2957 Disorders of the Adrenal Cortex CHAPTER 386

hypothalamic CRH release and activation of the entire HPA axis.

The ITT involves administration of regular insulin 0.1 U/kg IV (dose

should be lower if hypopituitarism is likely) and collection of blood

samples at 0, 30, 60, and 120 min for glucose, cortisol, and growth

hormone (GH), if also assessing the GH axis. Oral or IV glucose is

administered after the patient has achieved symptomatic hypoglycemia

(usually plasma glucose <40 mg/dL). A normal response is defined as a

cortisol >20 μg/dL and GH >5.1 μg/L, again with assay-specific cutoff

variability. The ITT requires careful clinical monitoring and sequential

measurements of glucose. It is contraindicated in patients with coronary disease, cerebrovascular disease, or seizure disorders, which has

made the short cosyntropin test the commonly accepted first-line test.

Mineralocorticoid production is controlled by the RAA regulatory

cycle, which is initiated by the release of renin from the juxtaglomerular cells in the kidney, resulting in cleavage of angiotensinogen to

angiotensin I in the liver (Fig. 386-4). Angiotensin-converting enzyme

(ACE) cleaves angiotensin I to angiotensin II, which binds and activates the angiotensin II receptor type 1 (AT1 receptor [AT1R]), resulting in increased adrenal aldosterone production and vasoconstriction.

Aldosterone enhances sodium retention and potassium excretion

and increases the arterial perfusion pressure, which in turn regulates

renin release. Because mineralocorticoid synthesis is primarily under

the control of the RAA system, hypothalamic-pituitary damage does

not significantly impact the capacity of the adrenal to synthesize

aldosterone.

Similar to the HPA axis, the assessment of the RAA system can be

used for diagnostic purposes. If mineralocorticoid excess is present,

there is a counter-regulatory downregulation of plasma renin (see

below for testing). Conversely, in mineralocorticoid deficiency, plasma

renin is markedly increased. Physiologically, oral or IV sodium loading

results in suppression of aldosterone, a response that is attenuated or

absent in patients with autonomous mineralocorticoid excess.

■ STEROID HORMONE SYNTHESIS,

METABOLISM, AND ACTION

ACTH stimulation is required for the initiation of steroidogenesis. The

ACTH receptor MC2R (melanocortin 2 receptor) interacts with the

MC2R-accessory protein MRAP, and the complex is transported to

the adrenocortical cell membrane, where it binds to ACTH (Fig. 386-5).

ACTH stimulation generates cyclic AMP (cAMP), which upregulates

the protein kinase A (PKA) signaling pathway. Inactive PKA is a

tetramer of two regulatory and two catalytic subunits that is dissociated

by cAMP into a dimer of two regulatory subunits bound to cAMP and

two free and active catalytic subunits. PKA activation impacts steroidogenesis in three distinct ways: (1) increases the import of cholesterol

esters; (2) increases the activity of hormone-sensitive lipase, which

cleaves cholesterol esters to cholesterol for import into the mitochondrion; and (3) increases the availability and phosphorylation of CREB

(cAMP response element binding), a transcription factor that enhances

transcription of CYP11A1 and other enzymes required for glucocorticoid synthesis.

Adrenal steroidogenesis occurs in a zone-specific fashion, with

mineralocorticoid synthesis occurring in the outer zona glomerulosa,

glucocorticoid synthesis in the zona fasciculata, and adrenal androgen

biosynthesis in the inner zona reticularis serving as precursors for

both classic and 11-oxygenated androgens (Fig. 386-1). All steroidogenic pathways require cholesterol import into the mitochondrion, a

process initiated by the action of the steroidogenic acute regulatory

(StAR) protein, which shuttles cholesterol from the outer to the inner

mitochondrial membrane. The majority of steroidogenic enzymes

are cytochrome P450 (CYP) enzymes, which are either located in

the mitochondrion (side chain cleavage enzyme, CYP11A1; 11βhydroxylase, CYP11B1; aldosterone synthase, CYP11B2) or in the

endoplasmic reticulum membrane (17α-hydroxylase, CYP17A1;

21-hydroxylase, CYP21A2; aromatase, CYP19A1). These enzymes

require electron donation via specific redox cofactor enzymes, P450

oxidoreductase (POR), and adrenodoxin/adrenodoxin reductase

(ADX/ADR) for the microsomal and mitochondrial CYP enzymes,

respectively. In addition, the short-chain dehydrogenase 3β-hydroxysteroid dehydrogenase type 2 (3β-HSD2), also termed Δ4, Δ5

isomerase, plays a major role in adrenal steroidogenesis.

The cholesterol side chain cleavage enzyme CYP11A1 generates pregnenolone. Glucocorticoid synthesis requires conversion of

pregnenolone to progesterone by 3β-HSD2, followed by conversion

Circulating blood volume

Kidney

Angiotensin II

Adrenal

Aldosterone release

Activation of

Angiotensin II receptor

type 1 (AT1 receptor)

Angiotensinconverting

enzyme (ACE)

Vasoconstriction

Renal sodium

retention (and

potassium excretion) Renal perfusion

pressure

Juxtaglomerular

cells

Angiotensin I

Angiotensinogen

 Renin release

FIGURE 386-4 Regulation of the renin-angiotensin-aldosterone (RAA) system.

2958 PART 12 Endocrinology and Metabolism

to 17-hydroxyprogesterone (17OHP) by CYP17A1, further hydroxylation at carbon 21 by CYP21A2, and eventually, 11β-hydroxylation

by CYP11B1 to generate active cortisol (Fig. 386-1). Mineralocorticoid synthesis also requires progesterone, which is first converted

to deoxycorticosterone (DOC) by CYP21A2 and then converted via

corticosterone and 18-hydroxycorticosterone to aldosterone in three

steps catalyzed by CYP11B2. For adrenal androgen synthesis, pregnenolone undergoes conversion by CYP17A1, which uniquely catalyzes

two enzymatic reactions. Via its 17α-hydroxylase activity, CYP17A1

converts pregnenolone to 17-hydroxypregnenolone, followed by generation of the universal sex steroid precursor DHEA via CYP17A1 17,20

lyase activity. The majority of DHEA is secreted by the adrenal in the

form of its sulfate ester, DHEAS, generated by DHEA sulfotransferase

(SULT2A1). DHEA is converted to androstenedione, which can be

activated to testosterone or channeled into the 11-oxygenated androgen pathway by 11β-hydroxylation (CYP11B1).

Following its release from the adrenal, cortisol circulates in the

bloodstream mainly bound to cortisol-binding globulin (CBG) and,

to a lesser extent, to albumin, with only a minor fraction circulating as

free, unbound hormone. Free cortisol is thought to enter cells directly,

not requiring active transport. In addition, in a multitude of peripheral

target tissues of glucocorticoid action, including adipose, liver, muscle,

and brain, cortisol is generated from inactive cortisone within the cell

by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

(Fig. 386-6). Thereby, 11β-HSD1 functions as a tissue-specific prereceptor regulator of glucocorticoid action. For the conversion of inactive

cortisone to active cortisol, 11β-HSD1 requires nicotinamide adenine

dinucleotide phosphate (NADPH [reduced form]), which is provided

by the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Like the

catalytic domain of 11β-HSD1, H6PDH is located in the lumen of the

endoplasmic reticulum and converts glucose-6-phosphate (G6P) to

6-phosphogluconate (6PGL), thereby regenerating NADP+ to NADPH,

which drives the activation of cortisol from cortisone by 11β-HSD1.

In the cytosol of target cells, cortisol binds and activates the GR,

which results in dissociation of heat shock proteins (HSPs) from the

receptor and subsequent dimerization (Fig. 386-6). Cortisol-bound

GR dimers translocate to the nucleus and activate glucocorticoid

response elements (GREs) in the DNA sequence, thereby enhancing

transcription of glucocorticoid-regulated genes (GR transactivation).

