serum cortisol ≥10μg/dL at 24h
after the last administered dose of glucocorticoids.
180
L. A. Stewart and L. F. Morris-Wiseman
Perioperative Concerns [4, 9, 11]
• Because elevated cortisol levels are associated with immunosuppression and a
catabolic state, the risk of surgical site infection is increased.
• Excess cortisol also promotes a hypercoagulable state, increasing the risk of
venous thromboembolism. Patients should be continued on pharmacologic
venous thromboembolism prophylaxis following adrenalectomy.
• Glucocorticoid withdrawal syndrome occurs in patients with a history of overt
Cushing syndrome and can present with symptoms similar to adrenal insufciency (nausea, fatigue, arthralgia, myalgia, headache, decreased quality of life,
depression, and anxiety).
– Symptoms may last up to 12months and patients should be counseled about this
outcome. Increasing the steroid dosing temporarily may help alleviate symptoms.
References
1. Yeh M, Livhits M, Duh Q.The adrenal glands. In: Townsend CM, Beauchamp RD, Evers BM,
Mattox KL, editors. Sabiston: textbook of surgery: the biological basis of modern surgical
practice. 21st ed. St. Louis: Elsevier; 2022.
2. Arlt W.Disorders of the adrenal cortex. In: Jameson JL, Fauci AS, Kasper DL, etal., editors.
Harrison’s principles of internal medicine. 20th ed. NewYork: McGraw Hill; 2018.
3. Nieman LK, Biller MK, Findling JW, Murad MH, Newell-Price J, Savage MO, Tabarin
A.Clinical practice guideline: treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807–31.
4. Chen Cardenas SM, Santhanam P, Morris-Wiseman L, Salvatori R, Hamrahian
AH.Perioperative evaluation and management of patients on glucocorticoids. J Endocr Soc.
2022;7(2):bvac185.
5. Olson JA, Turner DJ.Adrenal Gland. In: Mulholland MW, Lillemoe KD, Doherty GM, etal.,
editors. Greeneld’s surgery: scientic principles and practice. 6th ed. Philadelphia: Wolters
Kluwer; 2017.
6. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing’s syndrome. Lancet.
2015;386(9996):913–27.
7. Limumpornpetch P, Morgan AW, Tiganescu A, etal. The effect of endogenous cushing syndrome
on all-cause and cause-specic mortality. J Clin Endocrinol Metab. 2022;107(8):2377–88.
https://doi.org/10.1210/clinem/dgac265.
8. Barbot M, Zilio M, Scaroni C.Cushing’s syndrome: overview of clinical presentation, diagnostic tools and complications. Best Pract Res Clin Endocrinol Metab. 2020;34(2):101380.
9. Yip L, Duh QY, Wachtel H, Jimenez C, Sturgeon C, Lee C, Velázquez-Fernández D, Berber
E, Hammer GD, Bancos I, Lee JA, Marko J, Morris-Wiseman LF, Hughes MS, Livhits MJ,
Han MA, Smith PW, Wilhelm S, Asa SL, Fahey TJ 3rd, McKenzie TJ, Strong VE, Perrier
ND.American Association of Endocrine Surgeons Guidelines for adrenalectomy: executive
summary. JAMA Surg. 2022;157(10):870–7.
10. Fleseriu M, Auchus R, Bancos I, etal. Consensus on diagnosis and management of Cushing’s
disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847–75. https://doi.
org/10.1016/S2213- 8587(21)00235- 7.
11. Miller B.Management of adrenal cortical tumors. In: Cameron J, Cameron A, editors. Current
surgical therapy. 13th ed. Philadelphia: Elsevier; 2020.
12. Grant C.Surgical anatomy of the thyroid, parathyroid, and adrenal glands. In: Fischer JE,
Ellison EC, Upchurch GR, etal., editors. Fischer’s mastery of surgery. 7th ed. Philadelphia:
Wolters Kluwer; 2018.
Chapter 20
Hyperaldosteronism
RogehHabashi andAminMadani
Physiology and Pathogenesis [1–3]
• The renin-angiotensin-aldosterone system (RAAS) is a critical regulator of intra-
vascular volume and osmolality (Fig.20.1).
