[PATH] Adrenal Glands Flashcards
1
Q
Bilateral cortical hyperplasia of the adrenal glands is seen in which variants of Cushing Syndrome?
A
ACTH-dependent —> ACTH-producing pituitary adenoma or Ectopic ACTH-producing tumors
2
Q
Atrophic adrenals would be expected in which variant of Cushing Syndrome?
A
“Iatrogenic” Cushing Syndrome from administration of exogenous glucocorticoids
3
Q
What are the 2 most common underlying causes of ACTH-independent Cushing Syndrome?
A
- Adrenal adenoma
- Adrenal carcinoma
4
Q
What are the serum levels of cortisol and ACTH like in adrenal adenomas/carcinomas?
A
- ↑↑↑ serum cortisol
- ↓↓↓ serum ACTH
5
Q
What is the most common morphological alteration observed in the pituitary resulting from high levels of endogenous or exogenous glucocorticoids called?
A
Crooke hyaline change
6
Q
Crooke hyaline change of the ACTH-producing cells of the anterior pituitary seen in Cushing Syndrome is the result of the accumulation of what?
A
Intermediate KERATIN filaments in the cytoplasm
7
Q
What is a major morphological difference between adrenocortical adenomas and adrenocortical carcinomas?
A
- Adenomas tend to be smaller w/ thin- or well-developed capsules
- Carcinomas are MUCH larger and are UNencapsulated masses
8
Q
Both benign and malignant adrenocortical adenomas are more common in which sex and age range?
A
Women in their 30s to 50s
9
Q
Hypercortisolism causes selective atrophy of fast-twitch myofibers resulting in what clinical manifestations?
A
- Decreased muscle mass
- Proximal limb weakness
10
Q
Which cause of Cushing Syndrome will have elevated levels of ACTH which is completely insensitive to low or high doses of exogenous dexamethasone?
A
Ectopic ACTH-producing tumors
11
Q
Which 4 settings of HTN should raise suspicion of Primary Hyperaldosteronism (“Conn’s syndrome”)?
A
- Refractory HTN
- Adrenal mass + HTN
- HTN at a young age
- Severe HTN (>160/100 mmHg)
12
Q
What is the most common underlying cause of primary hyperaldosteronism and what is seen morhphologically in the adrenal glands?
A
- Bilateral idiopathic hyperaldosteornism (IHA)
- Characterized by bilateral nodular hyperplasia of adrenal glands
13
Q
Germline and somatic mutations of which gene are present in familial idiopathic hyperaldosteronism and some aldosterone-secreting adenomas?
A
KCNJ5 encoding a K+ channel
14
Q
Glucocorticoid-remediable hyperaldosteronism is an uncommon cause of primary familial hyperaldosteronism and may be due to which genetic rearrangement and involving what chromosome?
A
Rearrangement on Cr. 8 placing CYP11B2 (gene encoding aldosterone synthase) under control of the ACTH-responsive CYP11B1 gene promoter
15
Q
In glucocorticoid-remediable hyperaldosteronism what is the function of ACTH?
A
ACTH is able to stimulate the production of aldosterone synthase
16
Q
Due to the unusual circumstance in glucocorticoid-remediable hyperaldosteronism where aldosterone production is under the control of ACTH, how can this production be suppressed?
A
Suppressible by dexamethasone
17
Q
Secondary hyperaldosteronism occurs in response to conditions which do what?
A
Activate the RAAS
18
Q
List 5 conditions where there is an increased activation of RAAS which may lead to secondary hyperaldosteronism?
A
- Diuretic use
- ↓ renal perfusion (i.e., arteriolar nephrosclerosis, renal a. stenosis)
- Arterial hypovolemia (i.e., CHF, cirrhosis, nephrotic syndrome)
- Pregnancy (estrogen-induced ↑ in plasma renin substrate)
- Renin-secreting tumors
19
Q
How does activity of the RAAS and levels of renin differ between primary and secondary hyperaldosteronism?
A
- Primary assoc. w/ suppression of RAAS and ↓ renin
- Secondary assoc. w/ activation of RAAS and ↑↑↑ renin
20
Q
Do aldosterone-secreting adenomas typically produce visible enlargement?
A
NO, often small (<2 cm) and buried within the gland
21
Q
What is a characteristic histological feature of aldosterone-secreting adenomas?
