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.
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 2
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
levels of
abstraction
Type of lecture,
methods and means
of activating
students, equipment
Time
distribution
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1.
2.
Preparatory stage
Setting a learning goal
Providing positive motivation
І
І
In accordance with
the publication
"Guidelines for
planning,
preparation and
analysis of lectures"
5%
(5 min)
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 3
ІІ
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
ІІ
ІІ
ІІ
ІІ
ІІ
ІІ
ІІ
ІІ
ІІ
ІІ
Slide presentation of
lecture material
Extracts from
medical histories of
patients. Excerpts
from clinical
guidelines for the
provision of medical
care to patients.
85%
(75 min)
ІІІ
4.
5.
6.
The final stage
Lecture summary, general
conclusions
Answers to possible questions
Tasks for self-training
ІІІ
ІІІ
ІІІ
References,
questions, tasks
10%
(10 min)
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.
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 4
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
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 5
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
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 6
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.
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 7
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
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 8
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
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 9
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
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 10
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.
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 11
- 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.
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 12
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
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 13
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.
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 14
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.
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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:
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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
ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.
Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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)
ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.
Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.
Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
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Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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.
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Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
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Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.
Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
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Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
ONMedU, Department of Internal medicine 1 with cardio-vascular pathology course, Lecture №04.
Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
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Diseases of adrenal glands. Chronic adrenal failure. Hormone-producing tumors
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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
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 27
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:
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 28
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
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 29
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
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 30
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
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 31
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
4) https://emedicine.medscape.com/article/117365-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.
8) https://emedicine.medscape.com/article/124059-overview
9) https://emedicine.medscape.com/article/127080-overview