• Low intravascular volume leads to renal hypoperfusion with decreased sodium
delivery to the macula densa, which triggers renin release via the juxtaglomerular cells. Renin catalyzes the cleavage of angiotensinogen produced in the liver
to angiotensin I, which is further metabolized to angiotensin II by the angiotensinconverting enzyme (ACE) over the surface of pulmonary and renal endothelia.
• Angiotensin II leads to (1) arterial vasoconstriction, (2) increased proximal iso-
tonic sodium and water reabsorption, leading to reduced distal nephron delivery
of sodium, (3) vasopressin release, and (4) physiologic hyperaldosteronism.
• Aldosterone binds the MR of the distal nephron principal cells, resulting in over-
production of luminal epithelial sodium channels and thereby increased distal
sodium reabsorption. To neutralize the negative intraluminal potential from
sodium reabsorption, potassium and hydrogen are excreted.
• The pathophysiology of PA entails uninhibited renin-independent hyperal-
dosteronism in the context of sodium excess and replete intravascular volume (Fig. 20.1). The spiral of sodium reabsorption, glomerular hyperltration,
and volume expansion leads to chronic hypokalemia, hypertension, as well as
progressive cardiovascular and renal disease.
• The pathogenesis of primary hyperaldosteronism remains unknown. However,
two hypothetical models exist. Both of which can lead to either adenomatous
primary aldosteronism or bilateral adrenal hyperplasia.
R. Habashi (*) · A. Madani
Department of Surgery, University of Toronto, Toronto, ON, Canada
e-mail: rogeh.habashi@uhn.ca; amin.madani@uhn.ca
Switzerland AG 2024
R. M. Gartland, J. A. Lee (eds.), Endocrine Surgery Clerkship, Contemporary
Surgical Clerkships, https://doi.org/10.1007/978-3-031-62091-1_20
181© The Author(s), under exclusive license to Springer Nature
182
B. Primary Hyperaldosteronism
Renal Morbidity
R. Habashi and A. Madani
A. Healthy
Angiotensinogen
Renin
Angiotensin I
Angiotensin
Converting
Enzyme (ACE)
Angiotensin II
Angiotensinogen
Suppressed
ACE
Aldosterone
Dysregulated
Hyperaldosteronism
Renin
Decreased
Angiotensin I
Decreased
Angiotensin II
1. Sodium Retention
2. Volume Expansion
3. Hypertensionand Hypokalemia
4. Increased Cardiovascular and
Fig. 20.1 Physiology of aldosterone and pathophysiology of primary hyperaldosteronism. Liver,
kidney, and lung images by Vectorportal.com; adrenal image by Canva.com. All are copyright free.
(a) Healthy. (b) Primary Hyperaldosteronism
– One theory proposes a proliferative insult in the adrenal cortex followed by a
somatic secretory mutation, whereby a non-functional adenoma or hyperplasia begins to over-express aldosterone.
– The second theory suggests an initial secretory insult leading to autonomous
hyperaldosteronism with no obvious structural abnormality, which can be
subsequently transformed into neoplasia after an acquired proliferative mutation. The culprit here is thought to be aldosterone-producing cell clusters
(APCC) , which are non-neoplastic foci of disinhibited aldosteronism.
20 Hyperaldosteronism
183
Evaluation
Epidemiology [1–4]
• 5% of adrenal lesions are picked up incidentally on work up for another pathol-
ogy. The prevalence of biochemically and radiologically conrmed PA among
incidentalomas is 1–4%.
• The prevalence is understated and can often be subclinical as some prospective
studies diagnosed PA in 13–14% of normotensive individuals using conrmatory
tests despite normal aldosterone-renin ratios and normokalaemia. In fact, on
post-mortem studies, 30% of normotensive individuals had APCCs.
• PA is the most prevalent etiology of endocrine-induced hypertension. The preva-
lence of PA increases with the severity of hypertension. In general, the prevalence of PA ranges from 5% in mild hypertension to 29% in resistant hypertension
with the majority of patients having normokalemia.