However, cortisol-bound GR can also form heterodimers with transcription factors such as AP-1 or NF-κB, resulting in transrepression

of proinflammatory genes, a mechanism of major importance for the

anti-inflammatory action of glucocorticoids. It is important to note

that corticosterone also exerts glucocorticoid activity, albeit much

weaker than cortisol itself. However, in rodents, corticosterone is the

major glucocorticoid, and in patients with 17-hydroxylase deficiency,

lack of cortisol can be compensated for by higher concentrations of corticosterone that accumulates as a consequence of the enzymatic block.

Cortisol is inactivated to cortisone by the microsomal enzyme

11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) (Fig. 386-7),

mainly in the kidney, but also in the colon, salivary glands, and other

target tissues. Cortisol and aldosterone bind the mineralocorticoid

receptor (MR) with equal affinity; however, cortisol circulates in the

bloodstream at about a 1000-fold higher concentration. Thus, only

rapid inactivation of cortisol to cortisone by 11β-HSD2 prevents MR

activation by excess cortisol, thereby acting as a tissue-specific modulator of the MR pathway. In addition to cortisol and aldosterone, DOC

(Fig. 386-1) also exerts mineralocorticoid activity. DOC accumulation

due to 11β-hydroxylase deficiency or due to tumor-related excess production can result in mineralocorticoid excess.

Aldosterone synthesis in the adrenal zona glomerulosa cells is

driven by the enzyme aldosterone synthase (CYP11B2). The binding of

angiotensin II to the AT1 receptor causes glomerulosa cell membrane

depolarization by increasing intracellular sodium through inhibition

of sodium potassium (Na+/K+) ATPase enzymes as well as potassium

channels. This drives an increase in intracellular calcium by opening

of voltage-dependent calcium channels or inhibition of calcium (Ca2+)

ATPase enzymes. Consequently, the calcium signaling pathway is triggered, resulting in upregulation of CYP11B2 transcription (Fig. 386-8).

Analogous to cortisol action via the GR, aldosterone (or cortisol)

binding to the MR in the kidney tubule cell dissociates the HSP-receptor

complex, allowing homodimerization of the MR and translocation

of the hormone-bound MR dimer to the nucleus (Fig. 386-7). The

activated MR enhances transcription of the epithelial sodium channel (ENaC) and serum glucocorticoid-inducible kinase 1 (SGK-1).

In the cytosol, interaction of ENaC with Nedd4 prevents cell surface

P

Endoplasmic

reticulum

Nucleus

Cytosol

Cell membrane

ACTH

StAR

HSL

SOAT1

TSPO

CYP11A1

ACTH

Transcription of CYP11A1

and other steroidogenic

enzymes

Pregnenolone

CRE

CREB

CREB

Scavenger

receptor B1

Cholesterol

Translocator

protein

Cholesterol

ester

Cholesterol

ester

Adrenal cortex cell

ATP

Adenylate

cyclase

MC2R

MRAP

N Mitochondrion

N

N

N

N

N

C

C

C

C

Gsα

γ

C

C

Protein

kinase A cAMP

cAMP

β

R

C

R

C

C

C

R R

FIGURE 386-5 ACTH effects on adrenal steroidogenesis. ACTH, adrenocorticotropic hormone; CREB, cAMP response element–binding protein; HSL, hormone-sensitive

lipase; MRAP, MC2R-accessory protein; protein kinase A catalytic subunit (C; PRKACA), PKA regulatory subunit (R; PRKAR1A); SOAT1, sterol O-acyltransferase 1; StAR,

steroidogenic acute regulatory (protein); TSPO, translocator protein.

2959 Disorders of the Adrenal Cortex CHAPTER 386

expression of ENaC. However, SGK-1 phosphorylates serine residues

within the Nedd4 protein, reduces the interaction between Nedd4 and

ENaC, and consequently, enhances the trafficking of ENaC to the cell

surface, where it mediates sodium retention.

■ CUSHING’S SYNDROME

(See also Chap. 380) Cushing’s syndrome reflects a constellation

of clinical features that result from chronic exposure to excess

glucocorticoids of any etiology. The disorder can be ACTH-dependent

(e.g., pituitary corticotrope adenoma, ectopic secretion of ACTH by

nonpituitary tumor) or ACTH-independent (e.g., adrenocortical adenoma, adrenocortical carcinoma [ACC], nodular adrenal hyperplasia),

as well as iatrogenic (e.g., administration of exogenous glucocorticoids

to treat various inflammatory conditions). The term Cushing’s disease

refers specifically to Cushing’s syndrome caused by a pituitary corticotrope adenoma.

Nucleus

No transcription

GR transrepression GR transactivation

Nucleus

or

NADPH NADP+

11β-HSD1

H6PDH

Cytosol

AP-1

Endoplasmic

reticulum

G6P

6PGL

Cortisone

Cortisol

Transcription

Coactivator

complex

HSP

GR

GR

GR

GR GR

GRE

Glucocorticoid target cell

GR

FIGURE 386-6 Prereceptor activation of cortisol and glucocorticoid receptor (GR) action. AP-1, activator protein-1; G6P, glucose-6-phosphate; GREs, glucocorticoid

response elements; HSPs, heat shock proteins; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); 6PGL, 6-phosphogluconate.

Nucleus

ER Lumen

NADH

Cortisone

Blood

(basal site)

Lumen

(apical site)

11β_HSD2

NAD+

Cortisol

Aldosterone Cytosol

Transcription

of

HSP

ENaC

ENaC

ENaC Na+

Na+ ENaC

MR

MR

MR

MR

MRMR

MR

MR

HRE

and

ENaC

Nedd4

Nedd4

SGK-1

SGK-1

Kidney distal convoluted tubule cell

K+

K+

K+

Na+

ROMK

ROMK

ATP

FIGURE 386-7 Prereceptor inactivation of cortisol and mineralocorticoid receptor action. ENaC, epithelial sodium channel; HRE, hormone response element; Na+

/K+

-

ATPase, sodium-potassium adenosine triphosphatase; NADH, nicotinamide adenine dinucleotide; ROMK, renal outer medullary potassium channel; SGK-1, serum

glucocorticoid-inducible kinase-1.

2960 PART 12 Endocrinology and Metabolism

Adrenal zona glomerulosa cell

Na+, K+–

ATPase

AT1R

Ang II

K+

channel

Na+, Ca2+

exchanger

Ca2+

channel

Ca2+–

ATPase

Na+

Depolarization

Ca2+

Ca2+

Ca2+

Na+

K+

K+

Nucleus

CYP11B2 Aldosterone

FIGURE 386-8 Regulation of adrenal aldosterone synthesis. Ang II, angiotensin II; AT1R, angiotensin II receptor

type 1; CYP11B2, aldosterone synthase.

TABLE 386-1 Causes of Cushing’s Syndrome

CAUSES OF CUSHING’S SYNDROME

FEMALE:MALE

RATIO %

ACTH-Dependent Cushing’s 90

Cushing’s disease (= ACTH-producing pituitary

adenoma)

4:1 75

Ectopic ACTH syndrome (due to ACTH secretion by

bronchial or pancreatic carcinoid tumors, smallcell lung cancer, medullary thyroid carcinoma,

pheochromocytoma, and others)

1:1 15

ACTH-Independent Cushing’s 4:1 10

Adrenocortical adenoma 5–10

Adrenocortical carcinoma 1

Rare causes: macronodular adrenal hyperplasia;

primary pigmented nodular adrenal disease (microand/or macronodular); McCune-Albright syndrome

<1

Abbreviation: ACTH, adrenocorticotropic hormone.

Epidemiology Cushing’s syndrome is generally considered a rare

disease. It occurs with an incidence of 1–2 per 100,000 population per

year. However, it is debated whether mild cortisol excess may be more

prevalent among patients with features of Cushing’s such as centripetal

obesity, type 2 diabetes, and osteoporotic vertebral fractures, recognizing that these are relatively nonspecific and common in the population.

