METHODOLOGICAL RECOMMENDATION ON THE LECTURE

ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.

Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors

Methodological recommendations on lecture, EPP “Medicine”, 4 course, International faculty,

Discipline “Endocrinology” Page 1

ODESA NATIONAL MEDICAL UNIVERSITY

Department of Internal medicine №1 with the cardiovascular pathology course

APPROVED by

Head of department

_________(prof. Karpenko I.I)

“27” September 2021

METHODOLOGICAL RECOMMENDATION ON THE LECTURE

Course: IV Faculty: International

Academic discipline “Endocrinology”

Lecture № 04 Topic “Diseases of adrenal glands. Chronic adrenal failure.

Hormone-producing tumors”

The lecture was created by

Assistant

___________ (Blikhar O.V.)

The lecture was discussed at

the methodical meeting of the

department

«27» September 2021 y.

Protocol № 2.

Odesa – 2021 y.





Lecture № 04

Topic: “Diseases of adrenal glands. Chronic adrenal failure. Hormone-

producing tumors”

The goals of the lecture : explain the essence of adrenal diseases, causes, role in the

etiopathogenesis of various factors, approaches to diagnosis, treatment and

prevention.

Specific objectives of the lecture:

- give a modern definition of adrenal diseases;

- present generalized and systematized material on etiopathogenesis based on the

results of modern controlled clinical trials;

- present the basic concepts of classification, clinical features and diagnostic

approaches;

- to determine the basic principles of differential diagnosis with further substantiation

of final diagnosis based on the analysis of patient complaints, anamnesis, physical

symptoms, laboratory and instrumental examination data;

- explain the principles of treatment of adrenal diseases provided by national clinical

guidelines;

- to present modern methods of determining the prognosis and expert assessment of

the patient's ability to work based on the international recommendations;

- to demonstrate the principles of medical ethics and deontology, to promote the

formation of a professionally significant structure of the doctor's personality on the

example of the peculiarities of working with patients.

Key words: adrenal glands, Addison disease, Cushing syndrome,

pheochromocytoma, Conn`s syndrome, Addison crises

Lecture plan and organizational structure

№ The main stages of the lecture

and their content

Goals in

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abstraction

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methods and means

of activating

students, equipment

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2.

Preparatory stage

Setting a learning goal

Providing positive motivation

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In accordance with

the publication

"Guidelines for

planning,

preparation and

analysis of lectures"

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3.

The main stage

Teaching lecture material

according to the plan:

1. Relevance of the topic

2. Definition

3. Classification

4. Etiology and main links of

pathogenesis

5. Symptoms and signs

6. Diagnostic criteria

7. Main syndromes and

differential diagnosis

8. Criteria for the severity of

disease

9. Treatment

10. Prevention

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Slide presentation of

lecture material

Extracts from

medical histories of

patients. Excerpts

from clinical

guidelines for the

provision of medical

care to patients.

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(75 min)

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4.

5.

6.

The final stage

Lecture summary, general

conclusions

Answers to possible questions

Tasks for self-training

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References,

questions, tasks

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Content of the lecture

Normal anatomy and physiology

The suprarenal glands, also known as adrenal glands, belong to the endocrine

system. They are a pair of triangular-shaped glands, each about 2 in long and 1

in wide, that sit on top of the kidneys. The suprarenal glands are responsible for the

release of hormones that regulate metabolism, immune system function, and the salt-

water balance in the bloodstream; they also aid in the body’s response to stress.





Each suprarenal gland is composed of 2 distinct tissues: the suprarenal cortex and the

suprarenal medulla. The suprarenal cortex serves as the outer layer of the suprarenal

gland, and the suprarenal medulla serves as the inner layer. These 2 major regions are

encapsulated by connective tissue known as the capsule.

Suprarenal cortex

The suprarenal cortex is the largest part of the gland and is composed of 3

zones: the zona glomerulosa (outer zone), the zona fasciculata (middle zone), and the

zona reticularis (inner zone). The zona glomerulosa is responsible for the production

of mineralocorticoids, mainly aldosterone, which regulates blood pressure and

electrolyte balance.

The zona fasciculata, is responsible for the production of glucocorticoids,

predominantly cortisol, which increases blood sugar levels via gluconeogenesis,

suppresses the immune system, and aids in metabolism. This zone secretes cortisol

both at a basal level and as a response to the release of adrenocorticotropic hormone

(ACTH) from the pituitary gland.

The zona reticularis produces gonadocorticoids and is responsible for

administering these hormones to the reproductive regions of the body. Most of the

hormones released by this layer are androgens. The main androgen produced by this

layer is dehydroepiandrosterone (DHEA), which is the most abundant hormone in the

body and serves as the starting material for many other important hormones produced

by the suprarenal gland, such as estrogen, progesterone, testosterone, and cortisol.

Suprarenal medulla

The suprarenal medulla is composed of special cells called chromaffin cells,

which are organized in clusters around blood vessels. The cells in the suprarenal

medulla produce epinephrine (also known as adrenaline) and norepinephrine. These 2





hormones prepare the body for the fight-or-flight response by increasing the heart

rate, constricting blood vessels, increasing the metabolic rate, heightening cognitive

awareness, and increasing the respiratory rate.

Vascular anatomy

The suprarenal glands require a large supply of blood and release hormones

directly into the bloodstream. The suprarenal glands are among the most extensively

vascularized organs in the body. Three sources of arteries maintain blood supply to

the suprarenal glands. The superior suprarenal arteries are multiple small branches

from the inferior phrenic artery, whereas the middle suprarenal artery is a direct

branch from the abdominal aorta. An inferior suprarenal artery, sometimes multiple,

arises from the renal artery on each side. After the suprarenal glands have been

supplied with blood from these arteries, the blood drains through the suprarenal vein

to the left renal vein or directly to the inferior vena cava on the right side.

Adrenocortical insufficiency (Addison disease )

Addison disease (or Addison's disease) is adrenocortical insufficiency due to

the destruction or dysfunction of the entire adrenal cortex. It affects glucocorticoid

and mineralocorticoid function. The onset of disease usually occurs when 90% or

more of both adrenal cortices are dysfunctional or destroyed.

The occurrence of Addison disease is rare. The reported prevalence in countries

where data are available is 39 cases per 1 million population in Great Britain and 60

cases per 1 million population in Denmark. A study by Hong et al found the

prevalence of primary adrenal insufficiency in Korea to be 4.17 per 1 million

population

Addison disease is not associated with a racial predilection.

Idiopathic autoimmune Addison disease tends to be more common in females

and children.

The most common age at presentation in adults is 30-50 years, but the disease

could present earlier in patients with any of the polyglandular autoimmune

syndromes, congenital adrenal hyperplasia (CAH), or if onset is due to a disorder of

long-chain fatty acid metabolism.

Causes

The most common cause of Addison disease is idiopathic autoimmune

adrenocortical insufficiency resulting from autoimmune atrophy, fibrosis, and

lymphocytic infiltration of the adrenal cortex, usually with sparing of the adrenal

medulla. This accounts for more than 80% of reported cases. Idiopathic autoimmune

adrenocortical atrophy and tuberculosis (TB) account for nearly 90% of cases of

Addison disease.

Antibodies against the adrenal tissue are present in a significant number of

these patients, and evidence of cell-mediated immunity against the adrenal gland also

may be present. The steroidogenic enzyme 21-hydroxylase (21OH) is the main





autoantigen, but antibodies against this enzyme are not directly involved in the tissue

destruction.

Patients may have a hereditary predisposition to autoimmune Addison disease.

Idiopathic autoimmune Addison disease may occur in isolation or in association with

other autoimmune phenomena (eg, Schmidt syndrome, polyglandular autoimmune

disease types 1 and 2).

Celiac disease

Idiopathic hypoparathyroidism

Mucocutaneous candidiasis

Type 1 diabetes mellitus

Hashimoto thyroiditis

Graves disease

Vitiligo

Alopecia areata, totalis and universalis

Premature ovarian or testicular failure

Pernicious anemia

Myasthenia gravis

Idiopathic hypophysitis

Chronic active hepatitis

Primary biliary cirrhosis

The association of Addison disease and Hashimoto thyroiditis is known as

Schmidt syndrome.

