2969 Disorders of the Adrenal Cortex CHAPTER 386

is the Weiss score, taking into account high nuclear grade; mitotic

rate (>5/HPF); atypical mitosis; <25% clear cells; diffuse architecture;

and presence of necrosis, venous invasion, and invasion of sinusoidal

structures and tumor capsule. The presence of three or more elements

suggests ACC. However, FNA is a feasible option if looking for metastases of an extra-adrenal primary or other adrenal tumor entities, such

as ganglioneuroma.

Although 60–70% of ACCs show biochemical evidence of steroid

overproduction, in many patients, this is not clinically apparent due to

the relatively inefficient steroid production by the adrenocortical cancer cells. Excess production of glucocorticoids and adrenal androgen

precursors are most common and indicative of malignancy.

Tumor staging at ACC diagnosis (Table 386-6) has important prognostic implications and requires scanning of the chest and abdomen for

local organ invasion, lymphadenopathy, and metastases. Intravenous

contrast medium is necessary for maximum sensitivity for hepatic

metastases. An adrenal origin may be difficult to determine on standard axial CT imaging if the tumors are large and invasive, but CT

reconstructions and MRI are more informative (Fig. 386-14) using

multiple planes and different sequences. Vascular and adjacent organ

invasion is diagnostic of malignancy. 18-Fluoro-2-deoxy-D-glucose

positron emission tomography (18-FDG-PET) is highly sensitive for

the detection of malignancy and can be used to detect small metastases

or local recurrence that may not be obvious on CT (Fig. 386-14). However, FDG-PET has limited specificity and therefore cannot be used for

differentiating benign from malignant adrenal lesions. Metastasis in

ACC most frequently occurs to liver and lung.

There is no established grading system for ACC, and the Weiss

score carries no prognostic value; the most important prognostic histopathologic parameter is the Ki67 proliferation index, with Ki67 <10%

indicative of slow to moderate growth velocity, whereas a Ki67 ≥10% is

associated with poor prognosis including high risk of recurrence and

rapid progression.

Cure of ACC can only be achieved by early detection and complete

surgical removal. Capsule violation during primary surgery, metastasis

at diagnosis, and primary treatment in a nonspecialist center and by a

nonspecialist surgeon are major determinants of poor survival. If the

primary tumor invades adjacent organs, en bloc removal of kidney

and spleen should be considered to reduce the risk of recurrence, and

regional lymph node dissection may further reduce this risk. Surgery

can also be considered in a patient with metastases if there is severe

tumor-related hormone excess. This indication needs to be carefully

weighed against surgical risk, including thromboembolic complications, and the resulting delay in the introduction of other therapeutic

options. Patients with confirmed ACC and successful removal of

the primary tumor should receive adjuvant treatment with mitotane

(o,p’DDD), particularly in patients with a high risk of recurrence as

determined by tumor size >8 cm, histopathologic signs of vascular

invasion, capsule invasion or violation, and a Ki67 proliferation index

≥10%. Adjuvant mitotane should be continued for at least 2 years,

if side effects are tolerated. Regular monitoring of plasma mitotane

levels is mandatory (therapeutic range 14–20 mg/L; neurotoxic complications more frequent at >20 mg/L). Mitotane is usually started at

500  mg tid, with stepwise increases to a maximum dose of 2000 mg

tid in days (high-dose saturation) or weeks (low-dose saturation) as

tolerated. Once therapeutic range plasma mitotane levels are achieved,

the dose can be tapered to maintenance doses mostly ranging from

1000–1500 mg tid. Mitotane treatment results in disruption of cortisol

synthesis and thus requires glucocorticoid replacement; glucocorticoid

replacement dose should be at least double of that usually used in

adrenal insufficiency (i.e., 20 mg tid) because mitotane induces hepatic

CYP3A4 activity, resulting in rapid inactivation of glucocorticoids.

Mitotane also increases circulating CBG, thereby decreasing the available free cortisol fraction. Single metastases can be addressed surgically

or with radiofrequency ablation as appropriate. If the tumor recurs or

progresses during mitotane treatment, cytotoxic chemotherapy should

be considered; the established first-line chemotherapy regimen is the

TABLE 386-6 Classification System for Staging of

Adrenocortical Carcinoma

ENSAT STAGE TNM STAGE TNM DEFINITIONS

I T1,N0,M0 T1, tumor ≤5 cm

N0, no positive lymph node

M0, no distant metastases

II T2,N0,M0 T2, tumor >5 cm

N0, no positive lymph node

M0, no distant metastases

III T1–T2,N1,M0 N1, positive lymph node(s)

T3–T4,N0–N1,M0 M0, no distant metastases

T3, tumor infiltration into surrounding

tissue

T4, tumor invasion into adjacent organs or

venous tumor thrombus in vena cava or

renal vein

IV T1–T4,N0–N1,M1 M1, presence of distant metastases

Abbreviations: ENSAT, European Network for the Study of Adrenal Tumors; TNM,

tumor, node, metastasis.

A B

C D

E F

FIGURE 386-14 Imaging in adrenocortical carcinoma (ACC). Magnetic resonance imaging scan with (A) frontal and (B) lateral views of a right ACC that was detected

incidentally. Computed tomography (CT) scan with (C) coronal and (D) transverse views depicting a right-sided ACC. Note the irregular border and inhomogeneous structure.

CT scan (E) and positron emission tomography/CT (F) visualizing a peritoneal metastasis of an ACC in close proximity to the right kidney (arrow).

2970 PART 12 Endocrinology and Metabolism

combination of cisplatin, etoposide, and doxorubicin plus continuing

mitotane. Painful bone metastasis responds to irradiation. Overall

survival in ACC is still poor, with 5-year survival rates of 30–40% and

a median survival of 15 months in metastatic ACC.

