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Endocrinology > Adrenal > Flashcards

Adrenal Flashcards

1
Q

Features of an adrenal mass with a high lipid content

A

Low attenuation on unenhanced CT (< 10 HU)
Loss of signal in out-of-phase sequencing on MRI
Greater than 60% absolute and 40% relative washout on delayed protocols

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2
Q

When is confirmatory testing not required in primary aldosteronism?

A
  1. spontaneous hypokalemia
  2. undetectable plasma renin and
  3. plasma aldosterone greater than 20 ng/dl
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3
Q

Medications that result in a false-negative screen for primary aldosteronism:
MOA?

A
  1. mineralocorticoid receptor antagonists - spironolactone and eplerenone
  2. epithelial sodium channel inhibitors - amiloride and triamterene

These meds work on the DISTAL nephron–> decrease Na reabsorption–> limit volume expansion/induce volume contraction –> rise in renin and therefore lowers aldosterone-to-renin ratio

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4
Q

Bilateral macronodular adrenal hyperplasia

  1. clinical features?
  2. etiology
  3. imaging findings
  4. how is BMAH different from PPNAD?
  5. treatment of BMAH
A
  1. an ACTH-independent state of cortisol excess
  2. due to aberrant receptors; germline mutation in ARMC5 gene
  3. multiple nonpigmented bilateral adrenal nodules larger than 10 mm
  4. in PPNAD, the adrenal glands are often not enlarged and missed on CT or MRI
  5. unilateral adrenalectomy of the larger gland; or mifepristone or levoketoconazole
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5
Q

what medications can cause false-positive test results in pheo screening?

A

TCAs (-iptyline, -ipramine)
SSRIs
SNRIs (venlafaxine)
MAOIs (isocarboxazid, phenelzine, selegiline, tranylcypromine)
Phenoxybenzamine

**these meds can induce greater than 2-fold elevations in metanephrines, but not more than 4-fold as would a real pheo
*anxiety can also increase levels, but less than 2-fold

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6
Q

Mifepristone:

  1. MOA? Indication for use?
  2. SEs in treatment for Cushing syndrome (and why?)
A
  1. a progesterone and glucocorticoid receptor antagonist. Use when HYPERGLYCEMIA is present
  2. hypertension, hypokalemia, and endometrial thickening (d/t providing more cortisol substrate for 11beta-hydroxysteroid dehydrogenase 2 and the mineralocorticoid receptor –> pseudohyperaldosteronism, but aldo and renin are appropriately suppressed. Also progesterone receptor antagonism leads to endometrial hypertrophy)
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7
Q

how does licorice (which contains glycyrrhizic acid) cause HTN?

A

Glycyrrhizic acid inhibits 11-beta-hydroxysteroid dehydrogenase 2 in the kidney. This enzyme inactivates cortisol, and therefore, leads to massive activation of the mineralocorticoid by cortisol. It suppresses the renin-angiotensin-aldosterone system due to alternative mineralocorticoid receptor activation.
*Of note, cortisol is 100- to 1000-fold more potent in activating the mineralocorticoid receptor.

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8
Q

clinically significant pheochromocytomas are usually what size?

A

3 cm or larger

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9
Q

what 3 hormone elevations are pathognomonic for adrenocortical carcinoma

A

DHEAS,
testosterone,
11-deoxycortisol
(ACCs are relative deficient in 11-beta hydroxylase, leading to 11-deoxycortisol elevation and upstream)

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10
Q
  1. What is the initial test for the ddx of Cushing’s?
A
  1. plasma ACTH
    - if ACTH > 25 –> likely an ACTH-secreting neoplasm –> pituitary MRI
    - if ACTH < 10 –> adrenal dependent hypercortisolism –> adrenal CT
    - if ACTH 10-25 –> adrenal imaging
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11
Q

In patients with an adrenal mass what biochemical testing should be done?

A

Biochemical testing for PHEOCHROMOCYTOMA should be undertaken

  • for cortisol screening, need to conduct 1 mg dexamethasone suppression test since 24 hr urinary free cortisol is not sensitive enough to assess autonomous cortisol secretion from an adrenal mass
  • Only patients with an incidental adrenal mass and hypertension or hypokalemia require screening for primary aldosteronism
  • In women, rapid onset of hirsutism, menstrual irregularities, and virilization should raise suspicion for tumoral hyperandrogenism –> measure DHEAS
  • an adrenal mass with suspicious findings include: size > 4 cm, heterogeneous enhancement with contrast administration, irregular margins, presence of calcifications or necrosis
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12
Q

Signs of androgen excess such as progressive hirsutism and virilization over a short period of time in female patients suggest the diagnosis of?

A
  • an androgen-producing adrenal or ovarian tumor

- if testosterone is above 150, likely ovarian tumor so get pelvic US; otherwise, get abdominal CT to look at adrenals

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13
Q

Adrenalectomy is recommended for?