The association of Addison disease with hypoparathyroidism and

mucocutaneous candidiasis is described as polyglandular autoimmune

syndrome type 1. It may have an autosomal recessive mode of inheritance. It

has no human leukocyte antigen (HLA) associations. It is also termed

autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

(APECED). It is caused by mutations in the autoimmune regulator gene

(AIRE).

The association of Addison disease with type 1 diabetes mellitus and

Hashimoto thyroiditis or Graves disease is described as polyglandular

autoimmune syndrome type 2 and may be associated with HLA-B8 and DR-3.

Other autoimmune phenomena, as outlined above, can occur in either of the 2

polyglandular syndromes.

Additional causes of chronic Addison disease:

Chronic granulomatous diseases

o TB, sarcoidosis, histoplasmosis, blastomycosis, and cryptococcosis

could involve the adrenal glands.

o In the preantibiotic era, TB was the most common cause and still may be

a major consideration in areas where TB is common. It tends to involve

both the adrenal cortex and the medulla; however, medullary

involvement may not have any major consequences.





o TB of the adrenal glands usually is a tertiary disease due to the

hematogenous spread of infection to the adrenal glands, but clinical

evidence of the primary infection is not always present.

Hematologic malignancies

o Malignant infiltration of the adrenal cortices, as with Hodgkin and non-

Hodgkin lymphoma and leukemia, may cause Addison disease.

o Hodgkin and non-Hodgkin lymphoma initially could present with

adrenal gland involvement and features of adrenocortical insufficiency.

Metastatic malignant disease - Bilateral involvement of the adrenal glands

could occur in the setting of metastatic cancer of the lung, breast, or colon or

renal cell carcinoma.

Infiltrative metabolic disorders - Amyloidosis and hemochromatosis could

involve the adrenal glands and lead to primary adrenocortical insufficiency.

Acquired immunodeficiency syndrome (AIDS)

o The adrenocortical insufficiency in patients with AIDS tends to occur

late and usually in the setting of a low CD4 cell count.

o It is caused by opportunistic infections such as cytomegalovirus,

Mycobacterium avium intracellulare, cryptococci, or Kaposi sarcoma.

o Adrenocortical hypofunction in patients with HIV may be due to

glucocorticoid resistance syndrome. These patients tend to present with

features of adrenocortical insufficiency and mucocutaneous

hyperpigmentation but also with increased plasma and urinary cortisol

levels and a slight elevation in ACTH levels. Hyperpigmentation in

patients with HIV is thought to be due to elevated alpha-interferon

levels.

o Another possible cause of adrenocortical insufficiency in patients with

AIDS is the use of megestrol acetate (Megace) as an appetite stimulant

to stem HIV wasting disease. However, this causes secondary

adrenocortical insufficiency and not Addison disease. The glucocorticoid

effect of megestrol acetate suppresses pituitary ACTH production and

leads to secondary adrenocortical insufficiency.

Allgrove syndrome

o Although patients with congenital adrenocortical unresponsiveness to

ACTH (Allgrove syndrome) may present with features of glucocorticoid

deficiency and skin hyperpigmentation, the aldosterone production and

function in these patients is normal and responds appropriately to low

sodium intake.

o This typically presents in childhood with failure to thrive, features of

adrenocortical insufficiency, and hypoglycemia.

o Some patients may have components of alacrima and achalasia. It is also

sometimes called triple A syndrome.

Abnormalities of beta oxidation of very-long-chain fatty acids





o These patients (usually men) present with adrenocortical insufficiency

and features of progressive demyelination of the CNS. It is caused by

mutation in the ABCD1 gene. it is the most common cause of adrenal

insufficiency in a male child less than 7 years of age.

o This is caused by the accumulation of very-long-chain fatty acids

(VLCFA) in various organs, including the adrenal cortex, brain, testis,

and liver.

o These disorders are X-linked recessive, with poor penetrance.

o Other symptoms include cognitive dysfunction, behavioral problems,

disturbance of gait, and emotional lability.

o Two subtypes are described. The first subtype is adrenoleukodystrophy

(ALD). This usually presents in childhood. Thirty percent of cases may

present with adrenal insufficiency before the onset of neurologic

symptoms. Other features include severe hypotonia, seizure disorder,

retinitis pigmentosa, and optic atrophy. The second subtype is

adrenomyeloneuropathy (AMN). This usually is mild. It tends to present

in the 20- to 40-year age group with features of adrenal insufficiency and

progressive CNS demyelination.

Congenital adrenal hyperplasia

o Primary adrenocortical insufficiency may occur in patients with the

StAR or 20,22-desmolase enzyme deficiency, 3-beta hydroxysteroid

dehydrogenase enzyme deficiency, and the severe form of the 21-

hydroxylase enzyme deficiency (virilizing and salt wasting).

o Infants usually present in shock, with hypoglycemia and adrenal

insufficiency.

o In 3-beta hydroxysteroid dehydrogenase enzyme deficiency, female

infants appear virilized, whereas male infants may have

pseudohermaphroditism from insufficient androgen activity.

o Lipoid congenital adrenal hyperplasia is a severe disorder of adrenal and

gonadal steroidogenesis caused by mutations in the steroidogenic acute

regulatory protein (StAR). Affected children typically present with life-

threatening adrenal insufficiency in early infancy due to a failure of

glucocorticoid (cortisol) and mineralocorticoid (aldosterone)

biosynthesis. Male infants usually have features of

pseudohermaphroditism due to an associated deficiency of gonadal

steroids.

o The rapid ACTH test usually helps to establish the diagnosis. Patients

with CAH respond with a marked increase in 17-OH progesterone

levels, an increase in other precursors preceding the enzyme block, and a

subnormal cortisol response.

Drug-related causes





o Ketoconazole inhibits the adrenal cytochrome P450 steroidogenic

enzymes.

o Aminoglutethimide blocks the early conversion of cholesterol to

pregnenolone by inhibiting the 20,22-desmolase enzyme.

o Mitotane (O,P'-DDD) blocks adrenal mitochondrial steroid biosynthesis.

o Busulphan, etomidate, and trilostane inhibit or interfere with adrenal

steroid biosynthesis.

o Methadone, perhaps by depleting pituitary ACTH, may cause secondary

adrenocortical insufficiency in some patients.

Abdominal irradiation

o Addison disease could result from situations where a radiation field

involves the adrenal glands.

o The lag time to onset of disease usually is 2-7 years, but the disease

could occur earlier depending on the dose of the radiation.

Hypogandotropic Hypogonadism and DAX-1 gene mutation

Causes of acute Addison disease:

Stress - Acute adrenal crisis precipitated by infection, trauma, surgery,

emotional turmoil, or other stress factors may be the initial presentation of

Addison disease in as many as 25% of cases.

Failure to increase steroids

o Failure to appropriately increase daily replacement steroid doses in

patients with adrenocortical insufficiency in times of stress could

precipitate an adrenal crisis.

o Failure to adjust the replacement steroid dose in patients on cytochrome

P450 enzyme-inducing medications such as rifampin and Dilantin also

could precipitate an adrenal crisis.

Bilateral adrenal hemorrhage

o This may be the cause of an acute adrenal crisis, and it may occur as a

complication of bacterial infection with Meningococcus or Pseudomonas

species, as in Waterhouse-Friderichsen syndrome.

o It also may occur as a complication of pregnancy, anticoagulant therapy

with heparin or warfarin, and as a complication of coagulopathies such

as antiphospholipid syndrome (APS) in patients with systemic lupus

erythematosus (SLE).

o The mechanism of action of adrenal hemorrhage is not fully understood.

Diagnosis usually is made in the setting of a critically ill patient on

anticoagulants (or with any of the causes mentioned above) who

becomes acutely hypotensive with tachycardia, nausea, vomiting, fever,

and confusion or disorientation. Abdominal or flank pain with associated

tenderness may develop.

o A rapid ACTH test usually should be performed in this setting, and the

patient should be started on hydrocortisone without waiting for the





results. When time is critical, a random cortisol should be drawn and the

patient started on hydrocortisone in stress doses. An abdominal

computed tomography (CT) scan often reveals bilateral adrenal gland

enlargement.