■ ADRENAL INSUFFICIENCY

Epidemiology The prevalence of well-documented, permanent

adrenal insufficiency is 5 in 10,000 in the general population. Hypothalamic-pituitary origin of disease is most frequent, with a prevalence

of 3 in 10,000, whereas primary adrenal insufficiency has a prevalence

of 2 in 10,000. Approximately one-half of the latter cases are acquired,

mostly caused by autoimmune destruction of the adrenal glands;

the other one-half are genetic, most commonly caused by distinct

enzymatic blocks in adrenal steroidogenesis affecting glucocorticoid

synthesis (i.e., CAH).

Adrenal insufficiency arising from suppression of the HPA axis

as a consequence of exogenous glucocorticoid treatment is much

more common, occurring in 0.5–2% of the population in developed

countries.

Etiology Primary adrenal insufficiency is most commonly caused by

autoimmune adrenalitis. Isolated autoimmune adrenalitis accounts for

30–40%, whereas 60–70% develop adrenal insufficiency as part of autoimmune polyglandular syndromes (APSs) (Chap. 388) (Table  386-7).

APS1, also termed APECED (autoimmune polyendocrinopathycandidiasis-ectodermal dystrophy), is the underlying cause in 10% of

patients affected by APS. APS1 is transmitted in an autosomal recessive

manner and is caused by mutations in the autoimmune regulator gene

AIRE. Associated autoimmune conditions overlap with those seen in

APS2 but may also include total alopecia, primary hypoparathyroidism,

and, in rare cases, lymphoma. APS1 patients invariably develop chronic

mucocutaneous candidiasis, usually manifested in childhood and

preceding adrenal insufficiency by years or decades. The much more

prevalent APS2 is of polygenic inheritance, with confirmed associations

with the HLA-DR3 gene region in the major histocompatibility complex

and distinct gene regions involved in immune regulation (CTLA-4,

PTPN22, CLEC16A). Coincident autoimmune disease most frequently

includes thyroid autoimmune disease, vitiligo, and premature ovarian

failure. Less commonly, additional features may include type 1 diabetes

and pernicious anemia caused by vitamin B12 deficiency.

X-linked adrenoleukodystrophy has an incidence of 1:20,000 males

and is caused by mutations in the X-ALD gene encoding the peroxisomal membrane transporter protein ABCD1; its disruption results

in accumulation of very-long-chain (>24 carbon atoms) fatty acids.

Approximately 50% of cases manifest in early childhood with rapidly

progressive white matter disease (cerebral adrenoleukodystrophy);

35% present during adolescence or in early adulthood with neurologic features indicative of myelin and peripheral nervous system

TABLE 386-7 Causes of Primary Adrenal Insufficiency

DIAGNOSIS GENE ASSOCIATED FEATURES

Autoimmune polyglandular syndrome 1 (APS1) AIRE Hypoparathyroidism, chronic mucocutaneous candidiasis, other

autoimmune disorders, rarely lymphomas

Autoimmune polyglandular syndrome 2 (APS2) Associations with HLA-DR3, CTLA-4 Hypothyroidism, hyperthyroidism, premature ovarian failure, vitiligo, type 1

diabetes mellitus, pernicious anemia

Isolated autoimmune adrenalitis Associations with HLA-DR3, CTLA-4

Congenital adrenal hyperplasia (CAH) CYP21A2, CYP11B1, CYP17A1, HSD3B2, POR See Table 386-10 (see also Chap. 390)

Congenital lipoid adrenal hyperplasia (CLAH) STAR, CYP11A1 46,XY DSD, gonadal failure (see also Chap. 390)

Adrenal hypoplasia congenita (AHC) NR0B1 (DAX-1), NR5A1 (SF-1) 46,XY DSD, gonadal failure (see also Chap. 390)

Adrenoleukodystrophy (ALD),

adrenomyeloneuropathy (AMN)

ABCD1 Demyelination of central nervous system (ALD) or spinal cord and

peripheral nerves (AMN)

Familial glucocorticoid deficiency MC2R Tall stature

MRAP None

STAR None

NNT

TXNRD2

None

None

MCM4 Growth retardation, natural killer cell deficiency

Triple A syndrome AAAS Alacrima, achalasia, neurologic impairment

Smith-Lemli-Opitz syndrome SLOS Cholesterol synthesis disorder associated with mental retardation,

craniofacial malformations, growth failure

Kearns-Sayre syndrome Mitochondrial DNA deletions Progressive external ophthalmoplegia, pigmentary retinal degeneration,

cardiac conduction defects, gonadal failure, hypoparathyroidism, type 1

diabetes,

IMAGe syndrome CDKN1C Intrauterine growth retardation, metaphyseal dysplasia, genital anomalies

MIRAGE syndrome SAMD9 Myelodysplasia, infection, restriction of growth, genital phenotypes, and

enteropathy

Sphingosine-1-phosphate lyase deficiency SGPL1 Steroid-resistant nephrotic syndrome, immunodeficiency, neurological

defects, ichthyosis, primary hypothyroidism, cryptorchidism

Adrenal infections Tuberculosis, HIV, CMV, cryptococcosis, histoplasmosis,

coccidioidomycosis

Adrenal infiltration Metastases, lymphomas, sarcoidosis, amyloidosis, hemochromatosis

Adrenal hemorrhage Meningococcal sepsis (Waterhouse-Friderichsen syndrome), primary

antiphospholipid syndrome

Drug-induced Mitotane, aminoglutethimide, abiraterone, trilostane, etomidate,

ketoconazole, osilodrostat, suramin, RU486, interferon-alpha, ribavirin,

megestrol acetate, immune checkpoint inhibitors (rare)

Bilateral adrenalectomy E.g., in the management of Cushing’s syndrome or after bilateral nephrectomy

Abbreviations: AIRE, autoimmune regulator; CMV, cytomegalovirus; DSD, disordered sex development; MC2R, ACTH receptor; MCM4, mini chromosome maintenancedeficient 4 homologue; MRAP, MC2R-accessory protein; NNT, nicotinamide nucleotide transhydrogenase.