In the overwhelming majority of patients with endogenous Cushing’s syndrome, the underlying cause is an ACTH-producing corticotrope adenoma of the pituitary (Table 386-1), as initially described

by Harvey Cushing in 1912. Cushing’s disease more frequently affects

women, with the exception of prepubertal cases, where it is more common in boys. By contrast, ectopic ACTH syndrome is more frequently

identified in men. Only 10% of patients with Cushing’s syndrome have

a primary, adrenal cause of their disease (e.g., autonomous cortisol

excess independent of ACTH), and most of these patients are women.

However, overall, the medical use of glucocorticoids for immunosuppression or for the treatment of inflammatory disorders is the

most common cause of Cushing’s syndrome, also termed iatrogenic

Cushing’s.

Etiology In at least 90% of patients with

Cushing’s disease, ACTH excess is caused by

a corticotrope pituitary microadenoma, often

only a few millimeters in diameter. Pituitary

macroadenomas (i.e., tumors >1 cm in size)

are found in only 5–10% of patients. Pituitary

corticotrope adenomas usually occur sporadically but very rarely can be found in the

context of multiple endocrine neoplasia type

1 (MEN 1) (Chap. 388). Pituitary adenomas

causative of Cushing’s disease frequently harbor mutations in the deubiquitinase USP8,

which leads to constitutive activation of epidermal growth factor (EGF) signaling and

consequent upregulated expression of the

ACTH precursor POMC. USP8 mutations

are found more frequently in adults (41 vs

17% in children) and in women (43 vs 17%

in men) with Cushing’s disease.

Ectopic ACTH production is predominantly caused by occult carcinoid tumors,

most frequently in the lung, but also in

thymus or pancreas. Because of their small

size, these tumors are often difficult to locate.

Advanced small-cell lung cancer can cause

ectopic ACTH production. In rare cases,

ectopic CRH and/or ACTH production has

been found to originate from medullary thyroid carcinoma or pheochromocytoma, the

latter co-secreting catecholamines and ACTH.

The majority of patients with endogenous ACTH-independent

cortisol excess harbor a cortisol-producing adrenal adenoma, and

somatic mutations in the PKA catalytic subunit PRKACA have been

identified as cause of disease in 40% of these tumors. ACCs may also

cause ACTH-independent disease and are often large, with excess production of several corticosteroid classes.

A rare but notable cause of adrenal cortisol excess is primary bilateral macronodular adrenal hyperplasia (PBMAH) with low circulating

ACTH but with evidence for autocrine stimulation of cortisol production via intraadrenal ACTH production. These hyperplastic nodules

are often also characterized by ectopic expression of G protein–coupled

receptors not usually found in the adrenal, including receptors for

luteinizing hormone, vasopressin, serotonin, interleukin 1, catecholamines, or gastric inhibitory peptide (GIP), the cause of food-dependent

Cushing’s. Activation of these receptors results in upregulation of

PKA signaling, as physiologically occurs with ACTH, with a subsequent increase in cortisol production. A combination of germline and

somatic mutations in the tumor-suppressor gene ARMC5 have been

identified as a prevalent cause of Cushing’s due to bilateral macronodular adrenal hyperplasia; these patients often present with biochemical

evidence of Cushing’s but lack specific clinical signs, which develop

slowly over decades and accelerate cardiovascular risk. Constitutively

activating mutations in the PKA catalytic subunit PRKACA are found

as somatic mutations in one-third of cortisol-producing adrenocortical

adenomas and, as germline mutations, can also represent a rare cause

of macronodular adrenal hyperplasia associated with cortisol excess.

Germline mutations in one of the regulatory subunits of PKA,

PRKAR1A, are found in patients with primary pigmented nodular

adrenal disease (PPNAD) as part of Carney’s complex, an autosomal

dominant multiple neoplasia condition associated with cardiac myxomas, hyperlentiginosis, Sertoli cell tumors, and PPNAD. PPNAD

can present as micronodular or macronodular hyperplasia, or both.

Phosphodiesterases can influence intracellular cAMP and can thereby

impact PKA activation. Mutations in PDE11A and PDE8B have been

identified in patients with bilateral adrenal hyperplasia and Cushing’s,

with and without evidence of PPNAD.

Another rare cause of ACTH-independent Cushing’s is McCuneAlbright syndrome, also associated with polyostotic fibrous dysplasia,

unilateral café-au-lait spots, and precocious puberty. McCune-Albright

2961 Disorders of the Adrenal Cortex CHAPTER 386

syndrome is caused by activating mutations in the stimulatory G protein alpha subunit 1, GNAS-1 (guanine nucleotide-binding protein

alpha stimulating activity polypeptide 1), and such mutations have

also been found in bilateral macronodular hyperplasia without other

McCune-Albright features and, in rare instances, also in isolated cortisolproducing adrenal adenomas (Table 386-1; Chap. 412).

Clinical Manifestations Glucocorticoids affect almost all cells

of the body; thus, signs of cortisol excess impact multiple physiologic

systems (Table 386-2), with upregulation of gluconeogenesis, lipolysis,

and protein catabolism causing the most prominent features. In addition, excess glucocorticoid secretion overcomes the ability of 11βHSD2 to rapidly inactivate cortisol to cortisone in the kidney, thereby

exerting mineralocorticoid actions, manifest as diastolic hypertension,

hypokalemia, and edema. Excess glucocorticoids also interfere with

central regulatory systems, leading to suppression of gonadotropins

with subsequent hypogonadism and amenorrhea and suppression of

the hypothalamic-pituitary-thyroid axis, resulting in decreased thyroid-stimulating hormone (TSH) secretion.

The majority of clinical signs and symptoms observed in Cushing’s

syndrome are relatively nonspecific and include features such as obesity, diabetes, diastolic hypertension, hirsutism, and depression that

are commonly found in patients who do not have Cushing’s. Therefore, careful clinical assessment is an important aspect of evaluating

suspected cases. A diagnosis of Cushing’s should be considered when

several clinical features are found in the same patient, in particular

when more specific features are found or manifest at an unusual age,

e.g., osteoporosis in a young patient. Distinct features include fragility

of the skin, with easy bruising and broad (>1 cm), purplish striae

(Fig. 386-9), and signs of proximal myopathy, which becomes most

obvious when trying to stand up from a chair without the use of hands

or when climbing stairs. Clinical manifestations of Cushing’s do not

differ substantially among the different causes of Cushing’s. In ectopic

ACTH syndrome, hyperpigmentation of the knuckles, scars, or skin

areas exposed to increased friction can be observed (Fig. 386-9) and

is caused by stimulatory effects of excess ACTH and other POMC

cleavage products on melanocyte pigment production. Furthermore,

patients with ectopic ACTH syndrome, and some with ACC as the

cause of Cushing’s, may have a more brisk onset and rapid progression

of clinical signs and symptoms, namely of edema, hypokalemia, and

hypertension.

Patients with Cushing’s syndrome can be acutely endangered by

deep vein thrombosis, with subsequent pulmonary embolism, due to

a hypercoagulable state associated with Cushing’s. The majority of

patients also experience psychiatric symptoms, mostly in the form of

TABLE 386-2 Signs and Symptoms of Cushing’s Syndrome

BODY COMPARTMENT/

SYSTEM SIGNS AND SYMPTOMS

Body fat Weight gain, central obesity, rounded face, fat pad

on back of neck (“buffalo hump”)

Skin Facial plethora, thin and brittle skin, easy bruising,

broad and purple stretch marks, acne, hirsutism

Bone Osteopenia, osteoporosis (vertebral fractures),

decreased linear growth in children

Muscle Weakness, proximal myopathy (prominent atrophy

of gluteal and upper leg muscles with difficulty

climbing stairs or getting up from a chair)

Cardiovascular system Hypertension, hypokalemia, edema, atherosclerosis

Metabolism Glucose intolerance/diabetes, dyslipidemia

Reproductive system Decreased libido, in women amenorrhea (due

to cortisol-mediated inhibition of gonadotropin

release)

Central nervous system Irritability, emotional lability, depression, sometimes

cognitive defects; in severe cases, paranoid

psychosis

Blood and immune system Increased susceptibility to infections,

increased white blood cell count, eosinopenia,

hypercoagulation with increased risk of deep vein

thrombosis and pulmonary embolism

A

B

C

D

FIGURE 386-9 Clinical features of Cushing’s syndrome. A. Note central obesity and broad, purple stretch marks (B. close-up). C. Note thin and brittle skin in an elderly

patient with Cushing’s syndrome. D. Hyperpigmentation of the knuckles in a patient with ectopic adrenocorticotropic hormone (ACTH) excess.