Bilateral adrenal artery emboli and bilateral vein thrombosis

This is a very rare cause of Addison disease but may occur in critically ill

patients on heparin as a complication of heparin-induced thrombosis (HIT) or

as a complication of other states that predispose to thrombosis.

It also may occur as a complication of radiographic contrast studies involving

the adrenal glands.

Bilateral adrenalectomy for any reason

The surgical removal of a unilateral cortisol-producing adrenal adenoma in a

patient with Cushing syndrome can cause an acute adrenal crisis from

secondary adrenocortical insufficiency.

This is due to the atrophy of the normal adrenal cortex from lack of the

stimulant effect of pituitary ACTH.

History

Patients usually present with features of both glucocorticoid and

mineralocorticoid deficiency. The predominant symptoms vary depending on the

duration of disease.

Patients may present with clinical features of chronic Addison disease or in acute

addisonian crisis precipitated by stress factors such as infection, trauma, surgery,

vomiting, diarrhea, or noncompliance with replacement steroids.

Presentation of chronic Addison disease

The onset of symptoms most often is insidious and nonspecific.

- Hyperpigmentation of the skin and mucous membranes often precedes all

other symptoms by months to years. It is caused by the stimulant effect of excess

adrenocorticotrophic hormone (ACTH) on the melanocytes to produce melanin. The

hyperpigmentation is caused by high levels of circulating ACTH that bind to the

melanocortin 1 receptor on the surface of dermal melanocytes. Other melanocyte-

stimulating hormones produced by the pituitary and other tissues include alpha-MSH

(contained within the ACTH molecule), beta-MSH, and gamma-MSH. When

stimulated, the melanocyte changes the color of pigment to a dark brown or black.

Hyperpigmentation is usually generalized but most often prominent on the sun-

exposed areas of the skin, extensor surfaces, knuckles, elbows, knees, and scars

formed after the onset of disease. Scars formed before the onset of disease (before the

ACTH is elevated) usually are not affected. Palmar creases, nail beds, mucous

membranes of the oral cavity (especially the dentogingival margins and buccal areas),

and the vaginal and perianal mucosa may be similarly affected. Hyperpigmentation,

however, need not be present in every long-standing case and may not be present in

cases of short duration.





- Other skin findings include vitiligo, which most often is seen in association

with hyperpigmentation in idiopathic autoimmune Addison disease. It is due to the

autoimmune destruction of melanocytes.

- Almost all patients complain of progressive weakness, fatigue, poor appetite,

and weight loss.

- Prominent gastrointestinal symptoms may include nausea, vomiting, and

occasional diarrhea. Glucocorticoid-responsive steatorrhea has been reported.

- Dizziness with orthostasis due to hypotension occasionally may lead to

syncope. This is due to the combined effects of volume depletion, loss of the

mineralocorticoid effect of aldosterone, and loss of the permissive effect of cortisol in

enhancing the vasopressor effect of the catecholamines.

- Myalgias and flaccid muscle paralysis may occur due to hyperkalemia.

Patients may have a history of using medications known to affect

adrenocortical function or to increase cortisol metabolism.

- Other reported symptoms include muscle and joint pains; a heightened sense

of smell, taste, and hearing; and salt craving.

- Patients with diabetes that previously was well-controlled may suddenly

develop a marked decrease in insulin requirements and hypoglycemic episodes due to

an increase in insulin sensitivity.

- Impotence and decreased libido may occur in male patients, especially in

those with compromised or borderline testicular function.

- Female patients may have a history of amenorrhea due to the combined effect

of weight loss and chronic ill health or secondary to premature autoimmune ovarian

failure. Steroid-responsive hyperprolactinemia may contribute to the impairment of

gonadal function and to the amenorrhea.

Presentation of acute Addison disease

Patients in acute adrenal crisis most often have prominent nausea, vomiting,

and vascular collapse. They may be in shock and appear cyanotic and confused.

Abdominal symptoms may take on features of an acute abdomen.

Patients may have hyperpyrexia, with temperatures reaching 105° F or higher, and

may be comatose.

In acute adrenal hemorrhage, the patient, usually in an acute care setting, deteriorates

with sudden collapse, abdominal or flank pain, and nausea with or without

hyperpyrexia.

Physical

Physical examination in long-standing cases most often reveals increased

pigmentation of the skin and mucous membranes, with or without areas of vitiligo.

Patients show evidence of dehydration, hypotension, and orthostasis.

Female patients may show an absence of axillary and pubic hair and decreased

body hair. This is due to loss of the adrenal androgens, a major source of

androgens in women.





Addison disease caused by another specific disease may be accompanied by

clinical features of that disease.

Calcification of the ear and costochondral junctions is described but is a rare

physical finding.

Laboratory Studies

A quick review of the clinical presentation, physical examination findings, and

laboratory findings (when available) quickly heightens the index of suspicion and

possibly leads to more appropriate tests and diagnosis. A high index of suspicion is

necessary for diagnosis.

The diagnosis of adrenocortical insufficiency rests on the assessment of the

functional capacity of the adrenal cortex to synthesize cortisol. This is

accomplished primarily by use of the rapid ACTH stimulation test.

o ACTH, through complex mechanisms, activates cholesterol esterase

enzymes and leads to the release of free cholesterol from cholesterol

esters. It also activates the 20,22-desmolase enzyme, which catalyzes the

rate-limiting step in adrenal steroidogenesis and increases the NADPH

(nicotinamide adenine dinucleotide phosphate) levels necessary for the

various hydroxylation steps in steroidogenesis.

o Within 15-30 minutes of ACTH infusion, the normal adrenal cortex

releases 2-5 times its basal plasma cortisol output.

o Although ACTH stimulation is not normally the major stimulus for

aldosterone production, it increases aldosterone production to peak

levels within 30 minutes. This response, however, is affected by dietary

sodium intake.

o An increase in the plasma cortisol and aldosterone levels above basal

levels after ACTH injection reflects the functional integrity of the

adrenal cortex.

Performing the rapid adrenocorticotrophic hormone test

o Blood is drawn in 2 separate tubes for baseline cortisol and aldosterone

values.

o Synthetic ACTH (1-24 amino acid sequence) in a dose of 250 mcg (0.25

mg) is given IM or IV. Smaller doses of synthetic ACTH, as low as 1

mcg, have been used with accuracy approaching the standard test.

Proponents of this modified test argue that a dose of 1 mcg or lower is

more physiologic, whereas the 250-mcg dose is pharmacologic.

However, the modified test is more sensitive only for the 30-minute

samples, not the 60-minute samples.

o Thirty or 60 minutes after the ACTH injection, 2 more blood samples

are drawn; one for cortisol and one for aldosterone. No significant

reason exists to draw both the 30-minute and 60-minute samples because

the sensitivity of the 30-minute value for accurate diagnosis is well





documented. The baseline and 30-minute samples usually are adequate

to establish the diagnosis.