2971 Disorders of the Adrenal Cortex CHAPTER 386

involvement (adrenomyeloneuropathy [AMN]). In the remaining

15%, adrenal insufficiency is the sole manifestation of disease. Of note,

distinct mutations manifest with variable penetrance and phenotypes

within affected families.

Rarer causes of adrenal insufficiency involve destruction of the adrenal glands as a consequence of infection, hemorrhage, or infiltration

(Table 386-7); tuberculous adrenalitis is still a frequent cause of disease

in developing countries. Adrenal metastases rarely cause adrenal insufficiency, and this occurs only with bilateral, bulky metastases.

Inborn causes of primary adrenal insufficiency other than CAH

are rare, causing <1% of cases. However, their elucidation provides

important insights into adrenal gland development and physiology.

Mutations causing primary adrenal insufficiency (Table 386-7) include

factors regulating adrenal development and steroidogenesis (DAX-1,

SF-1), cholesterol synthesis, import and cleavage (DHCR7, StAR,

CYP11A1), elements of the adrenal ACTH response pathway (MC2R,

MRAP) (Fig. 386-5), and factors involved in redox regulation (NNT,

TXNRD2) and DNA repair (MCM4, CDKN1C).

Secondary (or central) adrenal insufficiency is the consequence of

dysfunction of the hypothalamic-pituitary component of the HPA axis

(Table 386-8). Excluding iatrogenic suppression, the overwhelming

majority of cases are caused by pituitary or hypothalamic tumors or

their treatment by surgery or irradiation (Chap. 380). Rarer causes

include pituitary apoplexy, either as a consequence of an infarcted

pituitary adenoma or transient reduction in the blood supply of the

pituitary during surgery or after rapid blood loss associated with

parturition, also termed Sheehan’s syndrome. Isolated ACTH deficiency is rarely caused by autoimmune disease or pituitary infiltration

(Table 386-8). Mutations in the ACTH precursor POMC or in factors

regulating pituitary development are genetic causes of ACTH deficiency (Table 386-8).

Clinical Manifestations In principle, the clinical features of primary

adrenal insufficiency (Addison’s disease) are characterized by the loss of

both glucocorticoid and mineralocorticoid secretion (Table 386-9). In

secondary adrenal insufficiency, only glucocorticoid deficiency is present, as the adrenal itself is intact and thus still amenable to regulation

by the RAA system. Adrenal androgen secretion is disrupted in both

primary and secondary adrenal insufficiency (Table  386-9). Hypothalamic-pituitary disease can lead to additional clinical manifestations due

to involvement of other endocrine axes (thyroid, gonads, GH, prolactin)

or visual impairment with bitemporal hemianopia caused by chiasmal

compression. It is important to recognize that iatrogenic adrenal insufficiency caused by exogenous glucocorticoid suppression of the HPA axis

may result in all symptoms associated with glucocorticoid deficiency

(Table 386-9), if exogenous glucocorticoids are stopped abruptly. However, patients will appear clinically cushingoid as a result of the preceding

overexposure to glucocorticoids.

Chronic adrenal insufficiency manifests with relatively nonspecific

signs and symptoms, such as fatigue and loss of energy, often resulting

in delayed or missed diagnoses (e.g., as depression or anorexia). A

distinguishing feature of primary adrenal insufficiency is hyperpigmentation, which is caused by excess ACTH stimulation of melanocytes. Hyperpigmentation is most pronounced in skin areas exposed

to increased friction or shear stress and is increased by sunlight

(Fig. 386-15). Conversely, in secondary adrenal insufficiency, the skin

has an alabaster-like paleness due to lack of ACTH secretion.

Hyponatremia is a characteristic biochemical feature in primary

adrenal insufficiency and is found in 80% of patients at presentation. Hyperkalemia is present in 40% of patients at initial diagnosis.

Hyponatremia is primarily caused by mineralocorticoid deficiency but

can also occur in secondary adrenal insufficiency due to diminished

inhibition of antidiuretic hormone (ADH) release by cortisol, resulting

in mild syndrome of inappropriate secretion of antidiuretic hormone

(SIADH). Glucocorticoid deficiency also results in slightly increased

TSH concentrations that normalize within days to weeks after initiation of glucocorticoid replacement.

Acute adrenal insufficiency, also termed adrenal crisis, usually occurs

after a prolonged period of nonspecific complaints and is more

frequently observed in patients with primary adrenal insufficiency,

due to the loss of both glucocorticoid and mineralocorticoid secretion.

Postural hypotension may progress to hypovolemic shock. Adrenal

insufficiency may mimic features of acute abdomen with abdominal

tenderness, nausea, vomiting, and fever. In some cases, the primary presentation may resemble neurologic disease, with decreased responsiveness progressing to stupor and coma. An adrenal crisis can be triggered

by an intercurrent illness, surgical or other stress, or increased glucocorticoid inactivation (e.g., hyperthyroidism). Prospective data indicate 8.3

adrenal crises and 0.5 adrenal crisis-related deaths per 100 patient-years.