2962 PART 12 Endocrinology and Metabolism

anxiety or depression, but acute paranoid or depressive psychosis may

occur. Even after cure, long-term health may be affected by persistently

impaired health-related quality of life and increased risk of cardiovascular disease and osteoporosis with vertebral fractures, depending on the duration and degree of exposure to significant cortisol

excess.

Diagnosis The most important first step in the management of

patients with suspected Cushing’s syndrome is to establish the correct

diagnosis. Most mistakes in clinical management, leading to unnecessary imaging or surgery, are made because the diagnostic protocol

is not followed (Fig. 386-10). This protocol requires establishing the

diagnosis of Cushing’s beyond doubt prior to employing any tests

used for the differential diagnosis of the condition. In principle, after

excluding exogenous glucocorticoid use as the cause of clinical signs

and symptoms, suspected cases should be tested if there are multiple

and progressive features of Cushing’s, particularly features with a

potentially higher discriminatory value. Exclusion of Cushing’s is also

indicated in patients with incidentally discovered adrenal masses.

A diagnosis of Cushing’s can be considered as established if the

results of several tests are consistently suggestive of Cushing’s. These

tests may include increased 24-h urinary free cortisol excretion in

three separate collections, failure to appropriately suppress morning

cortisol after overnight exposure to dexamethasone, and evidence

of loss of diurnal cortisol secretion with high levels at midnight, the

time of the physiologically lowest secretion (Fig. 386-10). Factors

potentially affecting the outcome of these diagnostic tests have to be

excluded such as incomplete 24-h urine collection or rapid inactivation of dexamethasone due to concurrent intake of CYP3A4-inducing

drugs (e.g., antiepileptics, rifampicin). Concurrent intake of oral contraceptives that raise CBG and thus total cortisol can cause failure to

suppress after dexamethasone. If in doubt, testing should be repeated

after 4–6 weeks off estrogens. Patients with pseudo-Cushing states, i.e.,

alcohol-related, and those with cyclic Cushing’s may require further

Neg.

Adrenal tumor

workup

• 24-h urinary free cortisol excretion increased above normal (≥2x)

• Dexamethasone overnight test (Plasma cortisol >50 nmol/L at

 8–9 am after 1 mg dexamethasone at 11 pm)

• Midnight salivary cortisol >5 nmol/L (≥2x)

 If further confirmation needed/desired:

• Low dose DEX test (Plasma cortisol >50 nmol/L after 0.5 mg

DEX q6h for 2 days or a single dose of 8 mg overnight)

Clinical suspicion of Cushing’s

(Central adiposity, proximal myopathy, striae, amenorrhea, hirsutism,

impaired glucose tolerance, diastolic hypertension, and osteoporosis)

Screening/confirmation of diagnosis

Positive Negative

Differential diagnosis 1: Plasma ACTH

ACTH normal or high

>15 pg/mL

CRH test and highdose DEX positive

ACTH suppressed

to <5 pg/mL

ACTH-dependent

Cushing’s

ACTH-independent

Cushing’s

Bilateral

micronodular

or

macronodular

adrenal

hyperplasia

Bilateral

adrenalectomy

Unilateral

adrenalectomy

Unilateral

adrenal mass

 Differential diagnosis 2

• MRI pituitary

• CRH test (ACTH increase >40% at

15–30 min + cortisol increase >20%

at 45–60 min after CRH 100 µg IV)

• High dose DEX test

 (Cortisol suppression >50% after

q6h 2 mg DEX for 2 days)

Inferior petrosal

sinus sampling

(petrosal/peripheral

ACTH ratio >2 at

baseline, >3 at 2–5 min

after CRH 100 µg IV)

Locate and

remove

ectopic

ACTH

source

Ectopic ACTH

Cushing’s disease production

Transsphenoidal

pituitary

surgery

CRH test and highdose DEX negative

Equivocal

results

Pos. Neg.

Unenhanced CT

adrenals

FIGURE 386-10 Management of the patient with suspected Cushing’s syndrome. ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CT, computed

tomography; DEX, dexamethasone; MRI, magnetic resonance imaging.

2963 Disorders of the Adrenal Cortex CHAPTER 386

testing to safely confirm or exclude the diagnosis of Cushing’s. In

addition, the biochemical assays employed can affect the test results,

with specificity representing a common problem with antibody-based

assays for the measurement of urinary free cortisol. These assays have

been greatly improved by the introduction of highly specific tandem

mass spectrometry.

Differential Diagnosis The evaluation of patients with confirmed

Cushing’s should be carried out by an endocrinologist and begins with

the differential diagnosis of ACTH-dependent and ACTH-independent

cortisol excess (Fig. 386-10). Generally, plasma ACTH levels are

suppressed in cases of autonomous adrenal cortisol excess, as a consequence of enhanced negative feedback to the hypothalamus and

pituitary. By contrast, patients with ACTH-dependent Cushing’s have

normal or increased plasma ACTH, with very high levels being found

in some patients with ectopic ACTH syndrome. Importantly, imaging

should only be used after it is established whether the cortisol excess is

ACTH-dependent or ACTH-independent because nodules in the pituitary or the adrenal are a common finding in the general population. In

patients with confirmed ACTH-independent excess, adrenal imaging

is indicated (Fig. 386-11), preferably using an unenhanced computed

tomography (CT) scan. This allows assessment of adrenal morphology

and determination of precontrast tumor density in Hounsfield units

(HUs), which helps to distinguish between benign and malignant

adrenal lesions.

For ACTH-dependent cortisol excess (Chap. 380), a magnetic

resonance image (MRI) of the pituitary is the investigation of choice,

but it may not show an abnormality in up to 40% of cases because

of small tumors below the sensitivity of detection. Characteristically,

pituitary corticotrope adenomas fail to enhance following gadolinium

administration on T1-weighted MRI images. In all cases of confirmed

ACTH-dependent Cushing’s, further tests are required for the differential diagnosis of pituitary Cushing’s disease and ectopic ACTH

syndrome. These tests exploit the fact that most pituitary corticotrope

adenomas still display regulatory features, including residual ACTH

suppression by high-dose glucocorticoids and CRH responsiveness. In

contrast, ectopic sources of ACTH are typically resistant to dexamethasone suppression and unresponsive to CRH (Fig. 386-10). However,

it should be noted that a small minority of ectopic ACTH-producing

tumors exhibit dynamic responses similar to pituitary corticotrope

tumors. If the two tests show discordant results or if there is any other

reason for doubt, the differential diagnosis can be further clarified by

performing bilateral inferior petrosal sinus sampling (IPSS) with concurrent blood sampling for ACTH in the right and left inferior petrosal

sinus and a peripheral vein. An increased central/peripheral plasma

ACTH ratio >2 at baseline and >3 at 2–5 min after CRH injection is

indicative of Cushing’s disease (Fig. 386-10), with very high sensitivity

and specificity. Of note, the results of the IPSS cannot be reliably used

for lateralization (i.e., prediction of the location of the tumor within

the pituitary) because there is broad interindividual variability in the

venous drainage of the pituitary region. Importantly, no cortisol-lowering agents should be used prior to IPSS.

