Adrenal pathology Flashcards
adrenal medulla comes from?
neural crest cells
The adrenal glands and their zones
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.
adrenal cortex- what is made where?
what’s made in the medulla?
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
Adrenocortical Hyperfunction (Hyperadrenalism)
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
history of weight gain, abnormal hair growth, hypertension
consider Cushings
Hypercortisolism (Cushing Syndrome)
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
Cushing disease
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
Secretion of ectopic ACTH by nonpituitary tumors
10% of ACTH-dependent Cushing syndrome.
often a small-cell carcinoma of the lung
most common underlying causes for ACTH-independent Cushing syndrome
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
Depending on the cause of the hypercortisolism the adrenals show one of the following abnormalities:
Cortical atrophy
Diffuse hyperplasia
Macronodular or micronodular hyperplasia
Adenoma or carcinoma
Clinical Course of Cushing syndrome
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.
The laboratory diagnosis of Cushing syndrome
) 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).
Dexamethasone suppression test
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.
Key Concepts: hypercortisolism
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.
Primary Hyperaldosteronism
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.
Bilateral idiopathic hyperaldosteronism
(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.
Adrenocortical neoplasm and hyperaldosteronism
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).
Glucocorticoid-remediable hyperaldosteronism
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)
Secondary hyperaldosteronism
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
Clinical Course of primary hyperaldosteronism
** 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
Disorders of sexual differentiation
such as virilization or feminization, can be caused by primary gonadal disorders and several primary adrenal disorders
Adrenogenital Syndromes
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)
21-hydroxylase deficiency - 3 types
(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.
The salt-wasting syndrome
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.
Simple virilizing adrenogenital syndrome without salt wasting
(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.
Nonclassic or late-onset adrenal virilism
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.
Clinical Course of congenital adrenal hyperplasia
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!
21-hydroxylase deficiency
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.
neonate with ambiguous genitalia
CAH should be suspected!
Adrenocortical Insufficiency
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
Primary Acute Adrenocortical Insufficiency
- 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.
Waterhouse-Friderichsen syndrome.
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
Primary Chronic Adrenocortical Insufficiency (Addison Disease)
- 3 causes
autoimmune (most common)
infections
metastatic neoplasms
Autoimmune adrenalitis
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.
infections and adrenocortical insufficience
Infections, particularly tuberculosis and those produced by fungi, may also cause primary chronic adrenocortical insufficiency.
Metastatic neoplasms and adrenocortical insufficiency
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
Clinical Course of Addison’s disease
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
Secondary Adrenocortical Insufficiency
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
Adrenocortical Neoplasms
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
malignant adrenocortical neoplasm goes with
kid, big lesion, virilization
benign adrenocortical neoplasm goes with
adult, non-functioning, found incidentally
Functional and nonfunctional adrenocortical neoplasms - distinguishing the two
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
Adrenocortical carcinomas
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
metastasis to adrenals
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.
adrenal incidentaloma
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.
Adrenal Medulla
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
Neuroendocrine cells similar to chromaffin cells
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
The most important diseases of the adrenal medulla are
neoplasms, which include neoplasms of chromaffin cells (pheochromocytomas) and neuronal neoplasms (neuroblastic tumors)
Pheochromocytoma
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
Pheochromocytomas have been summarized by the “rule of 10s”
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.
25% of individuals with pheochromocytomas and paragangliomas have
a germline mutation
Clinical Course of pheochromocytoma
- 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
laboratory diagnosis of pheochromocytoma
is based on the demonstration of increased urinary excretion of free catecholamines and their metabolites, such as vanillylmandelic acid and metanephrines
surgical excision of pheochromocytomas
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