Diagnosis The diagnosis of adrenal insufficiency is established by

the short cosyntropin test, a safe and reliable tool with excellent predictive diagnostic value (Fig. 386-16). The cutoff for failure is usually

defined at cortisol levels of <450–500 nmol/L (16–18 μg/dL) sampled

30–60 min after ACTH stimulation; the exact cutoff is dependent on

the locally available assay, with generally lower cutoffs for mass spectrometry–based assays. During the early phase of HPA disruption (e.g.,

within 4 weeks of pituitary insufficiency), patients may still respond

to exogenous ACTH stimulation. In this circumstance, the ITT is an

TABLE 386-8 Causes of Secondary Adrenal Insufficiency

DIAGNOSIS GENE ASSOCIATED FEATURES

Pituitary tumors

(endocrine active and

inactive adenomas, very

rare: carcinoma)

Depending on tumor size and

location: visual field impairment

(bilateral hemianopia),

hyperprolactinemia, secondary

hypothyroidism, hypogonadism,

growth hormone deficiency

Other mass lesions

affecting the

hypothalamic-pituitary

region

Craniopharyngioma, meningioma,

ependymoma, metastases

Pituitary irradiation Radiotherapy administered for

pituitary tumors, brain tumors, or

craniospinal irradiation in leukemia

Autoimmune hypophysitis Often associated with pregnancy;

may present with panhypopituitarism

or isolated ACTH deficiency; can be

associated with autoimmune thyroid

disease, more rarely with vitiligo,

premature ovarian failure, type 1

diabetes, pernicious anemia

Pituitary apoplexy/

hemorrhage

Hemorrhagic infarction of large

pituitary adenomas or pituitary

infarction consequent to traumatic

major blood loss (e.g., surgery or

pregnancy: Sheehan’s syndrome)

Pituitary infiltration Tuberculosis, actinomycosis,

sarcoidosis, histiocytosis X,

granulomatosis with polyangiitis

(Wegener’s), metastases

Drug-induced Chronic glucocorticoid excess

(endogenous or exogenous), immune

check point inhibitors

Congenital isolated ACTH

deficiency

TBX19 (Tpit)

Combined pituitary

hormone deficiency

(CPHD)

PROP-1 Progressive development of CPHD

in the order GH, PRL, TSH, LH/FSH,

ACTH

HESX1 CPHD and septo-optic dysplasia

LHX3 CPHD and limited neck rotation,

sensorineural deafness

LHX4 CPHD and cerebellar abnormalities

SOX3 CPHD and variable mental

retardation

Proopiomelanocortin

(POMC) deficiency

POMC Early-onset obesity, red hair

pigmentation

Abbreviations: ACTH, adrenocorticotropic hormone; GH, growth hormone; LH/

FSH, luteinizing hormone/follicle-stimulating hormone; PRL, prolactin; TSH, thyroidstimulating hormone.

2972 PART 12 Endocrinology and Metabolism

alternative choice but is more invasive and should be carried out only

under a specialist’s supervision (see above). Induction of hypoglycemia

is contraindicated in individuals with diabetes mellitus, cardiovascular

disease, or history of seizures. Random serum cortisol measurements

are of limited diagnostic value because baseline cortisol levels may be

coincidentally low due to the physiologic diurnal rhythm of cortisol

secretion (Fig. 386-3). Similarly, many patients with secondary adrenal

insufficiency have relatively normal baseline cortisol levels but fail to

mount an appropriate cortisol response to ACTH, which can only be

revealed by stimulation testing. Importantly, tests to establish the diagnosis of adrenal insufficiency should never delay treatment. Thus, in a

patient with suspected adrenal crisis, it is reasonable to draw baseline

cortisol levels, provide replacement therapy, and defer formal stimulation testing until a later time.

Once adrenal insufficiency is confirmed, measurement of plasma

ACTH is the next step, with increased or inappropriately low levels defining primary and secondary origin of disease, respectively

(Fig.  386-16). In primary adrenal insufficiency, increased plasma

renin will confirm the presence of mineralocorticoid deficiency.

At initial presentation, patients with primary adrenal insufficiency

should undergo screening for steroid autoantibodies as a marker of

autoimmune adrenalitis. If these tests are negative, adrenal imaging

by CT is indicated to investigate possible hemorrhage, infiltration, or

masses. In male patients with negative autoantibodies in the plasma,

very-long-chain fatty acids should be measured to exclude X-ALD.

Patients with inappropriately low ACTH, in the presence of confirmed

cortisol deficiency, should undergo hypothalamic-pituitary imaging

by MRI. Features suggestive of preceding pituitary apoplexy, such as

sudden-onset severe headache or history of previous head trauma,

should be carefully explored, particularly in patients with no obvious

MRI lesion.

TREATMENT

Acute Adrenal Insufficiency

Acute adrenal insufficiency requires immediate initiation of rehydration, usually carried out by saline infusion at initial rates of 1 L/h

with continuous cardiac monitoring. Glucocorticoid replacement

should be initiated by bolus injection of 100 mg hydrocortisone,

followed by the administration of 200 mg hydrocortisone over 24 h,

preferably by continuous infusion or alternatively by bolus IV or IM

injections. Mineralocorticoid replacement can be initiated once the

daily hydrocortisone dose has been reduced to <50 mg because at

higher doses hydrocortisone provides sufficient stimulation of MRs.

Glucocorticoid replacement for the treatment of chronic adrenal insufficiency should be administered at a dose that replaces the

physiologic daily cortisol production, which is usually achieved by

the oral administration of 15–25 mg hydrocortisone in two to three

divided doses. Pregnancy may require an increase in hydrocortisone dose by 50% during the last trimester. In all patients, at least

one-half of the daily dose should be administered in the morning.

Currently available glucocorticoid preparations fail to mimic the

physiologic cortisol secretion rhythm (Fig. 386-3). Long-acting

glucocorticoids such as prednisolone or dexamethasone are not

preferred because they result in increased glucocorticoid exposure

due to extended GR activation at times of physiologically low cortisol secretion. There are no well-established dose equivalencies, but

as a guide, equipotency can be assumed for 1 mg hydrocortisone,

1.6 mg cortisone acetate, 0.2 mg prednisolone, 0.25 mg prednisone,

and 0.025 mg dexamethasone.