If the differential diagnostic testing indicates ectopic ACTH syndrome, then further imaging should include high-resolution, fine-cut

CT scanning of the chest and abdomen for scrutiny of the lung, thymus, and pancreas. If no lesions are identified, an MRI of the chest

can be considered because carcinoid tumors usually show high signal

intensity on T2-weighted images. Furthermore, octreotide scintigraphy

can be helpful in some cases because ectopic ACTH-producing tumors

often express somatostatin receptors. Depending on the suspected

cause, patients with ectopic ACTH syndrome should also undergo

blood sampling for fasting gut hormones, chromogranin A, calcitonin,

and biochemical exclusion of pheochromocytoma.

TREATMENT

Cushing’s Syndrome

Overt Cushing’s is associated with a poor prognosis if left untreated.

In ACTH-independent disease, treatment consists of surgical

removal of the adrenal tumor. For smaller tumors, a minimally

invasive approach can be used, whereas for larger tumors and those

suspected of malignancy, an open approach is preferred.

In Cushing’s disease, the treatment of choice is selective removal

of the pituitary corticotrope tumor, usually via an endoscopic transsphenoidal approach. This results in an initial cure rate of 70–80%

when performed by a highly experienced surgeon. However, even

after initial remission following surgery, long-term follow-up is

important because late relapse occurs in a significant number

of patients. If pituitary disease recurs, there are several options,

including second surgery, radiotherapy, stereotactic radiosurgery,

and bilateral adrenalectomy. These options need to be applied in a

highly individualized fashion.

In some patients with very severe, overt Cushing’s (e.g., difficult

to control hypokalemic hypertension or acute psychosis), it may

be necessary to introduce medical therapy to rapidly control the

cortisol excess during the period leading up to surgery, which also

can help to alleviate hypercoagulability and, thus, operative risk.

Similarly, patients with metastasized, glucocorticoid-producing carcinomas may require long-term antiglucocorticoid drug treatment.

In case of ectopic ACTH syndrome, in which the tumor cannot be

located, one must carefully weigh whether drug treatment or bilateral adrenalectomy is the most appropriate choice, with the latter

facilitating immediate cure but requiring life-long corticosteroid

replacement. In this instance, it is paramount to ensure regular

imaging follow-up for identification of the ectopic ACTH source.

Oral agents with established efficacy in Cushing’s syndrome are

metyrapone and ketoconazole. Metyrapone inhibits cortisol synthesis at the level of 11β-hydroxylase (Fig. 386-1), whereas the antimycotic drug ketoconazole inhibits the early steps of steroidogenesis.

Typical starting doses are 500 mg tid for metyrapone (maximum

dose, 6 g) and 200 mg tid for ketoconazole (maximum dose, 1200

mg). Recently, the potent 11β-hydroxylase inhibitor osilodrostat has

been introduced for the treatment of Cushing’s, which also exerts

strong inhibition of aldosterone synthase (CYP11B2). Mitotane, a

derivative of the insecticide o,p’DDD, is an adrenolytic agent that

is also effective for reducing cortisol. Because of its side effect profile, it is most commonly used in the context of ACC, but low-dose

treatment (500–1000 mg/d) has also been used in benign Cushing’s.

In severe cases of cortisol excess, etomidate, an agent that potently

blocks 11β-hydroxylase and aldosterone synthase, can be used to

lower cortisol. It is administered by continuous IV infusion in low,

nonanesthetic doses. For Cushing’s disease, the subcutaneous administration of pasireotide, a somatostatin receptor agonist, represents

another therapeutic option, if surgical cure cannot be achieved.

After the successful removal of an ACTH- or cortisol-producing

tumor, the HPA axis will remain suppressed. Thus, hydrocortisone

replacement needs to be initiated at the time of surgery and slowly

tapered following recovery, to allow physiologic adaptation to normal cortisol levels. Depending on degree and duration of cortisol

excess, the HPA axis may require many months or even years to

resume normal function and sometimes does not recover. Generally, ectopic ACTH syndrome shows the best recovery rate (80%)

and adrenal Cushing’s has the lowest (40%), with Cushing’s disease

intermediate (60%).

■ MINERALOCORTICOID EXCESS

Epidemiology Following the first description of a patient with an

aldosterone-producing adrenal adenoma (Conn’s syndrome), mineralocorticoid excess was thought to represent a rare cause of hypertension.

However, in studies systematically screening all patients with hypertension, a much higher prevalence is now recognized, ranging from

5 to 12%. The prevalence is higher when patients are preselected for

hypokalemic hypertension.

Etiology The most common cause of mineralocorticoid excess is

primary aldosteronism, reflecting excess production of aldosterone by

the adrenal zona glomerulosa. Bilateral micronodular hyperplasia is

2964 PART 12 Endocrinology and Metabolism

somewhat more common than unilateral adrenal adenomas (Table 386-3).

Somatic mutations in channels and enzymes responsible for increasing

sodium and calcium influx in adrenal zona glomerulosa cells have

been identified as prevalent causes of aldosterone-producing adrenal

adenomas (Table 386-3) and, in the case of germline mutations, also

of primary aldosteronism due to bilateral macronodular adrenal

hyperplasia. However, bilateral adrenal hyperplasia as a cause of mineralocorticoid excess is usually micronodular but can also contain

larger nodules that might be mistaken for a unilateral adenoma. In

rare instances, primary aldosteronism is caused by an ACC. Carcinomas should be considered in younger patients and in those with larger

tumors because benign aldosterone-producing adenomas usually

measure <2 cm in diameter.

A rare cause of aldosterone excess is glucocorticoid-remediable

aldosteronism (GRA), which is caused by a chimeric gene resulting

from crossover of promoter sequences between the CYP11B1 and

CYP11B2 genes that are involved in glucocorticoid and mineralocorticoid synthesis, respectively (Fig. 386-1). This rearrangement brings

CYP11B2 transcription under the control of ACTH receptor signaling;

consequently, aldosterone production is regulated by ACTH rather

than by renin. The family history can be helpful because there may be

evidence for dominant transmission of hypertension. Recognition of

the disorder is important because it can be associated with early-onset

hypertension and strokes. In addition, glucocorticoid suppression can

reduce aldosterone production.

Other rare causes of mineralocorticoid excess are listed in

Table  386-3. An important cause is excess binding and activation of

the MR by a steroid other than aldosterone. Cortisol acts as a potent

mineralocorticoid if it escapes efficient inactivation to cortisone by

11β-HSD2 in the kidney (Fig. 386-7). This can be caused by inactivating mutations in the HSD11B2 gene resulting in the syndrome

of apparent mineralocorticoid excess (SAME) that characteristically manifests with severe hypokalemic hypertension in childhood.

However, milder mutations may cause normokalemic hypertension

manifesting in adulthood (type II SAME). Inhibition of 11β-HSD2

by excess licorice ingestion also results in hypokalemic hypertension,

as does overwhelming of 11β-HSD2 conversion capacity by cortisol

excess in Cushing’s syndrome. DOC also binds and activates the

MR and can cause hypertension if its circulating concentrations are

increased. This can arise through autonomous DOC secretion by an

ACC, but also when DOC accumulates as a consequence of an adrenal

enzymatic block, as seen in congenital adrenal hyperplasia (CAH) due

to CYP11B1 (11β-hydroxylase) or CYP17A1 (17α-hydroxylase) deficiency (Fig. 386-1). Progesterone can cause hypokalemic hypertension

in rare individuals who harbor a MR mutation that enhances binding

and activation by progesterone; physiologically, progesterone normally

exerts antimineralocorticoid activity. Finally, excess mineralocorticoid activity can be caused by mutations in the β or γ subunits of the

ENaC, disrupting its interaction with Nedd4 (Fig. 386-7), and thereby

decreasing receptor internalization and degradation. The constitutively

active ENaC drives hypokalemic hypertension, resulting in an autosomal dominant disorder termed Liddle’s syndrome.