A
Eosinophilic, laminated cytoplasmic inclusions –> Spironolactone bodies
22
Q
Is hypokalemia a mandatory feature of primary hyperaldosteronism?
A
- NO, although many patients will be hypokalemic
- Increasing numbers of patients who are normokalemic are being diagnosed
23
Q
Diagnosis of primary hyperaldosteronism is confirmed by what screening test, and if postive, what test must be performed?
A
- ↑↑↑ ratios of plasma aldosterone: plasma renin activity
- Confirmed w/ aldosterone suppression test
24
Q
What is the best therapy for primary hyperaldosteronism caused by an adenoma vs. bilateral hyperplasia?
A
- Adenomas are amendable to resection
- Bilateral hyperplasia is best managed w/ aldosterone antagonists i.e., spironolactone
25
Adrenocortical neoplasma associated with virilization are more likely to be of what type?
Androgen-secreting adrenal **carcinomas**
26
Androgen-secreting adrenal carcinomas often elaborate what other hormone?
**Cortisol** and are known as "**mixed syndromes"**
27
What is the inheritance pattern of the inherited metabolic errors causing congenital adrenal hyperplasia?
Autosomal **recessive**
28
Which enzyme involved in the biosynthesis of cortical steroids is most commonly seen as deficient?
**21-hydroxylase** deficiency
29
Which syndrome associated with 21-hydroxylase deficiency has a complete lack of the enzyme activity?
Salt wasting syndrome
30
What are the levels of mineralocorticoids, cortisol, and sex steroids like in salt wasting syndrome?
- **NO** mineralocorticoids or cortisol
- ↑↑↑ **sex steroids**
31
Salt wasting syndrome comes to attention soon after birth with what serum electrolyte abnormalities?
- **Salt wasting --\> HYPOnatremia**
- **HYPERkalemia**
- **HYPO**tension
32
How does the presentation of salt wasting syndrome differ in males vs. females at birth?
- **Females** will present w/ easily recognizable **virilization** at birth
- **Males** don't usually come to clinical attention until **5-15 days** after birth due to some **salt-losing crisis**
33
Patients w/ severe salt-wasting 21-hydroxylase deficiency will have **adrenomedullary dysplasia** which predisposes them to what long term consequences?
- ↓ catecholamine secretion
- **HYPO**tension
- **Circulatory collapse**
34
Simple virilizing adrenogenital syndrome without salt wasting is associated with what type of 21-hydroxylase activity and how does this typically present clinically?
- **Partial** lack of enzyme activity; **some mineralcorticoids** and **small amount of cortisol**, _NOT_ enough to prevent **ACTH overproduction**
- Presents as **genital ambiguity**
35
The most common form of 21-hydroxylase deficiency presents as nonclassic or late-onset adrenal virilism; what are the clinical manifestations?
- May be **virtually asymptomatic**
- **Mild manifestations** such a **precocious puberty**, **acne** and **hirsutism** at the time of puberty
36
In all cases of congenital adrenal hyperplasia what is the morphological change seen in the adrenals?
**BILATERAL hyperplastic**; some times ↑↑↑ 10-15x normal weights
37
Pt's with CAH are treated with what?
- **Exogenous glucocorticoids**, provides adequate levels _AND_ suppresses ACTH levels
- **Mineralocorticoid** supplementation given in salt-wasting variants
38
What are 2 means of diagnosis of congenital adrenal hyperplasia?
- **Serum 17-hydroxyprogesterone** levels will be ↑↑↑
- **ACTH-stimulation** test, which would normally ↑ **glucocorticoids** (but fails to do so in CAH)
39
Disseminated bacterial infection causing massive adrenal hemorrhagic necrosis and resultant primary acute adrenocortical insufficiency is known as what?
Waterhouse-Friderichsen Syndrome
40
Amyloidosis, sarcoidosis, and hemochromatosis may all lead to what type of adrenal dysfunction?
Primary adrenocortical insufficiency
41
In which 3 clinial settings does primary acute adrenocortical insufficiency most often occur?
- As a **crisis** in pt with **chronic** adrenocortical insufficiency precipitated by **any form of stress**
- **Rapid withdrawl of steroids** or failure to ↑ dose in response to acute stress
- **Massive adrenal hemorrhage**, as occurring in newborns following prolonged/difficult delivery; pt's on anticoagulant therapy who develop DIC; and in *Waterhouse-Friderichsen Syndrome*
42
Adrenal hemorrhage leading to primary acute adrenocortical insufficiency may occur in what 5 clinical settings?
