Adrenal Pathology - MT Flashcards
1
Q
What are the zones of an adrenal gland and what do they produce respectively?
A
capsule*
- outermost zona glomerulosa: mineralcorticoids (aldosterone
- zona fasciculata: glucocorticoids (cortisol)
- zona reticularis: glucocorticoids (cortisol), sex steroids (estrogen, androgens)
- Innermost adrenal medulla: chromaffin cells (catecholamines: Epi, NE)
2
Q
what are 3 syndromes of adrenal hyperfunction? (hyperadrenlism) and what are they characterized by?
A
- Cushing syndrome: excess cortisol
- Hyperaldosteronism: excess aldosterone
- Adrenogenital or virilizing syndromes: excess androgens
3
Q
What might you see on physical examination of a patient with cushing syndrome?
A
- central obesity
- moon facies
- abdominal striae
- HTN
- abnormal hair growth
4
Q
What can cause exogenous Cushing syndrome?
A
- Elevated glucocorticoid levels (cortisol) from steroid use (iatrogenic)
5
Q
What conditions can cause ACTH dependent endogenous cushing syndrome?
Which is most likely in most cases to be the cause (70%)?
A
- ACTH secreting pituitary adenomas (cushing disease)
- Secretion of ectopic ACTH by nonppituitary tumor (small cell carcinoma of lung)
- most likely ACTH sec pituitary adenoma (70%)
6
Q
What can cause ACTH independent endogenous cushing syndrome?
What lab values indicate these conditions?
A
- Adrenal adenoma (primary adrenal neoplasms) (10%)
- Adrenal carcinoma (5%)
- elevated serum cortisol, low ACTH
7
Q
Crooke hyaline change, what is it?
A
- most common alteration resulting from high levels of endogenus or exogenous glucocorticoids d/t accumulation of intermediate keratin filaments in cytoplasm (homogeneous and pale CTH producing cells in anterior pituitary)
- slide 13 visual
8
Q
Abnormalities found in Hypercortisolism (Cushing syndrome)
A
- Cortical atrophy
- Diffuse hyperplasia
- Macronodular or Micronodular hyperplasia
- Adenoma or carcinoma
9
Q
visuals on diffuse hyperplasia of adrenal gland and also micronodular adrenocortical hyperplasia visual
A
slide 15 and 16
10
Q
Clinical course of cushing syndrome
- presentation in early stages
- later presentation
A
- HTN and weight gain
- Truncal obesity, moon facies, accumulation of fat in posterior neck and back (buffalo hump).
- decreased muscle mass and proximal limb weakness d/t selective atrophy of fast twitch type 2 myofibers
- hyperglycemia, glucosuria, polydipsia (2nd diabetes)
- loss of collagen skin thin fragile, easy bruising
- STRIAE in abdominal area
- Osteoporosis resultant from bone resorption
- Mental disturbancs
- HIrutism, menstrual abnormalities
11
Q
What lab can be useful in the diagnosis of Cushing syndrome?
A
- 24 hour urine free cortisol concentration (increased in cushings)
- DEXAMETHASONE suppression test
12
Q
What is involved in a dexamethasone suppression test?
A
- in Pituitary cushing disease (most common form), ACTH levels that are elevated are not suppressed by admin of low dose dexamethasone –> no reduction in urinary excretion of 17 hydroxycorticosteroids
* increased dexamethasone will reduce ACTH secretion–>reduced urine steroid secretino
- Ectopic ACTH secretion causing ACTH elevation will have complete insensitivity to low or high dose of exogenous dexamethasone
- Adrenal tumor cushing syndrome ACTH low and will not respond to dexamethasone
13
Q
Cushing syndrome workup steps
A
- 24 hour urine cortisol
* if high (>100 mg/dL) suspect cushing problem (syndrome, disease, ectopic)
- Check ACTH levels
* low, suspect cushing syndrome–>CT/MRI adrenals
* high, suspect disease/ectopic–> high dose dexamethasone test
- if suppressed, investigate cushing disease
* MRI pituitary (mass ACTH producing, no mass = inf petrosal sinus sampling)
- if not suppressed, investigate ectopic ACTH w/ CT of chest
14
Q
cushing disease affects what populatin more?
what is causing it in most cases?