A

Incidental adrenal masses with radiologic features that suggest increased risk of an adrenal malignancy

  • size >4 cm
  • density ≥10 Hounsfield units
  • absolute contrast washout <50% at 10 minutes
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14
Q

What are the 2 most important factors governing prognosis of adrenocortical carcinoma?

A

disease stage and completeness of resection

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15
Q

Mitotane
1. what is it?
2. MOA
3. those on treatment are at risk of developing?
4. when starting mitotane, what should also be given to patient?
5. what other endocrinopathies can also occur?
6. how does mitotane lead effect TBG, SHBG, and CYP3A4?

A
  1. A derivative of the insecticide dichlorodiphenyltrichloroethane. Treatment for adrenocortical carcinoma (after surgery)
  2. adrenolytic; causes atrophy and inhibition of steroidogenesis in both tumoral and normal adrenocortical tissue
  3. hypoadrenalism; bone marrow suppression
  4. start full/supraphysiologic glucocorticoid replacement therapy (up to 2-3 fold increase in glucocorticoid replacement)
  5. hypothyroidism with low serum FT4 and inappropriately normal TSH; male hypogonadism
  6. it increases all. Therefore, LT4 often needs to be increased
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16
Q

Features that raise concern for a malignant adrenal tumor (8)?

A
  1. larger size ( > 4 or 6 cm)
  2. irregular shape or contour
  3. heterogenous content
  4. calcifications
  5. low lipid content on CT
  6. lack of signal dropout on in-phase or out-of-phase MRI imagine
  7. poor washout on delayed contrast CT imaging
  8. fluorodeoxyglucose-avidity on PET
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17
Q

If patient has MEN2 (A or B), new and even modest elevations in metanephrines can be diagnostic for?

A

early pheochromocytoma

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18
Q
  1. Radiographic characteristics of a pheochromocytoma
  2. CT characteristics?
  3. MRI characteristics?
A
  1. poor lipid content, high contrast uptake, poor contrast washout.
  2. high unenhanced attenuation (> 10 HU), a very high postcontrast attenuation, and poor washout after a 15-min delay (< 60% absolute and < 40% relative) but sometimes washout can be high
  3. T2 hyperintensity
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19
Q

In a male with classic congenital adrenal hyperplasia
1. what syndromes does this induce?
2. MOA?
3. treatment?
4. inadequate treatment or excess ACTH can lead to?

A
  1. primary AI and adrenal androgen excess
  2. low cortisol and aldosterone lead to ACTH elevation. High ACTH stimulates adrenal steroidogenesis –> elevated 17-hydroxyprogesterone and adrenal androgen
  3. primary AI - glucocorticoid and mineralocorticoid supplementation (HC and fludro).
  4. excess adrenal androgens, leading to premature puberty and secondary hypogonadism. Tx is to increase glucocorticoid dose, switch to nighttime admin.
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20
Q
  1. In a patient with small cell lung cancer complicated by ectopic ACTH, what must be done first to allow the patient to safely undergo systemic chemotherapy?
  2. most common agents used and MOA
A
  1. control of hypercortisolism (clinical presenation includes high Na and low K)
  2. a. ketoconazole (inhibits cholesterol side-chain cleavage enzyme, 11-beta hydroxylase and 17,20 desmolase lyase). Contraindication for use is elevated ALT > 3 xULN
    b. metyrapone: inhibits 11-beta hydroxylase and aldosterone synthase
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21
Q

Medical therapies for Cushing syndrome:
1. ACTH inhibitors
2. adrenal steroidogenesis inhibitors
3. cortisol receptor blockers

A
    • cabergoline
    • pasireotide
    • ketoconazole (levoketoconazole)
    • metyrapone
    • osilodrostat
    • etomidate
    • mitotane
    • mifepristone (use in the presence of hyperglycemia)
    • relacorilant
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22
Q

Special circumstances for using certain tx for Cushing syndrome:
1. etomidate
2. metyrapone and cabergoline
3. pasireotide
4. combination therapies
5. cabergoline or ketoconazole
6. temozolamide
7. mifepristone

A
  1. parenteral use; for quick control of severe CS
  2. pregnancy
  3. large tumors
  4. severe hypercortisolism
  5. first line if cost is an issue
  6. aggressive or metastatic disease
  7. hyperglycemia
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23
Q

Osilodrostat
1. MOA
2. AE

A
  1. inhibits 11-beta hydroxylase and aldosterone synthase
  2. nausea, anemia, arthralgia, h/a
    high cost
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24
Q

Ketoconazole
1. MOA
2. AE

A
  1. inhibits cholesterol side-chain cleavage enzyme, 11-beta hydroxylase and 17,20 desmolase lyase.
  2. Stomach acid is important for absorption. Stop PPI if patient is on it. Or if pt with h/o atrophic gastritis, use a different agent
    Contraindication for use is elevated ALT > 3 xULN. Keep an eye for 6 months of tx.
    Can cause low tesosterone due to inhibtion of 17-hydroxylase and 17,20 lyase enzymes.
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25
Q

Metyrapone
1. MOA
2. AE

A
  1. inhibits 11-beta hydroxylase and aldosterone synthase
  2. hyperK, hyperandrogenism (problem in women)
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26
Q

Etomidate
1. MOA
2. used for?

