Adrenal pathology

Question 1

adrenal medulla comes from?

Answer 1

neural crest cells

Question 2

The adrenal glands and their zones

Answer 2

paired endocrine organs w/ cortex and medulla,

In essence the cortex and medulla are two glands packaged as one structure.

The adrenal cortex has three zones: narrow zona glomerulosa, broad zona fsciculata, narrowzona reticularis abuts the medulla.

Question 3

adrenal cortex- what is made where?

what’s made in the medulla?

Answer 3

Glucocorticoids (principally cortisol), - zona fasciculata (and to a lesser degree in the zona reticularis)

Mineralocorticoids, (e.g. aldosterone*)- zona glomerulosa

Sex steroids (estrogens and androgens)- zona reticularis

The adrenal medulla is composed of chromaffin cells, which synthesize and secrete catecholamines, mainly epinephrine

Question 4

Adrenocortical Hyperfunction (Hyperadrenalism)

Answer 4

overproduction of the three major hormones of the adrenal cortex

(1) Cushing syndrome, characterized by an excess of cortisol
(2) Hyperaldosteronism as a result of excessive aldosterone
(3) Adrenogenital or virilizing syndromes caused by an excess of androgens

Question 5

history of weight gain, abnormal hair growth, hypertension

Answer 5

consider Cushings

Question 6

Hypercortisolism (Cushing Syndrome)

Answer 6

caused by conditions that produce elevated glucocorticoid levels

Cushing syndrome can be broadly divided into exogenous and endogenous causes.

most: result of the administration of exogenous glucocorticoids (“iatrogenic” Cushing syndrome).

Endogenous causes: ACTH dependent and ACTH independent

Question 7

Cushing disease

Answer 7

ACTH-secreting pituitary adenomas account for approximately 70% of cases of endogenous hypercortisolism

The pituitary form is referred to as Cushing disease. women 4x more than men
most frequently in young adults.
Most- caused by an ACTH-producing pituitary microadenoma

Question 8

Secretion of ectopic ACTH by nonpituitary tumors

Answer 8

10% of ACTH-dependent Cushing syndrome.

often a small-cell carcinoma of the lung

Question 9

most common underlying causes for ACTH-independent Cushing syndrome

Answer 9

Primary adrenal neoplasms, such as adrenal adenoma (~10%) and carcinoma (~5%)

The biochemical sine qua non of ACTH-independent Cushing syndrome is elevated serum levels of cortisol with low levels of ACTH

Question 10

Depending on the cause of the hypercortisolism the adrenals show one of the following abnormalities:

Answer 10

Cortical atrophy

Diffuse hyperplasia

Macronodular or micronodular hyperplasia

Adenoma or carcinoma

Question 11

Clinical Course of Cushing syndrome

Answer 11

develops slowly

Early stages : hypertension and weight gain.

With time : central pattern of adipose tissue deposition, form of truncal obesity, moon facies, and accumulation of fat in the posterior neck and back (buffalo hump).

Hypercortisolism –> selective atrophy of fast-twitch (type 2) myofibers, resulting in decreased muscle mass and proximal limb weakness.

Glucocorticoids induce gluconeogenesis and inhibit the uptake of glucose by cells, with resultant hyperglycemia, glucosuria and polydipsia (secondary diabetes). The catabolic effects cause loss of collagen and resorption of bones. Consequently the skin is thin, fragile, and easily bruised; wound healing is poor; and cutaneous striae are particularly common in the abdominal area.

Bone resorption results in the development of osteoporosis, with consequent backache and increased susceptibility to fractures. Persons with Cushing syndrome are at increased risk for a variety of infections, because glucocorticoids suppress the immune response. Additional manifestations include several mental disturbances, including mood swings, depression, and frank psychosis, as well as hirsutism and menstrual abnormalities.

Question 12

The laboratory diagnosis of Cushing syndrome

Answer 12

) 24-hour urine free-cortisol concentration, which is increased

(2) Loss of normal diurnal pattern of cortisol secretion. Determining the cause of Cushing syndrome depends on the serum ACTH and measurement of urinary steroid excretion after administration of dexamethasone (dexamethasone suppression test).