A
Young adult women
* most cases it is an ACTH producing pituitary microadenoma (endogenous ACTH dependent)
15
Q
The most common cause of hypercortisolism (cushing syndrome) is?
A
Exogenous administration of steroids
16
Q
How does primary hyperaldosteronism arise?
What conditions can cause primary Hyperaldosteronism?
A
- Primary
autonomous overproduction of aldosterone, w/ suppression of renin angiotensin system and DECREASED plasma renin activity
* Blood pressure elevation most common manifestation
- B/l idiopathic hyperadosteronism (IHA)
- Adrenocortical neoplasms
- Glucocorticoid remediable hyperaldosteronism
-
17
Q
What type of condition causing primary hyperaldosteronism is characterized by b/l nodular hyperplasia of adrenal glands and is the most common underlying cause of primary hyperaldosteronism? (60%)
- what population does this condition tend to affect?
A
B/l idiopathic hyperaldosteronism (IHA)
older people with less severe HTN than those presenting with adrenal neoplasms
18
Q
What causes Conn syndrome?
What population does it affect?
A
- Solitary aldosterone secreting adenoma (35% of primary hyperaldosternism cases) (adrenocortical neoplasm)
- adult middle life more common in women 2:1
19
Q
What is the genetic rearrangement that can cause Glucocorticoid remediable hyperaldosteronism? (Familial primary hyperaldosteronism)
what does this gene encode?
A
CYP11B2 gene which encodes aldosterone synthase
20
Q
What is the physiolgy that leads to secondary hyperaldosteronism?
Condition that cause this?
A
Aldosterone release occurs in response to activatino of renin angiotensin system
NON adrenal causes…
- Decreased renal perfusion (arteriolar nephrosclerosis, renal artery stenosis)
- Arterial hypovolemia and edema (CHF, cirrhois, nephrotic syndrome)
- Pregnancy (d/t estrogen induced increases in plasma renin substrate)
21
Q
What strucure might you see on histology of an aldosterone producing adenoma?
A
Spironolactone bodies (slide 28)
22
Q
- most important clinical consequence of hyperaldosteronism is?
A
HTN
23
Q
Long term effects of hyperaldosteronism induced HTN are?
A
Cardiovascular effects like:
- Left ventricular hypertrophy
- reduced diastolic volumes
increase incidence of strokes and MIs
24
Q
diagnosis of primary hyperaldosteronism is confirmed by what?
if this test is positive, what do you confirm it with?
A
elevated ratios of plasma aldosterone concentration to plasma renin activity
(elevated Plasma aldosterone / Plasma renin activity)
- if screening is positive, confirm with aldosterone suppression test
25
What are adrenogenital syndromes?
What causes them?
Disorders of sexual differentiation, such as virilization or feminization.
Caused by primary gonadal disorders and several primary adrenal disorders
26
Adrenal cortex secretes what two compounds that can be converted to testosterone in peripheral tissues?
dehydroepiandrosterone and androstenedione
27
What disorders can cause androgen excess?
Adrenocortical neoplasms, and
Congenital adrenal hyperplasias (CAH)
28
What is Congenital adrenal hyperplasia?
Several autosomal recessive inherited metabolic errors characterized by deficiency or total lack of a particular enzyme involve in biosynth of cortical steroids, particularly cortisol
29
Most common enzyme deficient in CAH?
21 hydroxylase deficiency 90% cases (mutation of CYP21A2)
30
3 distinct syndromes described for CAH?
1. Salt wasting (classic) adrenogenitalism
2. Virilizing adrenogenitalism (simple)
3. Non classic adrenogenitalism
31
In CAH the salt wasting syndrome results from what?
- how does it cause salt wasting?
- Lack of Hydroxylase (inability to convert progesterone into deoxycorticosterone)
- results in vitually no synthesis of mineralcorticoids
- also concomitant block in conversion of hydroxyprogesteroneinto deoxycortisol resulting in deficient cortisol synthesis
32
Pattern of salt wasting is usually detected when?
Why is it detected then and not in utero?
- after birth, becuase in utero maternal kidneys can maintain electrolytes and fluid for baby
- salt wasting, leads to hyponatremia, hyperkalemia--\> acidosis, hypotension--\>death from CV collapse
33
What causes the virilization in CAH?