Clinical Manifestations Excess activation of the MR leads to

potassium depletion and increased sodium retention, with the latter

causing an expansion of extracellular and plasma volume. Increased

ENaC activity also results in hydrogen depletion that can cause metabolic alkalosis. Aldosterone also has direct effects on the vascular system, where it increases cardiac remodeling and decreases compliance.

Aldosterone excess may cause direct damage to the myocardium and

the kidney glomeruli, in addition to secondary damage due to systemic

hypertension.

A C

B D

FIGURE 386-11 Adrenal imaging in Cushing’s syndrome. A. Adrenal computed tomography (CT) showing normal bilateral adrenal morphology (arrows). B. CT scan

depicting a right adrenocortical adenoma (arrow) causing Cushing’s syndrome. C. Magnetic resonance imaging (MRI) showing bilateral adrenal hyperplasia due to excess

adrenocorticotropic hormone stimulation in Cushing’s disease. D. MRI showing bilateral macronodular hyperplasia causing Cushing’s syndrome.

2965 Disorders of the Adrenal Cortex CHAPTER 386

The clinical hallmark of mineralocorticoid excess is hypokalemic

hypertension; however, only 50% of patients with primary aldosteronism exhibit hypokalemia. Serum sodium tends to be normal due

to the concurrent fluid retention, which in some cases can lead to

peripheral edema. Hypomagnesemia is also a common finding. Hypokalemia can be exacerbated by thiazide drug treatment, which leads to

increased delivery of sodium to the distal renal tubule, thereby driving

potassium excretion. Severe hypokalemia can be associated with muscle weakness, overt proximal myopathy, or even hypokalemic paralysis.

Severe alkalosis contributes to muscle cramps and, in severe cases, can

cause tetany.

Of note, patients with primary aldosteronism show increased rates

of osteoporosis, type 2 diabetes, and cognitive dysfunction. A significant proportion of patients suffer from concurrent mild autonomous

cortisol excess (MACE), termed Connshing syndrome.

Diagnosis Diagnostic screening for mineralocorticoid excess is not

currently recommended for all patients with hypertension but should

be restricted to those who exhibit hypertension associated with drug

resistance, hypokalemia, an adrenal mass, or onset of disease before

the age of 40 years (Fig. 386-12). The accepted screening test is concurrent measurement of plasma renin and aldosterone with subsequent

calculation of the aldosterone-renin ratio (ARR) (Fig. 386-12); serum

potassium needs to be normalized prior to testing. Stopping antihypertensive medication can be cumbersome, particularly in patients

with severe hypertension. Thus, for practical purposes, in the first

instance, the patient can remain on the usual antihypertensive medications, with the exception that MR antagonists need to be ceased

at least 4 weeks prior to ARR measurement. The remaining antihypertensive drugs usually do not affect the outcome of ARR testing,

except that beta blocker treatment can cause false-positive results and

ACE/AT1R inhibitors can cause false-negative results in milder cases

(Table 386-4).

ARR screening is positive if the ratio is >750 pmol/L per ng/mL

per hour, with a concurrently high normal or increased aldosterone (Fig.  386-12). If one relies on the ARR only, the likelihood of a

false-positive ARR becomes greater when renin levels are very low. The

characteristics of the biochemical assays are also important. Some labs

measure plasma renin activity, whereas others measure plasma renin

concentrations. Antibody-based assays for the measurement of serum

aldosterone lack the reliability of tandem mass spectrometry assays, but

these are not yet ubiquitously available.

Diagnostic confirmation of mineralocorticoid excess in a patient

with a positive ARR screening result should be undertaken by an endocrinologist as the tests lack optimized validation. The most straightforward is the saline infusion test, which involves the IV administration

of 2 L of physiologic saline over a 4-h period. Failure of aldosterone to

suppress <140 pmol/L (5 ng/dL) is indicative of autonomous mineralocorticoid excess. Alternative tests are the oral sodium loading test

(300 mmol NaCl/d for 3 days) or the fludrocortisone suppression test

(0.1 mg q6h with 30 mmol NaCl q8h for 4 days); the latter can be difficult because of the risk of profound hypokalemia and increased hypertension. In patients with overt hypokalemic hypertension, strongly

positive ARR, and concurrently increased aldosterone levels, confirmatory testing is usually not necessary.

Differential Diagnosis and Treatment After the diagnosis of

hyperaldosteronism is established, the next step is to use adrenal imaging to further assess the cause. Fine-cut CT scanning of the adrenal

region is the method of choice because it provides excellent visualization of adrenal morphology and most aldosterone-producing adenomas are <1 cm. CT will readily identify larger tumors suspicious of

malignancy but may miss lesions <5 mm. The differentiation between

bilateral micronodular hyperplasia and a unilateral adenoma is only

required if a surgical approach is feasible and desired. Consequently,

selective adrenal vein sampling (AVS) should only be carried out in

surgical candidates with either no obvious lesion on CT or evidence

of a unilateral lesion but with age >40 years because the latter patients

have a high likelihood of harboring a coincidental, endocrine-inactive

adrenal adenoma (Fig. 386-12). AVS is used to compare aldosterone

levels in the inferior vena cava and between the right and left adrenal

veins. AVS requires concurrent measurement of cortisol to document

correct placement of the catheter in the adrenal veins and should

demonstrate a cortisol gradient >3 between the vena cava and each

adrenal vein. Lateralization is confirmed by an aldosterone/cortisol

ratio that is at least twofold higher on one side than the other. AVS is a

TABLE 386-3 Causes of Mineralocorticoid Excess

CAUSES OF MINERALOCORTICOID EXCESS MECHANISM %

Primary Aldosteronism

Adrenal (Conn’s) adenoma Autonomous aldosterone excess can be caused by somatic (intratumor) mutations in the potassium

channel GIRK4 (encoded by KCNJ5; identified as cause of disease in 40% of aldosterone-producing

adenomas; rare germline mutations can cause bilateral macronodular adrenal hyperplasia). Further

causes include somatic mutations affecting the α-subunit of the Na+

/K+

-ATPase (encoded by ATP1A1),

the plasma membrane calcium-transporting ATPase 3 (encoded by ATP2B3), and somatic mutations in

CACNA1D or CACNA1H encoding the voltage-gated calcium channel CaV1.3 and CaV3.2, respectively.

All mutations result in upregulation of CYP11B2 and hence aldosterone synthesis.

40

Bilateral (micronodular) adrenal hyperplasia Autonomous aldosterone excess, mostly micronodular and rarely macronodular, with germline KCNJ5

mutations being a rare cause.

60

Glucocorticoid-remediable hyperaldosteronism

(dexamethasone-suppressible hyperaldosteronism)

Crossover between the CYP11B1 and CYP11B2 genes results in ACTH-driven aldosterone production <1

Other Causes (Rare) <1

Syndrome of apparent mineralocorticoid

excess (SAME)

Mutations in HSD11B2 result in lack of renal inactivation of cortisol to cortisone, leading to excess

activation of the MR by cortisol (inhibition of 11β-hydroxysteroid dehydrogenase type 2 by excess

licorice ingestion can have similar effects)

Cushing’s syndrome Cortisol excess overcomes the capacity of HSD11B2 to inactivate cortisol to cortisone, consequently

flooding the MR

Glucocorticoid resistance Upregulation of cortisol production due to GR mutations results in flooding of the MR by cortisol

Adrenocortical carcinoma Autonomous aldosterone and/or DOC excess

Congenital adrenal hyperplasia Accumulation of DOC due to mutations in CYP11B1 or CYP17A1

Progesterone-induced hypertension Progesterone acts as an abnormal ligand due to mutations in the MR gene

Liddle’s syndrome Mutant ENaC β or γ subunits resulting in reduced degradation of ENaC keeping the membrane channel

in open conformation for longer, enhancing mineralocorticoid action

Abbreviations: ACTH, adrenocorticotropic hormone; DOC, deoxycorticosterone; ENaC, epithelial sodium channel; GR, glucocorticoid receptor; HSD11B2, 11β-hydroxysteroid

dehydrogenase type 2; MR, mineralocorticoid receptor.