Question 13

Dexamethasone suppression test

Answer 13

In pituitary Cushing syndrome-ACTH levels elevated, cannot be suppressed w/ low dose of dexamethasone. –> no reduction in urinary excretion of 17-hydroxycorticosteroids.

higher doses–> the pituitary reduces ACTH secretion, –> suppression of urinary steroid secretion.

Ectopic ACTH secretion- completely insensitive to low or high doses of exogenous dexamethasone.

When Cushing syndrome is caused by an adrenal tumor, the ACTH level is quite low because of feedback inhibition of the pituitary. As with ectopic ACTH secretion, both low-dose and high-dose dexamethasone fail to suppress cortisol excretion.

Question 14

Key Concepts: hypercortisolism

Answer 14

most common cause- exogenous administration of steroids

endogenous- usually secondary to ACTH-producing pituitary microadenoma (Cushing disease), followed by primary adrenal neoplasms (ACTH-independent hypercortisolism) and paraneoplastic ACTH production by tumors (e.g. small cell lung cancer)

morphologic features in the adrenal- vary from bilateral cortical atrophy (exogenous) to bilateral diffuse or nodular hyperplasia (in endogenous Cushing sundrome), to an adrenocortical neoplasm.

Question 15

Primary Hyperaldosteronism

Answer 15

Hyperaldosteronism is the generic term for a group of closely related conditions characterized by chronic excess aldosterone secretion.

Hyperaldosteronism may be primary, or it may be secondary to an extra-adrenal cause.

Primary hyperaldosteronism stems from an autonomous overproduction of aldosterone, with resultant suppression of the renin-angiotensin system and decreased plasma renin activity.

Blood pressure elevation is the most common manifestation of primary hyperaldosteronism.

Question 16

Bilateral idiopathic hyperaldosteronism

Answer 16

(IHA), characterized by bilateral nodular hyperplasia of the adrenal glands, is the most common underlying cause of primary hyperaldosteronism, accounting for about 60% of cases. Individuals with idiopathic hyperaldosteronism tend to be older and to have less severe hypertension than those presenting with adrenal neoplasms.

Question 17

Adrenocortical neoplasm and hyperaldosteronism

Answer 17

either an aldosterone-producing adenoma (the most common cause) or, rarely, an adrenocortical carcinoma. In approximately 35% of cases, primary hyperaldosteronism is caused by a solitary aldosterone-secreting adenoma, a condition referred to as Conn syndrome. This syndrome occurs most frequently in adult middle life and is more common in women than in men (2 : 1).

Question 18

Glucocorticoid-remediable hyperaldosteronism

Answer 18

is an uncommon cause of primary familial hyperaldosteronism. In some families, it stems from a rearrangement involving chromosome 8 that places CYP11B2 (the gene that encodes aldosterone synthase)

Question 19

Secondary hyperaldosteronism

Answer 19

Aldosterone release occurs in response to activation of the renin-angiotensin system.

It is characterized by increased levels of plasma renin and is encountered in conditions such as the following:

Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
Arterial hypovolemia and edema (congestive heart failure, cirrhosis, nephrotic syndrome)
Pregnancy (due to estrogen-induced increases in plasma renin substrate

Question 20

Clinical Course of primary hyperaldosteronism

Answer 20

** hypertension

The long-term effects: 
cardiovascular compromise (e.g., left ventricular hypertrophy and reduced diastolic volumes) 
- increase in stroke and myocardial infarction. 

(Hypokalemia) - more normokalemic patients are now diagnosed

The diagnosis confirmed by elevated ratios of plasma aldosterone concentration to plasma renin activity; if this screening test is positive, a confirmatory aldosterone suppression test must be performed, because many unrelated causes can alter the plasma aldosterone and renin ratios

Question 21

Disorders of sexual differentiation

Answer 21

such as virilization or feminization, can be caused by primary gonadal disorders and several primary adrenal disorders

Question 22

Adrenogenital Syndromes

Answer 22

The adrenal cortex secretes two compounds—dehydroepiandrosterone and androstenedione, that can be converted to testosterone in peripheral tissues.