• Compared to essential hypertension and irrespective of the measured blood pres-
sure, PA with persistently suppressed renin levels despite MR antagonists therapy is associated with a two-fold higher risk of cardiovascular events and 30%
higher risk of mortality. Relative to essential hypertension, PA with suppressed
renin is associated with a disproportionate end-organ damage which includes left
ventricular hypertrophy, increased media thickening, arteritis, endothelial dysfunction, glomerular hyperltration, albuminuria, glomerulosclerosis, directly
reduced insulin secretion and sensitivity leading to diabetes as well as increased
overall mortality.
• Familial hyperaldosteronism is a rare entity, accounting for <7% of all PA.All
are autosomal dominant germline mutations. They present with early hypertension with incomplete penetrance. Mutations affect the following genes: chimeric
CYP11B1/2, CLCN2, KCNJ5, CACNA1H, and CACNA1D.
Screening andConrmatory Biochemistry [1, 5]
• There are multiple indications for PA screening, the most common of which is
hypertension in the context of spontaneous hypokalemia. An extensive list is
included in Table20.1.
• Most patients with incidentalomas also typically undergo screening, especially
in the context of hypertension or hypokalemia.
• Conventionally, positive screening entails plasma aldosterone-renin ratio (ARR)
of ≥30ng/dL per ng/mL/h with a suppressed renin (≤1.0ng/mL/h) and elevated
aldosterone of ≥15ng/dL.
• Due to the paradigm shift in the binary denition of PA (unilateral vs bilateral)
to a continuum of severity, a more relaxed selection criteria are proposed to diagnose the milder and subclinical PA with understandably a higher risk of false
184
Table 20.1 Classical and non-classical indications for primary aldosteronism (PA) screening
Classical indications Non-classical indications
Hypertension with spontaneous or diuretic-induced
hypokalemia, adrenal mass, or sleep apnea
BP>150/100mmHg on 3 or more occasions Hypertension associated with
BP>140/90mmHg resistant to 3 or more medications Solitary atrial brillation with
BP<140/90mmHg but on 4 or more medications Hypokalemia irrespective of BP
Family history of PA, early hypertension or stroke (age<40) Early hypertension (age<40)
Table 20.2 Interpretation for conrmatory biochemistry in primary aldosteronism
Test Methodology Positive interpretation
Oral sodium
suppression
Supine IV saline
suppression
Fludrocortisone
suppression
Captopril
challenge
Increase sodium intake to >200mmol/day for
3–4days. Measure 24h urine sodium,
aldosterone, and creatinine on day 3 or 4
After 1h of lying supine, infuse 2L of saline
over 4h Measure plasma renin and aldosterone
before and after infusion
Give 0.10mg of udrocortisone q6h for 4days
while maintaining high sodium intake and
normal potassium. Measure plasma renin and
aldosterone while seating on the morning of
day 4
Administer 25mg captopril after 1h of sitting.
Measure plasma renin and aldosterone before,
1h, and 2h post treatment while sitting
R. Habashi and A. Madani
Hypertension requiring 3 or
more medications
low renin
no etiology
Aldosterone excretion
>12–14μg
Post-infusion aldosterone
level of >10ng/dL
Seated aldosterone >6ng/
dL and renin <1.0ng/
mL/h
Either <30% reduction in
aldosterone or ARR post
captopril >30ng/dL per
ng/mL/h
positives. This is dened as an ARR ≥20ng/dL per ng/mL/h with a suppressed
renin (≤1.0ng/mL/h) and elevated aldosterone of ≥10ng/dL.Aldosterone in the
range of 5–10ng/dL can possibly be positive and requires at least a repeated ARR.
• Follow-up conrmatory testing is pursued for aldosterone in the range of
5–15ng/dL.Table20.2 lists the common conrmatory tests used for PA.
• Conrmatory testing can be bypassed if there is spontaneous hypokalemia, sup-
pressed renin, and ARR ≥20ng/dL.
Imaging and Adrenal Vein Sampling [3, 6, 7]
• CT, densitometry (HU) and washout characteristics do not provide information
about the secretory activity of the localized nodule. Thus, adrenal venous sampling (AVS) currently remains the gold standard for laterality subtyping in
PA.This is critical as CT is discordant with adrenal venous sampling in up to
40% of the patients. Furthermore when compared with AVS-guided
20 Hyperaldosteronism
adrenalectomy, CT-guided adrenalectomy had a lower biochemical remission
(80% vs 93%).