- **Sepsis**: *Waterhouse Friderichsen syndrome*
- **Neonatal period**
- **Trauma**
- **Postsurgical patients**
- **Coagulopathy**
43
Which 5 bacterial species may be associated with Waterhouse-Friderichsen Syndrome?
- *N. meningitidis* septicemia
- *H. influenzae*
- *Pseudomonas* species
- Pneumococci
- Staphylococci
44
What are the clinical signs/sx's associated with Waterhouse-Friderichsen Syndrome?
- **Rapidly progressive** **HYPO**tension ---\> **Shock**
- **DIC** assoc. w/ **widespread purpura**, particularly of the **skin**
- Massive **bilateral** adrenal hemorrhage --\> rapid adrenocortical insufficiency
45
Histological examination of the adrenals in Waterhouse-Friderichsen syndrome show hemorrhage that starts where and then travels how?
Starts within **medulla** near **thin-walled** venous sinusoids, then spreads peripherally into **cortex**, often leaving islands of recognizable cortical cells
46
What are 6 signs/sx's that should raise suspicion of **acute** adrenal insufficiency?
- **HYPOtension** (refractory to volume repletion)
- **HYPOnatremia**
- **HYPOglycemia**
- Abdominal pain
- Fever
- N/V
47
90% of all cases of primary chronic adrenocortical insufficiency can be attributed to one of what 4 disorders?
- **Autoimmune adrenalitis**
- **Tuberculosis**
- **AIDS**
- **Metastatic cancers**
48
Most common cause of primary chronic adrenocortical insufficiency in **developed** countries?
Autoimmune adrenalitis
49
Most common cause of primary chronic adrenocortical insufficiency **worldwide**?
**Tuberculosis** ---\> Autoimmune
50
Autoimmune polyendocrine syndrome type 1 is also know as what?
**A**utoimmune **P**oly**E**ndocrinopathy, **C**andidiasis and **E**ctodermal **D**ystrophy (**APECED**)
51
Autoimmune polyendocrinopathy syndrome type 1 (aka APECED) is characterized by what clinical findings?
- **Chronic mucocutaneous candidiasis**
- Abnormalities of **skin, dental enamel**, and **nails** (**ectodermal dystrophy**)
- Organ-specific autoimmune disorders: **autoimmune adrenalitis**, **hypoparathyroidism**, idiopathic **hypogonadism**, and **pernicious anemia**
52
Autoimmune polyendocrine syndrome type 1 is associated w/ mutations in which gene, on which chromosome?
***AIRE*** on chromosome **21q22**
53
Autoantibodies against which 2 cytokines seen in autoimmune polyendocrinopathy syndrome type 1 are the reason for chronic mucocuntaneous infections?
**IL-17** and **IL-22**
54
When does autoimmune polyendocrine syndrome type 2 usually develop and what are the characteristic findings?
- Starts in **early adulthood**
- Combination of **adrenal insufficiency (adrenalitis) + immune thyroiditis** OR **type 1 DM**
55
Which 3 infectious agents may cause primary chronic adrenocortical insufficiency?
- **Tuberculosis** used to be **most common** cause
- ***Histoplasma capsulatum***
- ***Coccidioides immitis***
56
AIDS patients are at risk for developing adrenal insufficiency from which 2 infections and as a complication of what?
- **CMV** and ***Mycobacterium avium-intracellulare***
- Noninfectious (**Kaposi Sarcoma**)
57
Metastatic neoplasms involving the adrenals and causing adrenocortical insufficiency most often arise from which 2 sites; what are some other sites which may be implicated?
- **Lungs** and **breast** carcinomas = **most common**
- May also be from **GI carcinomas**, **malignant melanoma**, and **hematopoietic neoplasms**
58
What are 2 genetic causes of adrenal insufficiency?
- **Congenital adrenal hypoplasia**
- **Adrenoleukodystrophy** (X-linked recessive)
59
What is the gross morphology and histology of the adrenal glands in primary autoimmune adrenalitis?
- **Irregularly SHRUNKEN** glands
- Scattered residual cortical cells in **collapsed** network of CT w/ a variable **lymphoid infiltrate** of the cortex
60
Which type of inflammatory reaction will be seen in the adrenal glands affected by tuberculosis and fungal disease?