The adrenal causes of androgen excess include adrenocortical neoplasms and a group of disorders that have been designated congenital adrenal hyperplasia (CAH)

Question 23

21-hydroxylase deficiency - 3 types

Answer 23

(caused by mutations of CYP21A2) is by far the most common, accounting for over 90% of cases

Three distinctive syndromes have been described:

(1) Salt-wasting (“classic”) adrenogenitalism
(2) Simple virilizing adrenogenitalism
(3) “Nonclassic” adrenogenitalism.

Question 24

The salt-wasting syndrome

Answer 24

results from an inability to convert progesterone into deoxycorticosterone because of a total lack of the hydroxylase. Thus, there is virtually no synthesis of mineralocorticoids, and concomitantly, there is a block in the conversion of hydroxyprogesterone into deoxycortisol resulting in deficient cortisol synthesis.

This pattern usually comes to light soon after birth, because in utero the electrolytes and fluids can be maintained by the maternal kidneys. There is salt wasting, hyponatremia, and hyperkalemia, which induce acidosis, hypotension, cardiovascular collapse, and possibly death.

The concomitant block in cortisol synthesis and excess production of androgens, however, lead to virilization, which is easily recognized in the female at birth or in utero. Males with this disorder are generally unrecognized at birth but come to clinical attention 5 to 15 days later because of some salt-losing crisis.

Question 25

Simple virilizing adrenogenital syndrome without salt wasting

Answer 25

(presenting as genital ambiguity) occurs in approximately a third of patients with 21-hydroxylase deficiency.

These patients generate sufficient mineralocorticoid to prevent a salt-wasting “crisis.”

However, the lowered glucocorticoid level fails to cause feed­back inhibition of ACTH secretion. Thus, the level of testosterone is increased, with resultant progressive virilization.

Question 26

Nonclassic or late-onset adrenal virilism

Answer 26

significantly more common than the classic patterns already described. There is only a partial deficiency in 21-hydroxylase function, which accounts for the later onset.

Individuals with this syndrome may be virtually asymptomatic or have mild manifestations, such as hirsutism, acne, and menstrual irregularities.

Nonclassic CAH cannot be diagnosed on routine newborn screening, and the diagnosis is usually rendered by demonstration of biosynthetic defects in steroidogenesis.

Question 27

Clinical Course of congenital adrenal hyperplasia

Answer 27

The clinical features of these disorders are determined by the specific enzyme deficiency and include abnormalities related to androgen excess, with or without aldosterone and glucocorticoid deficiency

Depending on the nature and severity of the enzymatic defect, the onset of clinical symptoms may occur in the perinatal period, later childhood, or, less commonly, adulthood!

Question 28

21-hydroxylase deficiency

Answer 28

excessive androgenic activity causes signs of masculinization in females, ranging from clitoral hypertrophy and pseudohermaphroditism in infants, to oligomenorrhea, hirsutism, and acne in postpubertal females.

In males, androgen excess is associated with enlargement of the external genitalia and other evidence of precocious puberty in prepubertal patients and oligospermia in older males.

Question 29

neonate with ambiguous genitalia

Answer 29

CAH should be suspected!

Question 30

Adrenocortical Insufficiency

Answer 30

Adrenocortical insufficiency, or hypofunction, may be caused by either primary adrenal disease (primary hypoadrenalism) or decreased stimulation of the adrenals due to a deficiency of ACTH (secondary hypoadrenalism)

(1) Primary acute adrenocortical insufficiency (adrenal crisis)
(2) Primary chronic adrenocortical insufficiency (Addison disease)
(3) Secondary adrenocortical insufficiency

Question 31

Primary Acute Adrenocortical Insufficiency

Answer 31

• crisis in individuals with chronic adrenocortical insufficiency precipitated by stress –> immediate increase in steroid output from glands incapable of responding
• In patients maintained on exogenous corticosteroids, in whom rapid withdrawal of steroids/ failure to increase steroid doses in response to an acute stress –> adrenal crisis, because of the inability of the atrophic adrenals to produce glucocorticoid hormones
• As a result of massive adrenal hemorrhage–> damages adrenal cortex–> acute adrenocortical insufficiency—as occurs in newborns following prolonged and difficult delivery with considerable trauma and hypoxia.
• In some patients maintained on anticoagulant therapy, in postsurgical patients who develop DIC and hemorrhagic infarction of the adrenals, and as a complication of disseminated bacterial infection; in this last setting, it is called Waterhouse-Friderichsen syndrome.