- The block in cortisol production and resultant excess production of androgens
\*recognized sooner in females at birth or in utero, males later b/c salt losing crisis
34
What is simple virilizing adrenogenital syndrome?
occurs in 1/3 patients with 21 hydroxylase deficiency
- no salt wasting, sufficient mineralcorticoid production
- lowered glucocorticoid level fails to cause feedback inhibition of ACTH secretion--\>increased testosterone w/ resultant progressive virilization
35
What is late onset non classic adrenal virilism?
partial deficiency in 21 hydroxylase, thus late onset
more common than simple virilizing adrenogenital sydrome
36
Clinical sx of late onset adrenal virilism?
- mild manifestations of Hirsutism, acne, irregular menses
\*cannot be diagnosed on routine newborne screening
37
Clinical features of CAH are determined by what?
specific enzyme deficiencies and include abnormalities related to androgen excess w/ or w/o galdosterone and glucocorticoid deficiency
38
21 hydroxylase deficiency excessive androgenic activity causes what?
masculinization in females
ranging effects of:
- clitoral hypertrophy
- pseudohermaphroditism in infants
- oligomenorrhea, hirsutism, acne in post pubertal females
39
Androgen excess associated with what in males?
Large penises
precocious puberty in prepubertal patients
oligospermia in older males
40
When should CAH be suspected in neonates?
in any neonate with ambiguous genitalia
41
3 causes of adrenocortical insufficiency
- Primary acute adrenocortical insufficiency (adrenal crisis)
- Primary chronic adrenocortical insufficiency (Addison disease)
- secondary adrenocortical insufficiency
42
Primary acute adrenocortical insufficiency causes... (x4)
1. Crisis from any form of stress in chronic adrenocortical insufficiency individuals
2. patients maintained on exogenous steroid who have a rapid withdrawal of those steroids
3. Massive adrenal hemorrhage (post partum in a difficult delivery for baby where there is trauma and hypoxia)
4. anticoagulant therapy patients, DIC patients, Waterhous friderichsen syndrome
43
What causes Waterhouse-Friderichsen syndrome?
what characterizes this condition?
overwhelming bacterial infection from Neisseria meningitidis septicemia
- ocassional from Pseudomonas, Haemophilus, Staphylococci
- rapid progressive hypotension leading to shock
- DIC associated w/ purpura widespread
- massive b/l adrenal hemorrhage
44
What causes primary chronic adrenocortical insufficiency? (Addison disease)
- Autoimmune adrenalitis (60-70% most common)
- Infections (TB, fungi)
- Metastatic neoplasms (carcinomas of lung and breast)
45
What are the main causes of autoimmune adrenalitis in Addison disease?
Autoimmune polyendocrine syndrome type I (APS 1)
type 2 (APS2)
46
Clinical symptoms of Addison's disease?
- insidious onset
- progressive weakness nd easy fatigability
- GI distrubances: anorexia, nausea, vomit, weight loss, diarrhea
- hyperpigmentation of skin caused by elevated POMCs derived from anterior pituitary
- Hypotension (Hyperkalemia, hyponatremia, volume depletion)
47
Secondary Adrenocortical insufficiency definition?
any disorder of Hypothalmus and Pituitary that reduces output of ACTH --\> hypoadrenalism similar to addison disease
48
How do you differentiate secondary adernocortical insufficiency from primary addison disease?
- Lack of hyperpigmentation found in addison disease b/c levels of melanocyte stim hormone are not elevated
- Secondary hypoadrenalism characterized by deficient cortisol and androgen output but NORMAL aldosterone synthesis
(no hyponatremia and hyperkalemia seen!!!)
49
What adrenocrtical neoplasm are common in adults?
Children?
- Adenomas and Carcinomas equal in adults
- Carcinomas in children predominate
50
What are 2 familial cancers syndromes associated w/ a predisposition for developing adrenocortical carcinomas?
What is the root cause of each?
- Li- Fraumeni syndrme (TP53 germline mutation)
- Beckwith-Wiedemann syndrome (epigenetic imprinting)
51
Functional Adenomas are most commonly associated with what?