2966 PART 12 Endocrinology and Metabolism

Unilateral

adrenalectomy

Drug treatment

(MR antagonists,

amiloride)

Dexamethasone

0.125-0.5 mg/d

Negative

Negative

• Severe hypertension (>3 BP drugs, drug-resistant) or

• Hypokalemia (spontaneous or diuretic-induced) or

• Adrenal mass or

• Family history of early-onset hypertension or cerebrovascular

events at <40 years of age

Screening

Measurement of aldosterone-renin ratio (ARR) on current

blood pressure medication (stop spironolactone for 4 weeks)

and with hypokalemia corrected (ARR screen positive if

ARR >750 pmol/L: ng/mL/h and aldosterone >450 pmol/L)

(consider repeat off β-blockers for 2 weeks if results are equivocal)

E.g., saline infusion test (2 L physiologic saline over 4 h IV),

oral sodium loading, fludrocortisone suppression

Adrenal

vein sampling

Bilateral

micronodular

hyperplasia

Normal

adrenal

morphology

24-h urinary steroid profile

(GC/MS)

 Diagnostic for

• Apparent mineralocorti-

 coid excess (HSD11B2 def.)

• CAH (CYP11B1

 or CYP17A1 def.)

• Adrenal tumor-related

 desoxycorticosterone excess

If negative, consider

• Liddle’s syndrome (ENaC

mutations) (responsive to

 amiloride trial)

Family history of early

onset hypertension?

Screen for glucocorticoidremediable aldosteronism

Clinical suspicion of mineralocorticoid excess

Patients with hypertension and

Positive Negative

Confirmation of diagnosis

Unenhanced CT adrenals

Age <40

years

Age >40 years

(if surgery

practical

and desired)

Pos. Neg. Pos.

Neg.

Rare:

Both renin

and aldosterone

suppressed

Unilateral

adrenal

mass*

FIGURE 386-12 Management of patients with suspected mineralocorticoid excess. *

Perform adrenal tumor workup (see Fig. 386-13). BP, blood pressure; CAH, congenital

adrenal hyperplasia; CT, computed tomography; ENaC, epithelial sodium channel; GC/MS, gas chromatography/mass spectrometry; MR, mineralocorticoid receptor; PRA,

plasma renin activity.

TABLE 386-4 Effects of Antihypertensive Drugs on the AldosteroneRenin Ratio (ARR)

DRUG

EFFECT ON

RENIN

EFFECT ON

ALDOSTERONE

NET EFFECT ON

ARR

β Blockers ↓ ↑ ↑

α1

 Blockers → → →

α2

 Sympathomimetics → → →

ACE inhibitors ↑ ↓ ↓

AT1R blockers ↑ ↓ ↓

Calcium antagonists → → →

Diuretics (↑) (↑) →/(↓)

Abbreviations: ACE, angiotensin-converting enzyme; AT1R, angiotensin II receptor

type 1.

complex procedure that requires a highly skilled interventional radiologist. Even then, the right adrenal vein can be difficult to cannulate

correctly, which, if not achieved, invalidates the procedure. There is

also no agreement as to whether the two adrenal veins should be cannulated simultaneously or successively and whether ACTH stimulation

enhances the diagnostic value of AVS.

Patients <40 years with confirmed mineralocorticoid excess and

a unilateral lesion on CT can go straight to surgery, which is also

indicated in patients with confirmed lateralization documented by

a valid AVS procedure. Laparoscopic adrenalectomy is the preferred

approach. Patients who are not surgical candidates, or with evidence of

bilateral hyperplasia based on CT or AVS, should be treated medically

(Fig. 386-12). Medical treatment, which can also be considered prior to

surgery to avoid postsurgical hypoaldosteronism, consists primarily of

the MR antagonist spironolactone. It can be started at 12.5–50 mg bid

2967 Disorders of the Adrenal Cortex CHAPTER 386

and titrated up to a maximum of 400 mg/d to control blood pressure

and normalize potassium. Side effects include menstrual irregularity,

decreased libido, and gynecomastia. The more selective MR antagonist

eplerenone can also be used. Doses start at 25 mg bid, and it can be

titrated up to 200 mg/d. Another useful drug is the sodium channel

blocker amiloride (5–10 mg bid).

In patients with normal adrenal morphology and family history of

early-onset, severe hypertension, a diagnosis of GRA should be considered and can be evaluated using genetic testing. Treatment of GRA

consists of administering dexamethasone, using the lowest dose possible to control blood pressure. Some patients also require additional MR

antagonist treatment.

The diagnosis of non-aldosterone-related mineralocorticoid excess

is based on documentation of suppressed renin and suppressed

aldosterone in the presence of hypokalemic hypertension. This testing

is best carried out by employing urinary steroid metabolite profiling

by gas chromatography/mass spectrometry (GC/MS). An increased

free cortisol over free cortisone ratio is suggestive of SAME and can be

treated with dexamethasone. Steroid profiling by GC/MS also detects

the steroids associated with CYP11B1 and CYP17A1 deficiency or the

irregular steroid secretion pattern in a DOC-producing ACC (Fig.

386-12). If the GC/MS profile is normal, Liddle’s syndrome should

be considered. It is very sensitive to amiloride treatment but will not

respond to MR antagonist treatment because the defect is due to a

constitutively active ENaC.

■ APPROACH TO THE PATIENT: INCIDENTALLY

DISCOVERED ADRENAL MASS

Epidemiology Incidentally discovered adrenal masses, commonly

termed adrenal “incidentalomas,” are common, with a prevalence of

2–5% in the general population as documented in CT and autopsy

series. The prevalence increases with age, with 1% of 40-year-olds and

7% of 70-year-olds harboring an adrenal mass. The widespread use of

cross-sectional imaging has also increased the recognized prevalence.

Etiology Most solitary adrenal tumors are monoclonal neoplasms.

Several genetic syndromes, including MEN 1 (MEN1), MEN 2 (RET),

Carney’s complex (PRKAR1A), and McCune-Albright (GNAS1), can

have adrenal tumors as one of their features. Somatic mutations in

MEN1, GNAS1, and PRKAR1A have been identified in a small proportion of sporadic adrenocortical adenomas. Aberrant expression of

membrane receptors (GIP, α- and β-adrenergic, luteinizing hormone,

vasopressin V1, and interleukin 1 receptors) has been identified in

some sporadic cases of macronodular adrenocortical hyperplasia.

The majority of adrenal nodules are endocrine-inactive adrenocortical adenomas. However, larger series suggest that up to 25% of

adrenal nodules are hormonally active, due to a cortisol- or aldosteroneproducing adrenocortical adenoma or a pheochromocytoma associated

with catecholamine excess (Table 386-5). ACC is rare but is the cause

of an adrenal mass in 5% of patients. However, metastases originating

from another solid tissue tumor are an additional cause of adrenal incidentaloma and have a higher incidence in patients undergoing imaging

for tumor staging or follow-up monitoring (Table 386-5).

Differential Diagnosis and Treatment Patients with an adrenal

mass >1 cm require a diagnostic evaluation. Two key questions need

to be addressed: (1) Does the tumor autonomously secrete hormones

that could have a detrimental effect on health? (2) Is the adrenal mass

benign or malignant?

Hormone secretion by an adrenal mass occurs along a continuum,

with a gradual increase in clinical manifestations in parallel with

hormone levels. Exclusion of catecholamine excess from a pheochromocytoma arising from the adrenal medulla is a mandatory part

of the diagnostic workup (Fig. 386-13). Furthermore, autonomous

cortisol resulting in Cushing’s syndrome requires exclusion and, in

patients with hypertension or low serum potassium, also primary

aldosteronism. Adrenal incidentalomas can be associated with MACE,

and patients usually lack overt clinical features of Cushing’s syndrome. Nonetheless, they may exhibit one or more components of the

metabolic syndrome (e.g., obesity, type 2 diabetes, or hypertension).