Interpreting the rapid adrenocorticotrophic hormone test

o Two criteria are necessary for diagnosis: (1) an increase in the baseline

cortisol value of 7 mcg/dL or more and (2) the value must rise to 20

mcg/dL or more in 30 or 60 minutes, establishing normal adrenal

glucocorticoid function.

o A low aldosterone value of less than 5 ng/100 mL that fails to double or

increase by at least 4 ng/100 mL 30 minutes after ACTH administration

denotes abnormal mineralocorticoid function of the adrenal cortex.

o The 30-minute aldosterone value is more sensitive than the 60-minute

value because aldosterone levels actually have been shown to decrease

in the 60-minute sample.

o The absolute 30- or 60-minute cortisol value carries more significance

than the incremental value, especially in patients who may be in great

stress and at their maximal adrenal output. These patients may not show

a significant increase in cortisol output with ACTH stimulation.

o A normal 30- or 60-minute rapid ACTH test excludes Addison disease

but may not adequately exclude mild impairment of the hypothalamic

pituitary adrenal axis in secondary adrenal insufficiency.

o In patients with Addison disease, both cortisol and aldosterone show

minimal or no change in response to ACTH, even with prolonged ACTH

stimulation tests lasting 24-48 hours.

o When the results of the rapid ACTH test are equivocal and do not meet

the 2 criteria mentioned above, further testing might be required to

distinguish Addison disease from secondary adrenocortical

insufficiency. Plasma ACTH values and prolonged ACTH stimulation

tests may be useful in making this distinction.

o ACTH levels often are elevated to higher than 250 pg/mL in patients

with Addison disease. However, ACTH is unstable in plasma, and

specimen collection and storage may require special attention. The

specimen should be collected in iced anticoagulated plastic containers

and frozen immediately.

o Importantly, note that ACTH levels also may be high in patients

recovering from steroid-induced secondary adrenocortical insufficiency

and in patients with ACTH-refractory syndromes.

o ACTH-inducing tests such as metyrapone stimulation and insulin-

induced hypoglycemia, which may be useful in the evaluation of some

cases of secondary adrenocortical insufficiency, have no role in the

diagnosis of Addison disease and may in fact be lethal to the patient with

Addison disease.





In acute adrenal crisis, where treatment should not be delayed in order to do the

tests, a blood sample for a random plasma cortisol level should be drawn prior

to starting hydrocortisone replacement.

o A random plasma cortisol value of 25 mcg/dL or greater effectively

excludes adrenal insufficiency of any kind. However, a random cortisol

value in patients who are acutely ill should be interpreted with caution

and in correlation with the circumstances of each individual patient.

Random cortisol levels should also be interpreted cautiously in critically

ill patients with hypoproteinemia (serum albumin < 2.5 g/dL).

Approximately 40% of these patients will have baseline and

cosyntropin-stimulated cortisol levels below the reference range even

though the patients have normal adrenal function (as evidenced by the

measurement of free cortisol levels). This phenomenon is because more

than 90% of circulating cortisol in human serum is protein bound.

o Cortisol is known to be elevated by stress, but exactly how high it should

rise to constitute a normal response in times of severe stress is not

known.

o An abnormal test result should prompt a proper evaluation of the

hypothalamic pituitary adrenal axis after the patient's condition improves

before committing a patient to lifelong steroid replacement.

o In order to perform the ACTH stimulation test in this situation, the

patient should be switched to dexamethasone and then tested 24-36

hours later. Dexamethasone does not interfere with the cortisol assay, as

does hydrocortisone or prednisone. However, dexamethasone may

interfere with interpretation of the random cortisol value drawn after

dexamethasone already has been initiated. Dexamethasone also does not

have any mineralocorticoid activity, which may be needed in patients

with Addison disease.

Other laboratory tests

o Comprehensive metabolic panel

The most prominent findings are hyponatremia, hyperkalemia,

and a mild non–anion-gap metabolic acidosis due to the loss of the

sodium-retaining and potassium and hydrogen ion-secreting

action of aldosterone.

Urinary and sweat sodium also may be elevated.

The most consistent finding is elevated blood urea nitrogen

(BUN) and creatinine due to the hypovolemia, a decreased

glomerular filtration rate, and a decreased renal plasma flow.

Hypercalcemia, the cause of which is not well understood, may be

present in a small percentage of patients. However, hypocalcemia

could occur in patients with Addison disease accompanied by

idiopathic hypoparathyroidism.





Hypoglycemia may be present in fasted patients, or it may occur

spontaneously. It is caused by the increased peripheral utilization

of glucose and increased insulin sensitivity. It is more prominent

in children and in patients with secondary adrenocortical

insufficiency.

Liver function tests may reveal a glucocorticoid-responsive liver

dysfunction.

o CBC count

CBC count may reveal a normocytic normochromic anemia,

which, upon initial presentation, may be masked by dehydration

and hemoconcentration. Relative lymphocytosis and eosinophilia

may be present.

All of these findings are responsive to glucocorticoid replacement.

o Thyroid-stimulating hormone

Increased thyroid-stimulating hormone (TSH), with or without

low thyroxine, with or without associated thyroid autoantibodies,

and with or without symptoms of hypothyroidism, may occur in

patients with Addison disease and in patients with secondary

adrenocortical insufficiency due to isolated ACTH deficiency.

These findings may be slowly reversible with cortisol

replacement.

In the setting of both adrenocortical insufficiency and

hypothyroidism that requires treatment, corticosteroids should be

given before thyroid hormone replacement to avoid precipitating

an acute adrenal crisis.

Autoantibody testing - Thyroid autoantibodies, specifically antithyroglobulin

(anti-Tg) and antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies,

and/or adrenal autoantibodies may be present.

Prolactin testing

o Modest hyperprolactinemia has been reported in cases of Addison

disease and also in secondary adrenocortical insufficiency. It is

responsive to glucocorticoid replacement.

o The cause of the hyperprolactinemia is thought to be the

hyperresponsiveness of the lactotroph to thyrotropin-releasing hormone

(TRH) in the absence of the steroid-induced or steroid-enhanced

hypothalamic dopaminergic tone.

Imaging Studies

Chest radiograph:

The chest radiograph may be normal but often reveals a small heart.

Stigmata of earlier infection or current evidence of TB or fungal infection may

be present when this is the cause of Addison disease.

CT scan:





Abdominal CT scan may be normal but may show bilateral enlargement of the

adrenal glands in patients with Addison disease because of TB, fungal

infections, adrenal hemorrhage, or infiltrating diseases involving the adrenal

glands.

In Addison disease due to TB or histoplasmosis, evidence of calcification

involving both adrenal glands may be present.

In idiopathic autoimmune Addison disease, the adrenal glands usually are

atrophic.

Other Tests

ECG may show low-voltage QRS tracing with nonspecific ST-T wave changes

and/or changes due to hyperkalemia. These changes are reversible with

glucocorticoid replacement.

Sputum examination, examination of gastric washings for acid-fast and alcohol-fast

bacilli, and a Mantoux or purified protein derivative (PPD) skin test may be needed if

TB is thought to be the cause.

Histologic Findings

In cases due to idiopathic autoimmune adrenocortical atrophy, the adrenal glands

usually are atrophic, with marked lymphocytic infiltration and fibrosis of the adrenal

capsule. The adrenal medulla is spared.

In cases due to TB, the adrenal glands may be enlarged and contain caseating

granulomas. Diffuse calcification may be evident, and the adrenal medulla usually is

involved.

In patients with AIDS, the adrenal glands may show necrotizing inflammation,

hemorrhage, and infarction.

Treatment

In patients in acute adrenal crisis, IV access should be established urgently, and an

infusion of isotonic sodium chloride solution should be begun to restore volume

deficit and correct hypotension. Some patients may require glucose supplementation.

The precipitating cause should be sought and corrected where possible.

In stress situations, the normal adrenal gland output of cortisol is

approximately 250-300 mg in 24 hours. This amount of hydrocortisone in

soluble form (hydrocortisone sodium succinate or phosphate) should be given,

preferably by continuous infusion.

o Administer 100 mg of hydrocortisone in 100 cc of isotonic sodium

chloride solution by continuous IV infusion at a rate of 10-12 cc/h.

Infusion may be initiated with 100 mg of hydrocortisone as an IV

bolus. Some hospitals mix 300-400 mg in 1 liter saline and infuse over

24 h to avoid needing to renew the infusion every 8-10 hours.

o An alternative method of hydrocortisone administration is 100 mg as an

IV bolus every 6-8 hours.

o The infusion method maintains plasma cortisol levels more adequately at

steady stress levels, especially in the small percentage of patients who





are rapid metabolizers and who may have low plasma cortisol levels

between the IV boluses.

Clinical improvement, especially blood pressure response, should be evident

within 4-6 hours of hydrocortisone infusion. Otherwise, the diagnosis of

adrenal insufficiency would be questionable.