Virilizing neoplasms associated with what?
- Hyperaldosteronism and Cushing syndrome
- Carcinoma
52
how is an adrenal cortical adenoma distinguished from nodular hyperplasia?
- solitary circuscribed nature
- functinoal status (cannot be predicted from microscopic appearance)
53
A histological feature of adrenal cortical adenoma is
- vacuolated neoplastic cell d/t intracytoplasmic lipid
54
Adrenalcortical carcinomas:
- population affected?
- functional or non functional?
- Associated with what?
- Most appear as
- any age, childhood too
- functional (more so than adenomas)
- Virilism or other clinical manifest of hyperadrenalism
- Large invasive lesion
55
Carcinomas of what origin may likely metastasize to adrenals?
- likelihood of metastases in adrenals vs. primary adrenocortical carcinoma?
- Bronchogenic origin
- metastases into adrenals more common than primary adrenocortical carcinomas
56
The vast majority of adrenal incidentalomas prognostically are?
- small nonsecreting cortical adenomas of no clinical importance. In asymptomatic individuals
57
Gross inspection of an adrenal carcinoma is likened to what?
- hamburger meat (caused by hemorrhagic and necrotic tumor)
58
Nml adrenal vs Adrenal carcinoma histology
slide 59
59
Cellular composition of the adrenal medulla consists of?
- Chromaffin cells ( specialized neural crest cells aka neuroendocrine cells)
- Supporting Sustentacular cells
60
Adrenal medulla provides a major source of what for the body?
- Catecholamines (Epi, NE)
61
- Neuroendocrine cells similar to chromaffin cells are widely dispersed where?
- What composes the paraganglion system?
- An extra adrenal system of clusters and nodules
- Extra adrenal system of clusters and nodules + Adrenal medulla
(branchiomeric, Intravagal, Aoticosympathetic)
62
The most important disease of adrenal medulla are?
Neoplasms:
- Pheochromocytoma (neoplasm of chromaffin cells)
- Neuroblastic tumors (neuronal neoplasms)
63
CT scan of a pheochromocytoma
slide 62
64
Why is it important to recognize and dx Pheochromocytomas?
- Rare cause of surgically correctable HTN
65
What can pheochromocytomas produce?
- Catecholamines
- peptide hormones in some instances
66
Rule of 10s for Pheochromocytomas?
- 10% are extra adrenal @ sites like organs of zuckerkandl and carotid body (Paragangliomas)
- 10% sporadic adrenal type are bilateral (can be 50% in familial)
- 10% adrenal type biologically malignant (more common in Paragangliomas) (germline mutation)
- 10% adrenal type not associated with HTN
if HTN present, 2/3 paroxysmal epiodes
67
25% of individuals with pheochromocytomas and paragangliomas harbor what?
Germline mutation
Pheochromocytoma (RET, NF1)
Paraganglioma (SDHC)
68
Gross observation of a pheochromocytoma would show?
- tumor enclosed in an attenuated cortex w/ areas of hemorrhage
69
Histologic change in Pheochromocytomas
- nest of cells (zellballen)
- salt and pepper chromatin
70
recognize dense core granules on EM for Pheochromocytoma
slide 68
71
Clinical presentation of Pheochromocytoma
- dominant manifestation is HTN in 90% of patients
- 2/3 of patients presenting with HTN will have episodic paroxysmal HTN
- episodes associated with tachycardia, palpitations, HA, sweating, tremor, sense of apprehension
72
What can precipitate paroxysmal episodes of HTN in patients with pheochromocytomas?
- emotional stress, exercies, change in posture, palpation in region of tumor
73
Acute consequences of suddne catecholamine release in a paroxysmal episode include
- CHF, Pulmonary edema, MI, Vfib, Stroke
- cardiac complications called Catecholamine cardiomyopathy (ventricular arrhythias)
74
Lab results that would help confirm Pheochromocytoma Dx
- increased urinary excretion of free catecholamines and their metabolites like:
- Vanillylmandelic acid + Metanephrines
75
Tx of pheochromocytomas
- isolated benign tumors are surgically excised
(use of adrenergic blocking agents is vital for preventing HTN crisis during surgery)
- multifocal lesions require long term medical Tx for HTN