Monitoring of glucocorticoid replacement is mainly based on

the history and examination for signs and symptoms suggestive of

glucocorticoid over- or underreplacement, including assessment of

body weight and blood pressure. Plasma ACTH, 24-h urinary free

cortisol, or serum cortisol day curves reflect whether hydrocortisone has been taken or not but do not convey reliable information

about replacement quality. In patients with isolated primary adrenal

insufficiency, monitoring should include screening for autoimmune

thyroid disease, and female patients should be made aware of the

possibility of premature ovarian failure. Supraphysiologic glucocorticoid treatment with doses equivalent to 30 mg hydrocortisone

or more will affect bone metabolism, and these patients should

undergo regular bone mineral density evaluation. All patients with

adrenal insufficiency need to be instructed about the requirement

for stress-related glucocorticoid dose adjustments. These generally

consist of doubling the routine oral glucocorticoid dose in the case

of intercurrent illness with fever and bed rest and the need for

immediate IV or IM injection of 100 mg hydrocortisone followed

by intravenous infusion of 200 mg hydrocortisone/24 h in cases of

prolonged vomiting, surgery, or trauma. All patients, but in particular those living or traveling in regions with delayed access to acute

health care, should carry a hydrocortisone self-injection emergency

kit, in addition to their usual steroid emergency cards and bracelets,

and should receive training in its use.

Mineralocorticoid replacement in primary adrenal insufficiency should be initiated at a dose of 100–150 μg fludrocortisone.

The adequacy of treatment can be evaluated by measuring blood

pressure, sitting and standing, to detect a postural drop indicative

of hypovolemia. In addition, serum sodium, potassium, and plasma

renin should be measured regularly. Renin levels should be kept in

the upper normal reference range. Changes in glucocorticoid dose

may also impact on mineralocorticoid replacement as cortisol also

binds the MR; 40 mg of hydrocortisone is equivalent to 100 μg of

fludrocortisone. It is important to note that prednisone and prednisolone have reduced mineralocorticoid activity and dexamethasone has none. In patients living or traveling in areas with hot or

tropical weather conditions, the fludrocortisone dose should be

increased by 50–100 μg during the summer. Mineralocorticoid dose

may also need to be adjusted during pregnancy due to the antimineralocorticoid activity of progesterone, but this is less often required

TABLE 386-9 Signs and Symptoms of Adrenal Insufficiency

Signs and Symptoms Caused by Glucocorticoid Deficiency

Fatigue, lack of energy

Weight loss, anorexia

Myalgia, joint pain

Fever

Normochromic anemia, lymphocytosis, eosinophilia

Slightly increased TSH (due to loss of feedback inhibition of TSH release)

Hypoglycemia (more frequent in children)

Low blood pressure, postural hypotension

Hyponatremia (due to loss of feedback inhibition of AVP release)

Signs and Symptoms Caused by Mineralocorticoid Deficiency (Primary

Adrenal Insufficiency Only)

Abdominal pain, nausea, vomiting

Dizziness, postural hypotension

Salt craving

Low blood pressure, postural hypotension

Increased serum creatinine (due to volume depletion)

Hyponatremia

Hyperkalemia

Signs and Symptoms Caused by Adrenal Androgen Deficiency

Lack of energy

Dry and itchy skin (in women)

Loss of libido (in women)

Loss of axillary and pubic hair (in women)

Other Signs and Symptoms

Hyperpigmentation (primary adrenal insufficiency only) (due to excess of

proopiomelanocortin [POMC]-derived peptides)

Alabaster-colored pale skin (secondary adrenal insufficiency only) (due to

deficiency of POMC-derived peptides)

Abbreviations: AVP, arginine vasopressin; TSH, thyroid-stimulating hormone.

2973 Disorders of the Adrenal Cortex CHAPTER 386

than hydrocortisone dose adjustment. Plasma renin cannot serve as

a monitoring tool during pregnancy because renin rises physiologically during gestation.

Adrenal androgen replacement is an option in patients with

lack of energy, despite optimized glucocorticoid and mineralocorticoid replacement. It may also be indicated in women with features

of androgen deficiency, including loss of libido. Adrenal androgen replacement can be achieved by once-daily administration

of 25–50  mg DHEA. Treatment is monitored by measurement of

DHEAS, androstenedione, testosterone, and sex hormone–binding

globulin (SHBG) 24 h after the last DHEA dose.

■ CONGENITAL ADRENAL HYPERPLASIA

(See also Chap. 390) CAH is caused by mutations in genes encoding

steroidogenic enzymes involved in glucocorticoid synthesis (CYP21A2,

CYP17A1, HSD3B2, CYP11B1) or in the cofactor enzyme P450 oxidoreductase that serves as an electron donor to CYP21A2 and CYP17A1

(Fig. 386-1). Invariably, patients affected by CAH exhibit glucocorticoid deficiency. Depending on the exact step of enzymatic block, they

may also have excess production of mineralocorticoids or deficient

production of sex steroids (Table 386-10). The diagnosis of CAH is

readily established by measurement of the steroids accumulating before

the distinct enzymatic block, either in serum or in urine, preferably by

the use of mass spectrometry–based assays (Table 386-10).

Mutations in CYP21A2 are the most prevalent cause of CAH,

responsible for 90–95% of cases. 21-Hydroxylase deficiency disrupts

glucocorticoid and mineralocorticoid synthesis (Fig. 386-1), resulting in diminished negative feedback via the HPA axis. This leads to

increased pituitary ACTH release, which drives increased synthesis

of adrenal androgen precursors and subsequent androgen excess.