After 2-3 days, the stress hydrocortisone dose should be reduced to 100-150

mg, infused over a 24-hour period, irrespective of the patient's clinical status.

This is to avoid stress gastrointestinal bleeding.

As the patient improves and as the clinical situation allows, the hydrocortisone

infusion can be gradually tapered over the next 4-5 days to daily replacement

doses of approximately 3 mg/h (72-75 mg over 24 h) and eventually to daily

oral replacement doses, when oral intake is possible.

As long as the patient is receiving 100 mg or more of hydrocortisone in 24

hours, no mineralocorticoid replacement is necessary. The mineralocorticoid

activity of hydrocortisone in this dosage is sufficient.

Thereafter, as the hydrocortisone dose is weaned further, mineralocorticoid

replacement should be instituted in doses equivalent to the daily adrenal gland

aldosterone output of 0.05-0.20 mg every 24 hours. The usual

mineralocorticoid used for this purpose is 9-alpha-fludrocortisone, usually in

doses of 0.05-0.10 mg per day or every other day.

Patients may need to be advised to increase salt intake in hot weather.

Surgical Care

Parenteral steroid coverage should be used in times of major stress, trauma, or

surgery and during any major procedure.

During surgical procedures, 100 mg of hydrocortisone should be given, preferably by

the IM route, prior to the start of a continuous IV infusion. The IM dose of

hydrocortisone assures steroid coverage in case of problems with the IV access.

When continuous IV infusion is not practical, an intermittent IV bolus injection

every 6-8 hours may be used.

After the procedure, the hydrocortisone may be rapidly tapered within 24-36

hours to the usual replacement doses, or as gradually as the clinical situation

dictates.

Mineralocorticoid replacement usually can be withheld until the patient

resumes daily replacement steroids.

Cushing syndrome / disease

Cushing syndrome is caused by prolonged exposure to elevated levels of either

endogenous glucocorticoids or exogenous glucocorticoids. Exogenous use of

glucocorticoids should always be considered and excluded in the etiology of Cushing

syndrome. Endogenous glucocorticoid overproduction, or hypercortisolism, can be

dependent on or independent of adrenocorticotropic hormone (ACTH)





Pathophysiology

Endogenous glucocorticoid overproduction or hypercortisolism that is

independent of ACTH is usually due to a primary adrenocortical neoplasm (most

commonly an adenoma and rarely a carcinoma). Bilateral micronodular hyperplasia

(primary pigmented nodular adrenocortical disease) and macronodular hyperplasia

are rare causes of Cushing syndrome.

ACTH level in ACTH-independent Cushing syndrome is low due to the

negative feedback to pituitary corticotroph cells from a high level of serum cortisol.

ACTH-dependent Cushing syndrome is characterized by elevated ACTH levels.

Elevated ACTH levels are usually due to an anterior pituitary tumor, which is classic

Cushing disease (60-70%). Nonpituitary ectopic sources of ACTH, such as small-cell

lung carcinoma (oat cell carcinoma), carcinoid tumor, medullary thyroid carcinoma,

or other neuroendocrine tumors can result in high ACTH levels and sequentially

hypercortisolism.

Ectopic corticotropin-releasing hormone (CRH) secretion leading to increased

ACTH secretion comprises a very rare group of cases of Cushing syndrome.

Etiology

The following conditions may cause endogenous glucocorticoid overproduction:

ACTH-independent Cushing syndrome

See the list below:

Primary adrenal lesions

o Overproduction of glucocorticoids may be due to an adrenal adenoma,

adrenal carcinoma, or macronodular or micronodular adrenal

hyperplasia. The zona fasciculata and zona reticularis layers of the

adrenal cortex normally produce glucocorticoids and androgens.

Glucocorticoid-secreting tumors are derived from these cells and, thus,

may secrete both glucocorticoids and androgens.

o In general, excess androgen secretion is suggestive of an adrenal

carcinoma rather than an adrenal adenoma. These glucocorticoid-

producing tumors do not usually secrete aldosterone, which is produced

in the zona glomerulosa layer of the adrenal cortex.

o The Carney complex is a familial form of micronodular hyperplasia of

the adrenal gland. It is an autosomal dominant disorder and ACTH-

independent cause of Cushing syndrome. Pigmented skin lesions and

mesenchymal and endocrine tumors characterize this disorder. Cushing

syndrome may be overt, subclinical, cyclical, or periodic.

o Primary bilateral macronodular adrenal hyperplasia is uncommon and

characterized by multiple nonpigmented nodules that are greater than 10

mm in diameter and enlarged adrenal glands. The exact etiology of this

condition is not quite clear, however, genetic mutations, paracrine





ACTH secretion, and aberrant hormone receptors have been reported to

play a role in its pathogenesis.

o McCune-Albright syndrome is a rare cause of precocious puberty. It is

associated with hyperfunction of the adrenal glands that may lead to

Cushing syndrome.

Ectopic cortisol secretion from a case of ovarian carcinoma has been reported

as a cause of ACTH independent Cushing syndrome.

ACTH-dependent Cushing syndrome

See the list below:

ACTH-producing pituitary adenoma

o Pituitary adenomas that secrete ACTH are derived from corticotroph

cells in the anterior pituitary.

o ACTH secreted by corticotroph cells is released into the circulation and

acts on the adrenal cortex to produce hyperplasia and stimulate the

secretion of adrenal steroids.

o These adenomas, if large, can result in loss of production of other

anterior pituitary hormones (TSH, FSH, LH, growth hormone, and

prolactin).

o Nelson syndrome has been described as corticotroph tumor progression

seen in patients who had bilateral adrenalectomy as radical treatment for

Cushing disease. In a retrospective study looking at 53 Cushing disease

patients who underwent bilateral adrenalectomy without pituitary

irradiation, corticotroph tumor progression was noted to be present in

half of the patients, mostly within 3 years of surgery. Patients with a

shorter duration of Cushing disease and a high plasma ACTH

concentration in the year after adrenalectomy were more likely to

develop Nelson’s syndrome. Enlarging corticotroph tumor can manifest

clinically with compressive symptoms such as headache, vision change,

ocular palsy and hyperpigmentation due to very high ACTH

concentrations.

Ectopic ACTH secretion is caused by small-cell lung tumors, carcinoid tumors,

or other tumors with neuroendocrine origin. These tumors themselves can

secrete ACTH, which subsequently stimulates the adrenal glands to make more

cortisol.

Ectopic CRH secretion leading to increased ACTH secretion comprises a very

rare group of cases of Cushing syndrome.

History

Patients with Cushing syndrome may complain of weight gain, especially in

the face, supraclavicular region, upper back, and torso. Frequently, patients notice

changes in their skin, including purple stretch marks, easy bruising, and other signs of





skin thinning. Because of progressive proximal muscle weakness, patients may have

difficulty climbing stairs, getting out of a low chair, and raising their arms.

Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in

women related to inhibition of pulsatile secretion of luteinizing hormone (LH) and

follicle-stimulating hormone (FSH), which likely is due to interruption of luteinizing

hormone-releasing hormone (LHRH) pulse generation. In men, inhibition of LHRH

and FSH/LH function may lead to decreased libido and impotence.

Psychological problems such as depression, cognitive dysfunction, and

emotional lability may develop. New-onset or worsening of hypertension and

diabetes mellitus, difficulty with wound healing, increased infections, osteopenia, and

osteoporotic fractures may occur.

Signs and symptoms specifically associated with endogenous Cushing syndrome

include the following:

Patients with an ACTH-producing pituitary tumor: Headaches, polyuria,

nocturia, visual problems, or galactorrhea

Patients with tumor mass effect on the anterior pituitary: Hyposomatotropism,

hypothyroidism, hyperprolactinemia or hypoprolactinemia, hypogonadism

Patients with an adrenal carcinoma as underlying cause of Cushing syndrome:

Rapid onset of symptoms of glucocorticoid excess in conjunction with

hyperandrogenism presenting as virilization in women or feminization in men

Physical Examination

Obesity

Patients may have increased adipose tissue in the face (moon facies), upper back at

the base of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).