**Granulomatous** inflammation
61
What are the initial manifestations (signs/sx's) of primary chronic adrenocortical insufficiency (Addison's disease)?
**Progressive weakness** and **easy fatigability**
62
What are the signs/sx's of primary chronic adrenocortical insufficiency as a result of corticosteroid and mineralocroticoid deficiency?
- ↓ **corticosteroids** --\> vague malaise, N/V, hypoglycemia, and refractory **hypo**tension
- ↓ **mineralocorticoids** --\> **hyper**kalemia and **hypo**natremia
63
Which type of adrenocortical insufficiency is associated with hyperpigmentation of the skin and which is not?
- **Primary** **adrenal** disease **will** have **hyperpigmentation**
- Adrenocortical insufficiency caused by **primary pituitary** or **hypothalamic** disease will **not**
64
How does the presentation of adrenal carcinomas differ from that of adenoma?
- **Carcinomas** are **larger** and produce **mass effect** causing **compression/invasion** of adjacent structures
- **Virilizing**
65
How does the production of cortisol, androgens, and aldosterone in secondary adrenocortical insufficiency differ from that of primary?
- Will have **deficient** cortisol and androgens
- But **normal** or **near-normal** synthesis of **aldosterone**
66
How can an ACTH-stimulation test help you differentiate primary vs. secondary adrenocortical insufficiency?
- **Primary** will have a **reduced** response to exogenous ACTH
- **Secondary** will show a prompt **rise** in plasma **cortisol** levels
67
Which 2 familial cancer syndromes are associated with a predisposition for developing adrenocortical carcinomas?
- **Li-Fraumeni syndrome**, due to germline ***TP53* mutations**
- **Beckwith-Wiedemann syndrome** a disorder of **epigenetic imprinting**
68
Adrenocortical carcinomas have a strong tendency to invade which structures?
- **Adrenal vein**
- **Vena cava**
- **Lymphatics** ---\> **regional** and **periaortic nodes** = **common**
69
Distant hematogenous spread by adrenocortical carcinomas to where is common; what is the prognosis of these neoplasms?
- **Lungs** and other viscera
- **Median pt survival** = about **2 years**
70
Which is more common, primary adrenocortical carcinomas or metastases to the adrenal cortex?
**Metastases**
71
Cortical and medullary neoplasms may undergo necrosis and cystic degeneration and may present as what type of lesion?
"**Nonfunctional cysts**"
72
Adrenal myelolipomas are unusual benign lesions composed of what?
**Mature fat** + **hematopoietic cells** (i.e., **bone marrow**)
73
What is the 10% rule associated with Pheochromocytomas (5 of them)?
- **10%** are **extra-adrenal** (paraganglioma)
- **10%** are **bilateral**
- **10%** in **kids**
- **10%** are **malignant**
- **10%** are **NOT** associated with **HTN**
74
What % of pheochromocytomas are now recognized as harboring germline mutations and as such are familial?
**25%**
75
What are the 3 groups of extra-adrenal paraganglia based on anatomic distribution?
1. **Branchiomeric**
2. **Intravagal**
3. **Aorticosympathetic**
76
What are 4 familial syndromes which are associated with pheochromocytomas and extra-adrenal paragangliomas?
- **MEN-2A**
- **MEN-2B**
- **NF-1**
- **Von Hippel-Lindau (VHL)**
77
How does the patient presentation and location of pheochromocytomas in pt's harboring germline mutations differ from that of sporadic types?
- Pt's are typically **younger**
- More often harbor **bilateral** disease
78
The histological pattern in pheochromocytomas is composed of clusters of polygonal to spindle-shaped chromaffin or chief cells surrounded by what?
Supporting sustentacular cells, creating **small nests** or **alveoli** (**zellballen**) that are supplied by **rich vascular network**
79
The cytoplasm of cells within a pheochromocytoma has a finely granular appearance and is best demonstrated with what stain due to granules containing catecholamines?
Silver Stain
80
What stain can be used for visualization of the peripheral sustentacular cells of a pheochromocytoma?
Stain w/ antibodies against **S-100**
81
Which histological feature of pheochromocytomas reliably predicts clinical behavior?
**NONE**
82
What is the definitive diagnosis of malignancy in pheochromocytomas based on?
**Exclusively** on the presence of **metastases**
83
What is the dominant clinical manifestation of pheochromocytomas and what is the **classic triad**?