Question 32

Waterhouse-Friderichsen syndrome.

Answer 32

Overwhelming bacterial infection, classically Neisseria meningitidis septicemia but occasionally caused by other highly virulent organisms, such as Pseudomonas species, pneumococci, Haemophilus influenzae, or even staphylococci
Rapidly progressive hypotension leading to shock
Disseminated intravascular coagulation associated with widespread purpura, particularly of the skin
Rapidly developing adrenocortical insufficiency associated with massive bilateral adrenal hemorrhage

Question 33

Primary Chronic Adrenocortical Insufficiency (Addison Disease)
- 3 causes

Answer 33

autoimmune (most common)
infections
metastatic neoplasms

Question 34

Autoimmune adrenalitis

Answer 34

most common cause of primary adrenal insufficiency in developed countries.

autoimmune destruction of steroidogenic cells. Autoimmune polyendocrine syndrome type 1 (APS1) and type 2 (APS2) are the main causes.

Question 35

infections and adrenocortical insufficience

Answer 35

Infections, particularly tuberculosis and those produced by fungi, may also cause primary chronic adrenocortical insufficiency.

Question 36

Metastatic neoplasms and adrenocortical insufficiency

Answer 36

another cause
common site for metastases in patients with disseminated carcinomas.

the metastatic tumors occasionally destroy enough adrenal cortex to produce a degree of adrenal insufficiency.

• lung and breast are the source of a majority of metastases

Question 37

Clinical Course of Addison’s disease

Answer 37

begins insidiously
does not come to attention until the levels of circulating glucocorticoids and mineralocorticoids are significantly decreased.
initial manifestations: progressive weakness and easy fatigability

common GI issues: anorexia, nausea, vomiting, weight loss, and diarrhea.

primary disease –> hyperpigmentation of skin at sun-exposed areas and pressure points (elbows, etc), caused by elevated pro-opiomelanocortin (POMC)- precursor to ACTH and MSH

• not seen with primary pituitary/ hypothalamic disease

potassium retention and sodium loss –> hyperkalemia, hyponatemia, volume depletion, hypotension

Question 38

Secondary Adrenocortical Insufficiency

Answer 38

Any disorder of the hypothalamus and pituitary, (metastatic cancer, infection, infarction, or irradiation) that reduces the output of ACTH leads to a syndrome of hypoadrenalism that has many similarities to Addison disease

2dary— hyperpigmentation of primary Addison disease is lacking, because levels of melanocyte-stimulating hormone are not elevated

also: deficient cortisol and androgen
normal or near-normal aldosterone synthesis. –> hyponatremia and hyperkalemia are not seen.

NORMAL ELECTROLYTES

Question 39

Adrenocortical Neoplasms

Answer 39

Adenomas and carcinomas are about equally common in adults; in children, carcinomas predominate.

While most cortical neoplasms are sporadic, two familial cancer syndromes are associated with a predisposition for developing adrenocortical carcinomas:
Li-Fraumeni syndrome, in patients who harbor germline TP53 mutations
Beckwith-Wiedemann syndrome, a disorder of epigenetic imprinting

Functional adenomas are most commonly associated with hyperaldosteronism and Cushing syndrome, whereas a virilizing neoplasm is more likely to be a carcinoma

Question 40

malignant adrenocortical neoplasm goes with

Answer 40

kid, big lesion, virilization

Question 41

benign adrenocortical neoplasm goes with

Answer 41

adult, non-functioning, found incidentally

Question 42

Functional and nonfunctional adrenocortical neoplasms - distinguishing the two

Answer 42

cannot be distinguished on the basis of morphologic features.