Central obesity may also appear as increased adipose tissue in the mediastinum and

peritoneum, increased waist-to-hip ratio greater than 1 in men and 0.8 in women; and,

upon CT scan of the abdomen, increased visceral fat is evident.

Skin

Facial plethora may be present, especially over the cheeks. Violaceous striae, often

wider than 0.5 cm, are observed most commonly over the abdomen, buttocks, lower

back, upper thighs, upper arms, and breasts. Ecchymosis may be present. Patients

may have telangiectasia and purpura, cutaneous atrophy with exposure of

subcutaneous vasculature tissue and tenting of skin may be evident. Glucocorticoid

excess may cause increased lanugo facial hair. If glucocorticoid excess is

accompanied by androgen excess, as occurs in adrenocortical carcinomas, hirsutism

and male pattern balding may be present in women. Steroid acne, consisting of

papular or pustular lesions over the face, chest, and back, may be present.

Acanthosis nigricans, which is associated with insulin resistance and

hyperinsulinemia, may be present. The most common sites are axilla and areas of

frequent rubbing, such as over elbows, around the neck, and under the breasts.





Cardiovascular and renal

Hypertension and possibly edema may be present due to cortisol activation of the

mineralocorticoid receptor leading to sodium and water retention. Cushing syndrome

is also associated with cardiac structural and functional changes. Left ventricular

(LV) hypertrophy and impaired LV diastolic function have been described in patients

with Cushing syndrome; however, these changes are reversed upon normalization of

corticosteroid excess.

Gastroenterologic

Peptic ulceration may occur with or without symptoms. Particularly at risk are

patients given high doses of glucocorticoids (rare in endogenous hypercortisolism).

Endocrine

Galactorrhea may occur when anterior pituitary tumors compress the pituitary stalk,

leading to elevated prolactin levels.

Signs of hypothyroidism, such as slow deep tendon reflex relaxation, may occur from

an anterior pituitary tumor whose size interferes with thyroid-stimulating hormone

(TSH) synthesis and release. Similarly, other pituitary function may be impacted as

well.

Low testosterone levels in men may lead to decreased testicular volume from

inhibition of LHRH and LH/FSH function. In women, low level of LHRH and

LH/FSH lead to menstrual irregularities or amenorrhea.

Skeletal/muscular

Proximal muscle weakness may be evident. Osteoporosis may lead to incident

fractures and kyphosis, height loss, and axial skeletal bone pain. Avascular necrosis

of the hip is also possible from glucocorticoid excess.

Neuropsychological

Patients may experience emotional lability, fatigue, and depression.

Visual-field defects, often bitemporal, and blurred vision may occur in individuals

with large ACTH-producing pituitary tumors that impinge on the optic chiasma.

Adrenal crisis

Patients with cushingoid features may present to the emergency department in

adrenal crisis. Adrenal crisis may occur in patients on steroids who stop taking their

glucocorticoids or neglect to increase their steroids during an acute illness. It may

also occur in patients who have recently undergone resection of an ACTH-producing

or cortisol-producing tumor or who are taking adrenal steroid inhibitors.

Physical findings that occur in a patient in adrenal crisis include hypotension,

abdominal pain, vomiting, and mental confusion (secondary to low serum sodium or

hypotension). Other findings include hypoglycemia, hyperkalemia, hyponatremia,

and metabolic acidosis

Laboratory Studies

The diagnosis of Cushing syndrome requires demonstration of inappropriately

high level of cortisol in the serum or urine. The levels should be measured when





cortisol, according to its physiologic circadian rhythm, is supposed to be suppressed,

that is, late evening or when a patient is given exogenous glucocorticoids.

This concept gives rise to the following tests, which have been recommended as

screening tests for Cushing syndrome:

Midnight serum or salivary cortisol

24-hour urine free cortisol

Low dose dexamethasone suppression test

Exogenous glucocorticoid use around time of testing must be addressed and

excluded to ensure the accuracy of the test result's interpretation.

Urinary free cortisol (UFC) determination has been widely used as an initial

screening tool for Cushing syndrome because it provides measurement of cortisol

over a 24-hour period. A valid result depends on adequate collection of the specimen.

Urinary creatinine excretion can be used to assess the reliability of the collection. 24-

Hour urine creatinine excretion should be 20-25 mg/kg (lean body weight) in adult

males younger than 50 years of age and 15-20 mg/kg (lean body weight) in adult

females younger than 50 years. However, in elderly patients, creatinine excretion

gradually declines over time, which makes this estimation less accurate than that for

younger individuals. Urine free cortisol values higher than 3 times the upper limit of

normal are highly suggestive of Cushing syndrome. Values higher than the normal

reference range but less than 3times the upper limit of normal are inconclusive.

Values within this range may indicate pseudo–Cushing syndrome or Cushing

syndrome and require further testing. Multiple collections are necessary because

patients with disease may have values that fall within the normal range.

The rationale for the dexamethasone suppression test is based on the normal

physiology of the hypothalamic-pituitary-adrenal axis; glucocorticoids inhibit

secretion of hypothalamic CRH and pituitary ACTH. Since cortisol production is

controlled by ACTH, decrease in ACTH lead to decrease in plasma and urine

cortisol. The overnight 1-mg dexamethasone suppression test requires administration

of 1 mg of dexamethasone at 11 PM with subsequent measurement of cortisol level at

8 am. To enhance the sensitivity of the test, a cutoff value of less than 1.8 mcg/dL (50

nmol/L) excludes Cushing syndrome. Its ease of administration makes the 1-mg

dexamethasone suppression test a widely used screening tool.

Late-night serum and salivary cortisol levels take advantage of the alterations in

circadian rhythm of cortisol secretion in patients with Cushing syndrome. Normally,

cortisol values are at their lowest level late at night. In patients with Cushing

syndrome, an elevated serum cortisol at 11 PM can be an early, but not definitive,

finding. Measuring serum cortisol levels requires hospitalization, with blood samples

obtained within 5-10 minutes of waking a patient, and is not a practical test.

The dexamethasone-CRH test is intended to distinguish patients with Cushing

syndrome from those with pseudo-Cushing states. It combines a 48-hour low-dose

dexamethasone suppression test with CRH stimulation. Dexamethasone (0.5 mg q6h)

is given 8 times starting at about 8 AM, CRH is administered 2 hours after the last





dose of dexamethasone and plasma cortisol and ACTH levels are obtained at 15-

minute intervals for 1 hour. A cortisol value at 15 minutes after CRH greater than 38

nmol/L (1.4 mcg/dL) identifies Cushing syndrome. The test has a sensitivity of 90-

100% and a specificity of 67-100%. This test is reserved for patients with high

clinical suspicion for Cushing syndrome but equivocal results on other diagnostic

tests.

Unfortunately, mild Cushing syndrome is often difficult to distinguish from

normal cortisol secretion or pseudo-Cushing states. The aforementioned tests can

produce both false-positive and false-negative results. False-positive results are

associated with obesity, alcoholism, chronic renal failure, affective disorders,

strenuous exercise, or eating disorders. Other potential confounders in the

interpretation of tests include the following:

Medications that increase corticosteroid-binding globulin, such as estrogen and

tamoxifen, may cause appropriate increases in serum cortisol levels.

Medications that facilitate the metabolism of dexamethasone, such as

phenobarbital, phenytoin, and rifampin, may cause false-positive results with

the dexamethasone suppression test.

Imaging Studies

Imaging studies for Cushing syndrome should be performed after the

biochemical evaluation has been performed. The rationale for this is that random





imaging of the pituitary or adrenal glands may yield a 10% incidence of incidental

nonfunctioning pituitary or adrenal adenomas, which may mislead one from proper

therapy and surgery. Ideally, the biochemical abnormalities should reconcile with the

anatomic abnormalities before definitive therapy is offered.

An abdominal CT scan is recommended if a primary adrenal pathology is

suspected. The presence of an adrenal mass larger than 4-6 cm raises the possibility

that the mass is an adrenal carcinoma.