- **HTN** which can be either **chronic** or **paroxysmal**
- **Triad =** **Headache** + **Palpitations** + **Diaphoresis**
84
What are some acute complications of pheochromocytomas which are associated with catecholamine surges?
- **CHF**
- **Pulmonary edema**
- **MI**
- **Ventricular fibrillation**
- **CVA**
85
What is a chronic cardiac complication which may arise in the setting of a pheochromocytoma?
**Catecholamine cardiomyopathy**
86
What is the laboratory diagosis of pheochromocytomas based on?
↑ urinary excretion and plasma **free catecholamines** + their **metabolites** i.e., **vanillylmandelic acid** and **metanephrines**
87
What 3 features of adrenal incidentalomas impact the appropriate managment of the mass?
- **SIZE**: **\>4cm** = more likely to be **carcinoma**
- **Positive functional assays**: i.e., dexamethasone suppression test for hypercortisolism or urinary metanephrines for pheochromo.
- **CT enhancement characteristics**
88
How do endocrine tumors arising in the context of MEN syndromes differ from their sporadic counterparts in terms of age, organs involved, behavior, and foci?
- Tend to occur at **younger age**
- Arise in **multiple** endocrine organs, either **synchronously** or **metachronously**
- Typically preceded by **asymptomatic stage of hyperplasia**
- Even in one organ, tumors are often **multifocal**
- Are usually **more aggressive** and **recur**
89
What are the "3 P's" of MEN, type 1?
- **P**rimary hyper**p**arathyroidism
- **P**ancreatic endocrine tumors
- **P**ituitary adenomas
90
What is the initial manifestation of MEN 1 in most patients, appearing in almost all patients by age 40-50?
**P**rimary hyper**p**arathyroidism
91
Which tumors of MEN-1 are the leading cause of morbidity and mortality due to their aggressiveness and metastases?
Pancreatic endocrine tumors
92
What is the most frequent pituitary adenoma encountered in MEN-1?
**Prolactinoma (lactotroph)**; may also see **somatotroph adenoma** (**GH**)
93
What is the most common site of gastrinomas present in pt's with MEN-1?
**Duodenum**; may also have synchronous **duodenal** + **pancreatic** tumors
94
MEN-1 is due to germline mutations in the *MEN1* tumor suppressor gene which encodes what protein?
**Menin**
95
What is the triad of MEN-2A?
- Pheochromocytoma
- Medullary thyroid carcinoma
- Parathyroid hyperplasia
\*There are **more 'A's'** in **Type 2 'A'**
96
Which tumor is seen in almost 100% of patients with MEN-2A?
**Medullary carcinoma of the thyroid**
97
The medullary thyroid carcinoma encountered in MEN-2A are usually multifocal and are virtually always associated with foci of what?
**C-cell hyperplasia** in the **adjacent thyroid**
98
MEN-2A is caused by which mutation and on what chromosome?
Germline **gain-of-function** mutations in ***RET*** on **Cr. 10q11.2**
99
What is the triad of MEN-2B?
- Pheochromocytomas
- Medullary thyroid carcinomas
- **Mucosal neuromas** (distinguishing feature from MEN-2A)
100
Which MEN syndrome is associated with a marfanoid habitus, characterized by long axial skeletal features and hyperextensible joints?
MEN-2B
101
How is the germline mutation associated with MEN-2B distinct from that of MEN-2A?
MEN-2B caused by germline mutation leading to a **single amino acid** change in **RET** (**specific point mutation**)
102
Familial medullary thyroid cancers are a variant of MEN-2A; how are they different?
- Develop at an **older age**
- Do not have the other clinical manifestation assoc. w/ MEN-2A
- Typically follow a more **indolent** course
103
About 1/3 of sporadic medullary thyroid carcinomas harbor the identical point mutation of RET encountered in MEN-2B and follow what type of course?
**More aggressive disease** and **adverse prognosis**
104
Diagnosis via screening of at-risk family members for which MEN syndrome is important?
**MEN-2A** due to medullary thyroid carcinoma being life-threatening, and can be prevented by **prophylactic thyroidectomy**
105
The pineocytes of the pineal gland are epithelial cells with what 2 functions?
**Photosensory** and **neuroendocrine** functions
106
Majority of tumors arising in the pineal gland are of what type?
- **Germ cell tumors** i.e., **germinomas**, **embryonal carcinomas**; **choriocarcinomas** and **mixtures** of the **2**