The degree of impairment of glucocorticoid and mineralocorticoid

secretion depends on the severity of mutations. Major loss-of-function

mutations result in combined glucocorticoid and mineralocorticoid

deficiency (classic CAH, neonatal presentation), whereas less severe

mutations affect glucocorticoid synthesis only (simple virilizing CAH,

neonatal or early childhood presentation). The mildest mutations

result in the least severe clinical phenotype, nonclassic CAH, usually

presenting during adolescence and early adulthood and with preserved

glucocorticoid production.

Androgen excess is present in all patients and manifests with broad

phenotypic variability, ranging from severe virilization of the external

genitalia in neonatal girls (e.g., 46,XX disordered sex development [DSD])

to hirsutism and oligomenorrhea resembling a polycystic ovary syndrome

phenotype in young women with nonclassic CAH. In countries without

neonatal screening for CAH, boys with classic CAH usually present with

life-threatening adrenal crisis in the first few weeks of life (salt-wasting

crisis); a simple-virilizing genotype manifests with precocious pseudopuberty and advanced bone age in early childhood, whereas men with

nonclassic CAH are usually detected only through family screening.

A B

C D

FIGURE 386-15 Clinical features of Addison’s disease. Note the hyperpigmentation in areas of increased friction including (A) palmar creases, (B) dorsal foot, (C) nipples

and axillary region, and (D) patchy hyperpigmentation of the oral mucosa.

2974 PART 12 Endocrinology and Metabolism

Negative

Adrenal autoantibodies

• Autoimmune

 adrenalitis;

• Autoimmune

 polyglandular

 syndrome (APS)

Hypothalamicpituitary mass lesion

• History of exogenous

 glucocorticoid treatment?

• History of head trauma?

• Consider isolated ACTH

 deficiency

MRI pituitary

Clinical suspicion of adrenal insufficiency

(weight loss, fatigue, postural hypotension, hyperpigmentation,

hyponatremia)

Differential diagnosis

Plasma ACTH, plasma renin, serum aldosterone

• Plasma cortisol 30–60 min after 250 µg cosyntropin IM or IV

(Cortisol post cosyntropin <450–500 nmol/L [assay-specific])

• CBC, serum sodium, potassium, creatinine, urea, TSH

Screening/confirmation of diagnosis

Secondary adrenal insufficiency

(Low-normal ACTH, normal renin,

normal aldosterone)

Primary adrenal insufficiency

(High ACTH, high renin, low

aldosterone)

Glucocorticoid + mineralocorticoid

replacement Glucocorticoid replacement

Positive

Positive

Negative Positive Negative

• Adrenal infection

 (tuberculosis),

• Infiltration

 (e.g., lymphoma)

• Hemorrhage

• Congenital adrenal

 hyperplasia (17OHP↑)

• Autoimmune

 adrenalitis most likely

 diagnosis

• In men, consider

 adrenoleukodystrophy

(VLCFA↑)

• Chest x-ray

• Serum 17OHP

• In men: plasma very-

 long-chain fatty acids

(VLCFA)

• Adrenal CT

FIGURE 386-16 Management of the patient with suspected adrenal insufficiency. ACTH, adrenocorticotropic hormone; CBC, complete blood count; MRI, magnetic

resonance imaging; PRA, plasma renin activity; TSH, thyroid-stimulating hormone.

TABLE 386-10 Variants of Congenital Adrenal Hyperplasia

VARIANT GENE IMPACT ON STEROID SYNTHESIS DIAGNOSTIC MARKER STEROIDS IN SERUM (AND URINE)

21-Hydroxylase deficiency (21OHD) CYP21A2 Glucocorticoid deficiency, mineralocorticoid

deficiency, adrenal androgen excess

17-Hydroxyprogesterone, 21-deoxycortisol (pregnanetriol,

17-hydroxypregnanolone, pregnanetriolone)

11β-Hydroxylase deficiency (11OHD) CYP11B1 Glucocorticoid deficiency, mineralocorticoid

excess, adrenal androgen excess

11-Deoxycortisol, 11-deoxycorticosterone (tetrahydro-11-

deoxycortisol, tetrahydro-11-deoxycorticosterone)

17α-Hydroxylase deficiency (17OHD) CYP17A1 (Glucocorticoid deficiency), mineralocorticoid

excess, androgen deficiency

11-Deoxycorticosterone, corticosterone, pregnenolone,

progesterone (tetrahydro-11-deoxycorticosterone,

tetrahydrocorticosterone, pregnenediol, pregnanediol)

3β-Hydroxysteroid dehydrogenase

deficiency (3bHSDD)

HSD3B2 Glucocorticoid deficiency, (mineralocorticoid

deficiency), adrenal androgen excess (females

and males), gonadal androgen deficiency (males)

17-Hydroxypregnanolone (pregnanetriol)

P450 oxidoreductase deficiency (PORD) POR Glucocorticoid deficiency, (mineralocorticoid

excess), prenatal androgen excess and postnatal

androgen deficiency, skeletal malformations

Pregnenolone, progesterone, 17-hydroxyprogesterone

(pregnanediol, pregnanetriol)

2975 Disorders of the Adrenal Cortex CHAPTER 386

Glucocorticoid treatment is more complex than for other causes of

primary adrenal insufficiency as it not only needed to replace missing

glucocorticoids but also to control the increased ACTH drive and

subsequent androgen excess. Current treatment is hampered by the

lack of glucocorticoid preparations that mimic the diurnal cortisol

secretion profile, resulting in a prolonged period of ACTH stimulation

and subsequent androgen production during the early morning hours.

In childhood, optimization of growth and pubertal development are

important goals of glucocorticoid treatment, in addition to prevention

of adrenal crisis and treatment of 46,XX DSD. In adults, the focus shifts

to preserving fertility and preventing side effects of glucocorticoid

overtreatment, namely, the metabolic syndrome and osteoporosis.