Determination of functionality is based on clinical evaluation, and measurement of hormones or hormone metabolites in the blood

Question 43

Adrenocortical carcinomas

Answer 43

rare neoplasms that can occur at any age, including childhood. They are more likely to be functional than adenomas and are often associated with virilism or other clinical manifestations of hyperadrenalism. In most cases adrenocortical carcinomas are large, invasive lesions, many exceeding 20 cm in diameter, which efface the native adrenal gland

Question 44

metastasis to adrenals

Answer 44

Carcinomas, particularly those of bronchogenic origin, may metastasize to the adrenals, and may be difficult to differentiate from primary cortical carcinomas. Of note, metastases to the adrenal cortex are significantly more common than primary adrenocortical carcinomas.

Question 45

adrenal incidentaloma

Answer 45

is a half-facetious moniker that has crept into the medical lexicon as advancements in medical imaging have led to the incidental discovery of adrenal masses in asymptomatic individuals or in individuals in whom the presenting complaint is not directly related to the adrenal gland.

The estimated population prevalence of “incidentalomas” discovered by imaging is approximately 4%, with an age-dependent increase in prevalence.

Fortunately, the vast majority of adrenal incidentalomas are small nonsecreting cortical adenomas of no clinical importance.

Question 46

Adrenal Medulla

Answer 46

developmentally, functionally, and structurally distinct from the adrenal cortex. It is composed of specialized neural crest (neuroendocrine) cells, termed chromaffin cells, and their supporting (sustentacular) cells. The adrenal medulla is the major source of catecholamines (epinephrine, norepinephrine) in the body

Question 47

Neuroendocrine cells similar to chromaffin cells

Answer 47

are widely dispersed in an extra-adrenal system of clusters and nodules that, together with the adrenal medulla, make up the paraganglion system. (1) branchiomeric, (2) intravagal, and (3) aorticosympathetic

Question 48

The most important diseases of the adrenal medulla are

Answer 48

neoplasms, which include neoplasms of chromaffin cells (pheochromocytomas) and neuronal neoplasms (neuroblastic tumors)

Question 49

Pheochromocytoma

Answer 49

Neoplasms composed of chromaffin cells, which synthesize and release catecholamines and in some instances peptide hormones. It is important to recognize these tumors because they are a rare cause of surgically correctable hypertension.

Zellballen- nests of cells
Salt and pepper chromatin

Question 50

Pheochromocytomas have been summarized by the “rule of 10s”

Answer 50

10% extra-adrenal, occurring in sites such as the organs of Zuckerkandl and the carotid body. = paragangliomas.

10% bilateral; this figure may rise to as high as 50% in cases that are associated with familial tumor syndromes.

10% biologically malignant, defined by the presence of metastatic disease. Malignancy is more common (20% to 40%) in extra-adrenal paragangliomas, and in tumors arising in the setting of certain germline mutations.

10% not associated with hypertension. Of the 90% that present with hypertension, approximately two thirds have “paroxysmal” episodes associated with sudden rise in blood pressure and palpitations, which can, on occasion, be fatal.

Question 51

25% of individuals with pheochromocytomas and paragangliomas have

Answer 51

a germline mutation

Question 52

Clinical Course of pheochromocytoma

Answer 52

• hypertension
  2/3 in paroxysmal episodes

associated with tachycardia, palpitations, headache, sweating, tremor, and a sense of apprehension

may also be associated with pain in the abdomen or chest, nausea, and vomiting.

may be precipitated by emotional stress, exercise, changes in posture, and palpation in the region of the tumor; patients with urinary bladder paragangliomas occasionally precipitate a paroxysm during micturition. The elevations of blood pressure are induced by the sudden release of catecholamines that may acutely precipitate congestive heart failure, pulmonary edema, myocardial infarction, ventricular fibrillation, and cerebrovascular accidents.

cardiac complications- attributed to catecholamine cardiomyopathy

Question 53

laboratory diagnosis of pheochromocytoma

Answer 53

is based on the demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines

Question 54

surgical excision of pheochromocytomas

Answer 54

Isolated benign tumors are treated with surgical excision, after preoperative and intraoperative medication of patients with adrenergic-blocking agents to prevent a hypertensive crisis. Multifocal lesions require long-term medical treatment for hypertension