There is ongoing debate about the optimal treatment for these patients.

Overproduction of adrenal androgen precursors, DHEA and its sulfate,

is rare and most frequently seen in the context of ACC, as are increased

levels of steroid precursors such as 17OHP.

For the differentiation of benign from malignant adrenal masses,

imaging is relatively sensitive, although specificity is suboptimal.

Unenhanced CT is the procedure of choice for imaging the adrenal

glands (Fig. 386-11). A diagnosis of ACC, pheochromocytoma, and

benign adrenal myelolipoma becomes more likely with increasing

diameter of the adrenal mass. However, size alone is of poor predictive

value, with only 80% specificity for the differentiation of benign from

malignant masses when using a 4-cm cutoff. Metastases are rare but

are found with similar frequency in adrenal masses of all sizes. The

tumor attenuation value on unenhanced CT is of high diagnostic value,

as many adrenocortical adenomas are lipid rich and thus present with

low attenuation values (i.e., densities of <20 Hounsfield units [HUs]).

However, similar numbers of adrenocortical adenomas are lipid poor

and present with higher HUs, making it difficult to differentiate them

from ACCs, as well as also pheochromocytomas, both of which invariably have high attenuation values (i.e., densities >20 HU on precontrast scans). Generally, benign lesions are rounded and homogenous,

whereas most malignant lesions appear lobulated and inhomogeneous.

Pheochromocytoma and adrenomyelolipoma may also exhibit lobulated and inhomogeneous features. MRI also allows for the visualization of the adrenal glands with somewhat lower resolution than CT.

However, because it does not involve exposure to ionizing radiation,

it is preferred in children, young adults, and during pregnancy. MRI

has a valuable role in the characterization of indeterminate adrenal

lesions using chemical shift analysis, with malignant tumors rarely

showing loss of signal on opposed-phase MRI; however, this may also

be observed in a proportion of benign adrenocortical adenomas.

Fine-needle aspiration (FNA) or CT-guided biopsy of an adrenal

mass is very rarely indicated. FNA of a pheochromocytoma can cause

a life-threatening hypertensive crisis. FNA of an ACC violates the

tumor capsule and can cause needle track metastasis. FNA should

only be considered in a patient with a history of nonadrenal malignancy and a newly detected adrenal mass, after careful exclusion of

TABLE 386-5 Classification of Unilateral Adrenal Masses

MASS

APPROXIMATE

PREVALENCE (%)

Benign

Adrenocortical adenoma

Endocrine-inactive 60–85

Cortisol-producing 5–10

Aldosterone-producing 2–5

Pheochromocytoma 5–10

Adrenal myelolipoma <1

Adrenal ganglioneuroma <0.1

Adrenal hemangioma <0.1

Adrenal cyst <1

Adrenal hematoma/hemorrhagic infarction <1

Indeterminate

Adrenocortical oncocytoma <1

Malignant

Adrenocortical carcinoma 2–5

Malignant pheochromocytoma <1

Adrenal neuroblastoma <0.1

Lymphomas (including primary adrenal lymphoma) <1

Metastases (most frequent: breast, lung) 1–2

Note: Bilateral adrenal enlargement/masses may be caused by congenital adrenal

hyperplasia, bilateral macronodular hyperplasia, bilateral hemorrhage (due

to antiphospholipid syndrome or sepsis-associated Waterhouse-Friderichsen

syndrome), granuloma, amyloidosis, or infiltrative disease including tuberculosis.

2968 PART 12 Endocrinology and Metabolism

pheochromocytoma, and if the outcome will influence therapeutic

management. It is important to recognize that in 25% of patients with

a previous history of nonadrenal malignancy, a newly detected mass

on CT is not a metastasis. While FNA can diagnose extra-adrenal

malignancies, it has very limited ability to differentiate between benign

and malignant adrenocortical lesions and hence should not be used for

diagnosis of ACC.

Adrenal masses associated with confirmed hormone excess or suspected malignancy are usually treated surgically (Fig. 386-13) or, if

adrenalectomy is not feasible or desired, with medication. Preoperative

exclusion of glucocorticoid excess is particularly important for the prediction of postoperative suppression of the contralateral adrenal gland,

which requires glucocorticoid replacement peri- and postoperatively.

Adrenal masses with normal endocrine biochemistry at diagnosis and

a tumor radiodensity of <20 HU on unenhanced CT can be considered

benign and do not require further follow-up. In adrenal masses with

suspicious imaging findings (>20 HU), further tests and surgery are

feasible options (Fig. 386-13); however, the latter will still result in

unnecessary surgery for benign tumors. A recently introduced diagnostic test, urine steroid metabolomics, has a twofold higher positive

predictive value than imaging in detecting adrenocortical carcinoma,

based on a distinct “steroid fingerprint” with accumulating precursor

steroids in 24-h urine.

■ ADRENOCORTICAL CARCINOMA

ACC is a rare malignancy with an annual incidence of 1–2 per million

population. ACC is generally considered a highly malignant tumor;

however, it presents with broad interindividual variability with regard

to biologic characteristics and clinical behavior. Somatic mutations

in the tumor-suppressor gene TP53 are found in 25% of apparently

sporadic ACC. Germline TP53 mutations are the cause of the LiFraumeni syndrome associated with multiple solid organ cancers

including ACC and are found in 25% of pediatric ACC cases; the TP53

mutation R337H is found in almost all pediatric ACC in Brazil. Other

genetic changes identified in ACC include alterations in the Wnt/βcatenin pathway and in the insulin-like growth factor 2 (IGF2) cluster;

IGF2 overexpression is found in 90% of ACCs.

Patients with large adrenal tumors suspicious of malignancy should

be managed by a multidisciplinary specialist team, including an

endocrinologist, an oncologist, a surgeon, a radiologist, and a histopathologist. FNA is not indicated in suspected ACC: first, cytology

and also histopathology of a core biopsy cannot differentiate between

benign and malignant primary adrenal masses; second, FNA violates

the tumor capsule and may even cause needle canal metastasis. Even

when the entire tumor specimen is available, the histopathologic differentiation between benign and malignant adrenocortical lesions is a

diagnostic challenge. The most common histopathologic classification

Adrenal

cancer likely:

Tumor ≥4 cm

and >20 HU

Urine steroid

metabolomics

(if available)

Adrenal cancer

highly unlikely:

Tumor <4 cm

 and >20 HU

Neg.

Neg.

MACE Pos.

Pos.

Evidence of

hormone excess

Confirmatory testing

as required

Discharge Surgery

Follow-up

No evidence of

hormone excess

Consider additional tests

(FDG-PET, biopsy), in

particular if history of

extra-adrenal cancer

Benign:

Tumor ≤20 HU

Discharge

CT/MRI finding of incidentally discovered adrenal mass

Unenhanced CT adrenals (or MRI adrenals with chemical shift analysis),

if not already done as the index scan

Screening for hormone excess

• Plasma metanephrines or 24-h urine for

 metanephrine excretion

• Dexamethasone 1 mg overnight test; if positive;

 also perform plasma ACTH, midnight salivary

 cortisol (≥2x), 24-h urine for free cortisol

 excretion (≥2x)

• Plasma aldosterone and plasma renin in patients

 with hypertension and/or hypokalemia

• If tumor >4 cm: Serum 17-hydroxyprogesterone,

 androstenedione, and DHEAS

FIGURE 386-13 Management of the patient with an incidentally discovered adrenal mass. ACTH, adrenocorticotropic hormone; CT, computed tomography; FDG-PET,

fluorodeoxyglucose positron emission tomography; MACE, mild autonomous cortisol excess; MRI, magnetic resonance imaging.