• AVS is a technically challenging interventional radiology procedure performed
via a percutaneous femoral access. Venous cortisol and aldosterone samples are
obtained from the IVC (periphery) and the bilateral adrenal veins. AVS guides
management by assessing if PA is unilateral vs bilateral disease, as well as
assessing which side is hypersecreting in the setting of unilateral disease. Overall
the AVS success rate is >90% in high-volume centers with very minimal complications of around 2%.
• While routine versus selective use of AVS is controversial and center-dependent,
some have suggested that AVS may be bypassed in the following scenarios:
– Young patient (<35years old) with unilateral disease and associated hyper-
tension and hypokalemia as the probability of unilateral disease is very high.
– Bilateral macronodular hyperplasia as the probability of bilateral PA is high.
– Unilateral mass with another indication for surgery (e.g., concomitant adrenal
Cushing syndrome).
185
Management
Medical [1, 3]
• The aim of medical therapy is two-fold: (1) MR blockade to revert the dysregulated hyperaldosteronism and increase the renin activity; and (2) antihypertensive therapy.
• As with essential hypertension, dietary salt intake should be restricted.
Concordant with the American Heart Association and other prospective studies,
sodium- restricted diet of <50–65mmol of sodium per day was associated with
normalization of ARR and increase in renin.
• Patients with bilateral PA or who are unwilling to pursue surgery should receive
lifelong MR antagonists, as detailed in table 20.3.
Surgical [2–4, 8]
• According to the AAES guidelines for adrenalectomy, surgery should be considered for any unilateral functional adrenal nodule, regardless of size (absolute).
• In general, minimally invasive adrenalectomy is recommended for patients with
unilateral PA disease.
• Surgical management is superior to lifelong medical therapy with lower cardiovascular morbidity and mortality only in the subgroup with suboptimal MR
blockade and persistently suppressed renin levels.
186
Table 20.3 Medical therapy in primary aldosteronism
Dose and
Medication Mechanism of action
Spironolactone Competitive MR antagonist; also
progesterone receptor agonist
and androgen receptor antagonist
Eplerenone Competitive MR antagonist 50mg twice a
Amiloride Epithelial sodium channel
blocker
frequency Side effects
12.5–25mg
daily
day
5–20mg
twice a day
R. Habashi and A. Madani
Males—Gynecomastia and
impotence. Females—
Menstrual irregularity
Both—Hyperkalemia
Hyperkalemia
Hyperkalemia, anorexia,
nausea and epigastric pain
• In patients with bilateral PA disease, adrenalectomy may be considered on a
case-by-case basis in one of the following contexts:
– Borderline lateralization on AVS.
– Profound side effects with medical therapy.
– Medically refractory hypertension.
• Postoperatively, electrolytes are sent to reassess for hypokalemia and the patient
is monitored for signs of adrenal insufciency. Potassium supplementation and
Spironolactone are routinely stopped.
• Discontinuation of other anti-hypertensive medications is dependent on the cure
rate predicted by the Primary Aldosteronism Surgical Outcome (PASO) score.
Surveillance [9]
• Post-surgical clinical and biochemical outcomes should be assessed in 3months
and annually thereafter to rule out persistence or recurrence including blood
pressure, use of antihypertensives, and plasma potassium, aldosterone, and
renin levels.
• One in every three patients with PA-induced hypertension is surgically cured in
the context of unilateral disease. 94% of the surgically treated PA achieve complete biochemical cure (normalized ARR) and only 37% attain complete clinical
remission (i.e., normokalemia and normotension).
References
1. Vaidya A, Mulatero P, Baudrand R, Adler GK. The expanding Spectrum of primary
Aldosteronism: implications for diagnosis, pathogenesis, and treatment. Endocr Rev.
2018;39:1057–88.
2. Yip L, Duh QY, Wachtel H, Jimenez C, Sturgeon C, Lee C, Velázquez-Fernández D, Berber
E, Hammer GD, Bancos I, Lee JA, Marko J, Morris-Wiseman LF, Hughes MS, Livhits MJ,