If a pituitary source of excess ACTH is suspected, patients should undergo a

contrast-enhanced magnetic resonance imaging (MRI) study of the pituitary.

Unfortunately, normal-appearing pituitaries may occur in some patients with Cushing

disease due to both diffuse hyperplasia of ACTH-producing cells and small

microadenomas that do not appear on imaging studies. In the latter case, ACTH

lateralization during an inferior petrosal sinus sampling (IPSS) study may be useful in

lateralizing the occult lesion and in guiding surgical therapy.

Chest and abdominal CT scans should be performed in patients with suspected

ectopic ACTH production.

Octreotide scintigraphy may be helpful in detecting ectopic ACTH tumors

because some neuroendocrine tumors typically have cell surface receptors for

somatostatin.

Procedures

Inferior petrosal sinus sampling (IPSS) is useful in distinguishing a pituitary

source from an ectopic source of ACTH. An experienced interventional radiologist

should perform this procedure to decrease the incidence of neurological

complications. This study should not be used to establish the diagnosis of Cushing

syndrome.

Bilateral IPSS and simultaneous peripheral ACTH measurements are made at

baseline and 2-3 minutes, 5 minutes, and 10 minutes after intravenous

administration of oCRH at 1 mcg/kg.

An IPS-to-peripheral ACTH ratio of greater than or equal to 2 at baseline and

greater than or equal to 3 after CRH administration is consistent with Cushing

disease. [28]

In approximately 70% of patients, a ratio of greater than 1.4 between the right

and left inferior petrosal sinuses is predictive of the location of the

microadenoma.

This study is not interpretable if pituitary venous drainage anatomy is

anomalous. False negative results can be seen in catheter misplacement,

asymmetric venous drainage, or anomalous venous drainage. False positive

results are rare.

Treatment

In 2015, the Endocrine Society released new guidelines for Cushing syndrome:

Optimal treatment of Cushing syndrome involves direct surgical removal of the

causal tumor, except in cases unlikely to cause a drop in glucocorticoids or in

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patients who are not candidates for surgery. Second-line therapy should be

individualized.

Other first-line treatments include surgical resection of ectopic ACTH-

secreting tumors; transsphenoidal selective adenomectomy; blocking hormone

receptors in bilateral micronodular adrenal hyperplasia; and surgical removal in

cases of bilateral adrenal disorders.

The choice of second-line treatments include medication, bilateral

adrenalectomy, and radiation therapy (for corticotrope tumors).

Effective treatment includes the normalization of cortisol levels or action. It

also includes the normalization of comorbidities (eg, hypertension, diabetes)

by adjunctive treatments (eg, antihypertensives). Lowering cortisol levels

improves hypertension, insulin resistance, dyslipidemia, and obesity.

In cases of benign unilateral adrenal adenoma, adrenalectomy is associated

with a high cure rate in both children and adults. Adrenal carcinoma is

associated with a poor prognosis; therefore, complete resection, and possibly

medical treatment to stabilize cortisol levels, are necessary.

Long-term follow-up is recommended for osteoporosis, cardiovascular disease,

and psychiatric conditions.

Pharmacotherapy

Medications used in the management of Cushing syndrome include the following:

11-beta-hydroxylase inhibitor: Osilodrostat

Somatostatin analogs: Pasireotide

Adrenal steroid inhibitors: Metyrapone, ketoconazole, etomidate

Glucocorticoid receptor antagonist: Mifepristone

Adrenolytic agents: Mitotane

Surgical Therapy

The treatment of choice for endogenous Cushing syndrome is surgical resection of

the causative tumor. The primary therapy for Cushing disease is transsphenoidal

surgery, and the primary therapy for adrenal tumors is adrenalectomy.

Other surgical interventions include the following:

Bilateral adrenalectomy

Unilateral adrenalectomy

Resection of carcinomas

Pheochromocytoma

A pheochromocytoma (see the image below) is a rare, catecholamine-secreting

tumor derived from chromaffin cells. The term pheochromocytoma (in Greek, phios

means dusky, chroma means color, and cytoma means tumor) refers to the color the

tumor cells acquire when stained with chromium salts.

About 30% of pheochromocytomas occur as part of hereditary syndromes. Although

pheochromocytomas have classically been associated with 3 syndromes—von

Hippel-Lindau (VHL) syndrome, multiple endocrine neoplasia type 2 (MEN 2), and





neurofibromatosis type 1 (NF1)—there are now 10 genes that have been identified as

sites of mutations leading to these tumors. These different genes produce

pheochromocytomas with different ages of onset, secretory profiles, locations, and

potential for malignancy.

Because of excessive catecholamine secretion, pheochromocytomas may

precipitate life-threatening hypertension or cardiac arrhythmias. If the diagnosis of a

pheochromocytoma is overlooked, the consequences can be disastrous, even fatal;

however, if a pheochromocytoma is found, it is potentially curable. (See

Pathophysiology, Prognosis, and Treatment.)

About 85% of pheochromocytomas are located within the adrenal glands, and

98% are within the abdomen. When such tumors arise outside of the adrenal gland,

they are termed extra-adrenal pheochromocytomas, or paragangliomas.

Extra-adrenal pheochromocytomas develop in the paraganglion chromaffin tissue of

the nervous system. They may occur anywhere from the base of the brain to the

urinary bladder. Common locations for extra-adrenal pheochromocytomas include the

organ of Zuckerkandl (close to the origin of the inferior mesenteric artery), bladder

wall, heart, mediastinum, and carotid and glomus jugulare bodies.

Malignancy

Approximately 10% of pheochromocytomas and 35% of extra-adrenal

pheochromocytomas are malignant. Only the presence of metastases defines

malignancy. However, specific histologic features help to differentiate adrenal

pheochromocytomas with a potential for biologically aggressive behavior from those

that behave in a benign fashion. Among the features that suggest a malignant course

are large tumor size and an abnormal DNA ploidy pattern (aneuploidy, tetraploidy).

Common metastatic sites include bone, liver, and lymph nodes.

Signs and symptoms of pheochromocytoma

Classically, pheochromocytoma manifests as spells with the following 4

characteristics:

Headaches

Palpitations

Diaphoresis

Severe hypertension

Typical patterns of the spells are as follows:

Frequency may vary from monthly to several times per day

Duration may vary from seconds to hours

Over time, spells tend to occur more frequently and become more severe as the

tumor grows

The following may also occur during spells:

Tremor

Nausea

Weakness

Anxiety, sense of doom





Epigastric pain

Flank pain

Constipation

Clinical signs associated with pheochromocytomas include the following:

Hypertension: Paroxysmal in 50% of cases

Postural hypotension: From volume contraction

Hypertensive retinopathy

Weight loss

Pallor

Fever

Tremor

Neurofibromas

Tachyarrhythmias

Pulmonary edema

Cardiomyopathy

Ileus

Café au lait spots

Diagnosis of pheochromocytoma

Diagnostic tests for pheochromocytoma include the following:

Plasma metanephrine testing: 96% sensitivity, 85% specificity

24-hour urinary collection for catecholamines and metanephrines: 87.5%

sensitivity, 99.7% specificity

Test selection criteria include the following:

Use plasma metanephrine testing in patients at high risk (ie, those with

predisposing genetic syndromes or a family or personal history of

pheochromocytoma)

Use 24-hour urinary collection for catecholamines and metanephrines in

patients at lower risk

Imaging studies should be performed only after biochemical studies have confirmed

the diagnosis of pheochromocytoma. Studies are as follows:

Abdominal CT scanning: Has accuracy of 85-95% for detecting adrenal masses

with a spatial resolution of 1 cm or greater

MRI: Preferred over CT scanning in children and pregnant or lactating women;

has reported sensitivity of up to 100% in detecting adrenal

pheochromocytomas

Scintigraphy: Reserved for biochemically confirmed cases in which CT

scanning or MRI does not show a tumor

PET scanning: A promising technique for detection and localization of

pheochromocytomas

Additional studies to rule out a familial syndrome in patients with confirmed

pheochromocytoma include the following:





Serum intact parathyroid hormone level and a simultaneous serum calcium

level to rule out primary hyperparathyroidism (which occurs in MEN 2A)

Screening for mutations in the ret proto-oncogene (which give rise to MEN 2A

and 2B) [6]

Genetic testing for mutations causing the MEN 2A and 2B syndromes

Consultation with an ophthalmologist to rule out retinal angiomas (VHL

disease)

Management of pheochromocytoma

Surgical resection of the tumor is the treatment of choice and usually cures the

hypertension. Careful preoperative treatment with alpha and beta blockers is required

to control blood pressure and prevent intraoperative hypertensive crises. [7]

Preoperative medical stabilization is provided as follows:

Start alpha blockade with phenoxybenzamine 7-10 days preoperatively

Provide volume expansion with isotonic sodium chloride solution

Encourage liberal salt intake

Initiate a beta blocker only after adequate alpha blockade, to avoid

precipitating a hypertensive crisis from unopposed alpha stimulation

Administer the last doses of oral alpha and beta blockers on the morning of

surgery

Primary Aldosteronism (Conn syndrome)

Although initially considered a rarity, primary aldosteronism now is considered

one of the more common causes of secondary hypertension (HTN). Conn syndrome,

as originally described, refers specifically to primary aldosteronism due to the

presence of an adrenal aldosteronoma (aldosterone-secreting benign adrenal

neoplasm).

Based on older data, it was originally estimated that primary aldosteronism

accounted for less than 1% of all patients with HTN. Subsequent data, however,

indicated that it may actually occur in as many as 5-15% of patients with HTN.

Primary aldosteronism may occur in an even greater percentage of patients with

treatment-resistant HTN and may be considerably underdiagnosed; this is especially

true if patients with treatment-refractory HTN are not specifically referred for

evaluation to an endocrinologist.

Although primary aldosteronism is still a considerable diagnostic challenge,

recognizing the condition is critical because primary aldosteronism–associated HTN

can often be cured (or at least optimally controlled) with the proper surgical or

medical intervention. The diagnosis is generally 3-tiered, involving an initial

screening, a confirmation of the diagnosis, and a determination of the specific

subtype of primary aldosteronism

Although prior studies suggested that aldosteronomas were the most common

cause of primary aldosteronism (70-80% of cases), later epidemiologic work

indicated that the prevalence of aldosteronism due to bilateral idiopathic adrenal

hyperplasia (IAH; sometimes also abbreviated as BAH) is higher than had previously

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been believed. These reports suggested that IAH may be responsible for as many as

75% of primary aldosteronism cases. Moreover, reports have described a rare

syndrome of primary aldosteronism characterized by histologic features intermediate

between adrenal adenoma and adrenal hyperplasia, which often is unilaterally

localized (also referred to in earlier literature as “intermediate aldosteronism”)

Clinically, the distinction between the 2 major causes of primary aldosteronism

is vital because the treatment of choice for each is markedly different. While the

treatment of choice for aldosteronomas is surgical extirpation, the treatment of choice

for IAH is medical therapy with aldosterone antagonists.

Entities known to cause aldosteronism include the following (see the image

below):

Aldosterone-producing adenomas (APAs)

Aldosterone-producing renin-responsive adenomas (AP-RAs; also abbreviated

as RRAs)

Bilateral idiopathic adrenal (glomerulosa) hyperplasia or IAH (also known as

primary adrenal hyperplasia or PAH)

Familial forms of primary aldosteronism

Ectopic secretion of aldosterone (The ovaries and kidneys are the 2 organs

described in the literature that, in the setting of neoplastic disease, can be

ectopic sources of aldosterone, but this is a rare occurrence.)

Pure aldosterone-producing adrenocortical carcinomas (very rare;

physiologically behave as APAs)

Aldosterone, by inducing renal reabsorption of sodium at the distal convoluted

tubule (DCT), enhances secretion of potassium and hydrogen ions, causing

hypernatremia, hypokalemia, and alkalosis.

Signs and symptoms of primary aldosteronism

Patients with primary aldosteronism do not present with distinctive clinical findings,

and a high index of suspicion based on the patient's history is vital in making the

diagnosis. The findings could include the following:

HTN - This condition almost invariably occurs, although a few rare cases of

primary aldosteronism unassociated with HTN have been described in the

literature

Weakness

Abdominal distention

Ileus from hypokalemia

Findings related to complications of HTN - These include cardiac failure,

hemiparesis due to stroke, carotid bruits, abdominal bruits, proteinuria, renal

insufficiency, hypertensive encephalopathy (confusion, headache, seizures,

changes in the level of consciousness), and hypertensive retinal changes

Workup in primary aldosteronism

Screening (first-tier) tests for primary aldosteronism include the following:

Serum potassium and bicarbonate levels





Sodium and magnesium levels

Plasma aldosterone/plasma renin activity ratio

Confirmatory (second-tier) tests include the following:

Serum aldosterone level

24-hour urinary aldosterone excretion test

Salt-loading test

Tests for determining the primary aldosteronism subtype (third-tier tests) include the

following:

Postural stimulation test

Furosemide (Lasix) stimulation test

Diurnal rhythm of aldosterone

The initial radiologic investigation in the workup of primary aldosteronism is high-

resolution, thin-sliced (2-2.5 mm) adrenal computed tomography (CT) scanning with

contrast.

Other tests include the following:

NP-59 iodo-methyl-norcholesterol scintigraphy: Although fairly difficult to set

up and not routinely available, this test can be useful in select cases for

distinguishing between adenomas and hyperplasia

Adrenal venous sampling: Adrenal venous sampling probably has its greatest

utility when adrenal imaging findings are completely normal despite

biochemical evidence for primary aldosteronism and in settings in which

bilateral adrenal pathology is present on imaging and the biochemistry suggests

the presence of a functional aldosteronoma

Dexamethasone suppression test: This test is relevant only in the setting of

possible familial aldosteronism

Metoclopramide (Reglan) test: This is a noninvasive test for distinguishing

between aldosteronomas and idiopathic adrenal hyperplasia (IAH)

Management of primary aldosteronism

Pharmacologic therapy includes use of the following:

Calcium channel blockers

Mineralocorticoid antagonists

Glucocorticoids

Surgery is the treatment of choice for the lateralizable variants of primary

aldosteronism, including typical aldosteronomas, renin-responsive adenomas (RRAs),

and primary adrenal hyperplasia (PAH). An adrenalectomy can be performed via a

formal laparotomy or by using a laparoscopic technique (with performance of the

latter becoming increasingly common).

Questions for the self-control

1. Anatomy of adrenals

2. Function of adrenal medulla

3. Function of adrenal cortex





4. Etiology of adrenal failure (Addison disease)

5. Treatment of Addison disease

6. Symptoms and signs of Cushing syndrome/disease

7. Laboratory diagnosis of Cushing syndrome/disease

8. Symptoms and signs of Pheochromocytoma

9. Treatment of Pheochromocytoma

10. Diagnosis and treatment of Conn syndrome

References

1) Reznik Y, Barat P, Bertherat J, et al. SFE/SFEDP adrenal insufficiency French

consensus: Introduction and handbook. Ann Endocrinol (Paris). 2018 Jan 12

2) Skov J, Sundstrom A, Ludvigsson JF, Kampe O, Bensing S. Sex-Specific Risk of

Cardiovascular Disease in Autoimmune Addison Disease-A Population-Based

Cohort Study. J Clin Endocrinol Metab. 2019 Jun 1. 104 (6):2031-40.

3) https://emedicine.medscape.com/article/116467-overview


5) Nieman LK. Recent Updates on the Diagnosis and Management of Cushing's

Syndrome. Endocrinol Metab (Seoul). 2018 Jun. 33 (2):139-46

6) Chaudhry HS, Bhimji SS. Cushing Syndrome. 2018 Jan.

7) Aymes S. Endocrine Society releases guidelines on treatment of Cushing’s

Syndrome. Endocrinology Advisor. Aug 26, 2015.



https://emedicine.medscape.com/article/116467-overview




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METHODOLOGICAL RECOMMENDATION ON THE LECTURE