Fertility can be compromised in women due to oligomenorrhea/amenorrhea with chronic anovulation as a consequence of androgen excess.

Men may develop testicular adrenal rest tissue (TART) (Fig. 386-17)

consisting of hyperplastic cells with shared adrenal and gonadal characteristics located in the rete testis, which should not be confused

with testicular tumors. TART can compromise sperm production and

induce testicular fibrosis that may be irreversible.

TREATMENT

Congenital Adrenal Hyperplasia

Hydrocortisone is a good treatment option for the prevention of

adrenal crisis, but longer acting prednisolone may be needed to

control androgen excess. In children, hydrocortisone is given in

divided doses at 1–1.5 times the normal cortisol production rate

(~10–13 mg/m2

 per day). In adults, if hydrocortisone does not suffice, intermediate-acting glucocorticoids (e.g., prednisone) may be

given, using the lowest dose necessary to suppress excess androgen

production. For achieving fertility, dexamethasone treatment may

be required but should only be given for the shortest possible time

period to limit adverse metabolic side effects. The recent introduction of modified and delayed-release hydrocortisone, which mimics

the endogenous physiologic cortisol release pattern, is promising,

A B

C D

FIGURE 386-17 Imaging in congenital adrenal hyperplasia (CAH). Adrenal computed tomography scans showing homogenous bilateral hyperplasia in a young patient

with classic CAH (A) and macronodular bilateral hyperplasia (B) in a middle-aged patient with classic CAH with longstanding poor disease control. Magnetic resonance

imaging scan with T1-weighted (C) and T2-weighted (D) images showing bilateral testicular adrenal rest tumors (arrows) in a young patient with salt-wasting CAH. (Used

with permission from N. Reisch.)

providing effective control of steroid precursor excess while the

daily hydrocortisone dose is lower than required for immediaterelease hydrocortisone.

Biochemical monitoring should include androstenedione and

testosterone, aiming for the normal sex-specific reference range.

17OHP is a useful marker of overtreatment, indicated by 17OHP

levels within the normal range of healthy controls. Glucocorticoid

overtreatment may suppress the hypothalamic-pituitary-gonadal

axis. Thus, treatment needs to be carefully titrated against clinical

features of disease control. Stress-dose glucocorticoids should be

given at double or triple the daily dose for surgery, acute illness, or

severe trauma. Poorly controlled CAH can result in adrenocortical

hyperplasia, which gave the disease its name, and may present

as macronodular hyperplasia subsequent to long-standing ACTH

excess (Fig. 386-17). The nodular areas can develop autonomous

adrenal androgen production and may be unresponsive to glucocorticoid treatment. The prevalence of adrenomyelolipomas is

increased in CAH; these are benign but can require surgical intervention due to lack of self-limiting growth.

Mineralocorticoid requirements change during life and are higher

in children, explained by relative mineralocorticoid resistance that

diminishes with ongoing maturation of the kidney. Children with

CAH usually receive mineralocorticoid and salt replacement. However, young adults with CAH should undergo reassessment of their

mineralocorticoid reserve. Plasma renin should be regularly monitored and kept within the upper half of the normal reference range.

■ FURTHER READING

Arlt W et al: Steroid metabolome analysis reveals prevalent glucocorticoid excess in primary aldosteronism. JCI Insight 2:e93136, 2017.

Bancos I et al: Urine steroid metabolomics for the differential diagnosis of adrenal incidentalomas in the EURINE-ACT study: A prospective test validation study. Lancet Diabetes Endocrinol 8:773, 2020.

Bornstein SR et al: Diagnosis and treatment of primary adrenal insufficiency: An Endocrine Society Clinical Practice guideline. J Clin

Endocrinol Metab 101:364, 2016.

2976 PART 12 Endocrinology and Metabolism

Pheochromocytomas and paragangliomas are catecholamine-producing

tumors derived from the sympathetic or parasympathetic nervous

system. These tumors may arise sporadically or be inherited as features

of multiple endocrine neoplasia type 2 (MEN 2), von Hippel–Lindau

(VHL) disease, or several other pheochromocytoma-associated syndromes. The diagnosis of pheochromocytomas identifies a potentially

correctable cause of hypertension, and their removal can prevent

hypertensive crises that can be lethal. The clinical presentation is variable, ranging from an adrenal incidentaloma to a hypertensive crisis

with associated cerebrovascular or cardiac complications.

■ EPIDEMIOLOGY

Pheochromocytoma is estimated to occur in 2–8 of 1 million persons

per year, and ~0.1% of hypertensive patients harbor a pheochromocytoma. The mean age at diagnosis is ~40 years, although the tumors

can occur from early childhood until late in life. The classic “rule of

tens” for pheochromocytomas states that ~10% are bilateral, 10% are

extra-adrenal, and 10% are metastatic.

■ ETIOLOGY AND PATHOGENESIS

Pheochromocytomas and paragangliomas are well-vascularized

tumors that arise from cells derived from the sympathetic (e.g., adrenal

medulla or sympathetic trunk) or parasympathetic (e.g., carotid body,

387 Pheochromocytoma

Hartmut P. H. Neumann

Claahsen-Van Der Grinten HL et al: Congenital adrenal hyperplasia: Current insights in pathophysiology, diagnostics and management. Endocr Rev 2021;7:bnab016.

Ebbehoj A et al: Epidemiology of adrenal tumours in Olmsted County,

Minnesota, USA: A population-based cohort study. Lancet Diabetes

Endocrinol 8:894, 2020.

Fassnacht M et al: Management of adrenal incidentalomas: European

Society of Endocrinology Clinical Practice Guideline in collaboration

with the European Network for the Study of Adrenal Tumors. Eur J

Endocrinol 175:G1, 2016.

Feelders RA et al: Advances in the medical treatment of Cushing’s

syndrome. Lancet Diabetes Endocrinol 7:300, 2019.

Funder JW et al: The management of primary aldosteronism: Case

detection, diagnosis and treatment: An Endocrine Society Clinical

Practice guideline. J Clin Endocrinol Metab 101:1889, 2016.

Hahner S et al: Adrenal insufficiency. Nat Rev Dis Primers 7:19, 2021.

Lodish M, Stratakis CA: A genetic and molecular update on adrenocortical causes of Cushing syndrome. Nat Rev Endocrinol 12:255,

2016.

Loriaux DL: Diagnosis and differential diagnosis of Cushing’s syndrome. N Engl J Med 376:1451, 2017.

Merke DP, Auchus RJ: Congenital adrenal hyperplasia due to

21-hydroxylase deficiency. N Engl J Med 383:1248, 2020.

Merke DP et al: Modified-release hydrocortisone in congenital adrenal hyperplasia. J Clin Endocrinol Metab 106:e2063, 2021.

Mulatero P et al: Genetics, prevalence, screening and confirmation

of primary aldosteronism: Position statement and consensus of the

Working Group on Endocrine Hypertension of the European Society

of Hypertension. J Hypertens 38:1919, 2020.

Nanba K, Rainey WE: Genetics in endocrinology: Impact of race

and sex on genetic causes of aldosterone-producing adenomas. Eur J

Endocrinol 185:R1, 2021.

Prete A et al: Prevention of adrenal crisis: Cortisol responses to

major stress compared to stress dose hydrocortisone delivery. J Clin

Endocrinol Metab 105:2262, 2020.

glomus tympanicum, glomus jugulare, glomus vagale) paraganglia

(Fig. 387-1). The name pheochromocytoma reflects the formerly used

black-colored staining caused by chromaffin oxidation of catecholamines; although a variety of terms have been used to describe these

tumors, most clinicians use this designation to describe symptomatic

catecholamine-producing tumors, including those in extra-adrenal

retroperitoneal, pelvic, and thoracic sites. The term paraganglioma is

used to describe catecholamine-producing tumors in the skull base and

neck; these tumors may secrete little or no catecholamine. In contrast

to common clinical parlance, the World Health Organization (WHO)

restricts the term pheochromocytoma to adrenal tumors and applies the

term paraganglioma to tumors at all other sites.

The etiology of sporadic pheochromocytomas and paragangliomas

is unknown. However, 25–33% of patients have an inherited condition, including germline mutations in the classically recognized RET

(rearranged during transfection), VHL, NF1 (neurofibromatosis type

1), SDHB, SDHC, and SDHD (subunits of SDH) genes or in the more

recently recognized SDHA, SDHAF2, TMEM127 (transmembrane protein 127), MAX (myc-associated factor X), FH (fumarate hydratase),

PDH1, PDH2 (pyruvate dehydrogenase), HIF1α and HIF2α (hypoxiainducible factor), MDH2 (malate dehydrogenase), KIF1Bβ (kinesin family member), IDH1, (isocitrate dehydrogenase 1), SLC25A11

(oxoglutarate/malate), H-RAS (transforming protein p21), and

DNMTA3 (DNA methyltransferase 3 alpha) genes. Biallelic gene inactivation, a characteristic of tumor-suppressor genes, has been demonstrated for the VHL, NF1, SDHx, TMEM127, MAX, FH, PDH1, PDH2,

MDH2, and KIF1Bβ genes. In contrast, RET is a protooncogene, and

mutations activate receptor tyrosine kinase activity. Succinate dehydrogenase (SDH) is an enzyme of the Krebs cycle and the mitochondrial

respiratory chain. The VHL protein is a component of a ubiquitin

E3 ligase. VHL mutations reduce protein degradation, resulting in

upregulation of components involved in cell-cycle progression, glucose

metabolism, and oxygen sensing. In addition to germline mutations,

somatic mutations have been observed in >20 genes, broadly grouped

into three different clusters of pathogenetically relevant genes: cluster

1, the pseudohypoxia group comprising mainly the genes SDHx (subunits of SDH), FH, VHL, and HIF2A; cluster 2, the kinase signaling

group (RET, NF1, TMEM127, MAX, HRAS, KIF1Bβ, PDH); and cluster

3, the Wnt signaling group (CSDE1, MAML3).

■ CLINICAL FEATURES

Its clinical presentation is so variable that pheochromocytoma has been

termed “the great masquerader” (Table 387-1). Among the presenting

manifestations, episodes of palpitation, headache, and profuse sweating

are typical, and these manifestations constitute a classic triad. The presence of all three manifestations in association with hypertension makes

pheochromocytoma a likely diagnosis. However, a pheochromocytoma

can be asymptomatic for years, and some tumors grow to a considerable size before patients note symptoms.

The dominant sign is hypertension. Classically, patients have

episodic hypertension, but sustained hypertension is also common.

Catecholamine crises can lead to heart failure, pulmonary edema,

arrhythmias, and intracranial hemorrhage. During episodes of hormone release, which can occur at widely divergent intervals, patients

are anxious and pale, and they experience tachycardia and palpitations.

These paroxysms generally last <1 h and may be precipitated by surgery, positional changes, exercise, pregnancy, urination (particularly

with bladder pheochromocytomas), and various medications (e.g.,

tricyclic antidepressants, opiates, metoclopramide).

■ DIAGNOSIS

The diagnosis is based on documentation of catecholamine excess by

biochemical testing and localization of the tumor by imaging. These

two criteria are of equal importance, although measurement of catecholamines or metanephrines (their methylated metabolites) is traditionally the first step in diagnosis.

Biochemical Testing Pheochromocytomas and paragangliomas

synthesize and store catecholamines, which include norepinephrine

(noradrenaline), epinephrine (adrenaline), and dopamine. Elevated