A
  1. inhibits 11-beta hydroxylase
  2. used for severe hypercortisolism
    IV infusion
27
Q

Mifepristone
1. MOA
2. AE
3. used for?

A
  1. a glucocorticoid receptor antagonist
    It blocks all types of glucocorticoids, including treatment of associated hypocortisolism. Monitor patient clinically since ACTH and cortisol remain high or go up with treatment.
  2. hypOkalemia, endometrial thickening, QT prolongation
  3. CS complicated by T2DM or glucose intolerance
28
Q

Mitotane
1. MOA
2. AE
3. used for

A
  1. inhibits 11-beta hydroxylase and cholesterol side-chain cleavage enzyme through its toxic effects on adrenocortical cell mitochondria
    increases CBG and cortisol metabolism
  2. GI and neurological side effects
    Monitor lipids and TFTs
    hypogonadism
    CONTRAINDICATED IN PREGNANCY
  3. Standard of care in patient with advanced (stage III and IV) ACC
29
Q

Pasireotide
1. MOA
2. AE

A
  1. ACTH inhibitor
  2. increased hyperglycemia –> can use GLP1RA, DPP4-i’s, or metformin.
    can also lower IGF-1 levels (hence why it’s used in acromegaly)
30
Q

In limited circumstances, it is reasonable to proceed directly to surgery without an AVS in patients with the following characteristics (4)

A
  1. < 35 yo
  2. spontaneous hypokalemia
  3. marked aldosterone excess
  4. unilateral adrenal lesion(s) with radiologic features of a cortical adenoma on adrenal CT
31
Q
  1. The most common cause of HTN and hypokalemia is?
  2. MOA?
A
  1. primary aldosteronism
  2. PA is a renin-independent aldosterone production (aldo is produced even though renin and angiotensin II are suppressed despite intravascular volume expansion, and often despite hypoK).
32
Q

DDx of primary aldosteronism (5)

A
  1. aldosterone producing adenomas (APAs)
  2. Bilateral idiopathic hyperaldosteronism (bilateral adrenal hyperplasia)
  3. Familial hyperaldosteronism (FH) types I to IV
  4. Unilateral adrenal hyperplasia
  5. Ectopic aldosterone-producing tumors
33
Q

4 Subtypes of Familial Hyperaldosteronism (FH) and the gene affected

A
  1. FH type 1: glucocorticoid-remediable aldosteronism with a chimeric CYP11B1/CYP11B2 gene; an ACTH dependent aldosterone production
  2. FH type 2: germline CLCN2 variants
  3. FH type 3: germline KCNJ5 pathogenic variants
  4. FH type 4: germline CACNA1H germline variants and primary aldosteronism with seizure syndromes (PASNA) syndrome; germline CACNA1D variants
34
Q

common inducers of CYP3A4

A

mitotane
rifampicin
carbamazepine/phenytoin
St. John’s Wort
dexamethasone

35
Q
  1. For a lipid-rich adrenal mass, is further radiographic imaging or surveillance necessary?
  2. if initial cortisol profiling indicates nonfunctional status, is repeated biochemical testing indicated? When?
A
  1. NO
  2. NO. Except maybe retesting for hypercortisolism if there is substantial change in patient’s weight, glycemic status, blood pressure, or bone density in later years (low chance).
36
Q

a self or family history of metastatic gastrointestinal stromal tumor should raise concern for?

A

a pathogenic variant in one of the succinate dehydrogenase (SDH) genes

In addition to pheo, other manifestations include renal cell CA (also seen in VHL)

37
Q

Aldosterone-independent causes of mineralocorticoid excess

A
  • rare CAH subtypes (11beta hydroxylase deficiency and 17 alpha hydroxylase deficiency –> excess 11-deoxycorticosterone production)
  • syndrome of apparent mineralocorticoid excess: decreased renal 11-beta hydroxysteroid dehydrogenase type 2 activity –> reduced conversion of cortisol to cortisone. Cortisol then activates mineralocorticoid receptor. Example is licorice ingestion due to glycyrrhizic acid.
  • Cushing syndrome; glucocorticoid resistance
  • 11-deoxycorticosterone producing tumor
  • Liddle syndrome: pathogenic variant of SCNN1B gene, leading to constitutive activation of the renal epithelium sodium channel
38
Q

Adrenal congenital hypOplasia
1. results from pathogenic variants in what gene?
2. lab values

A
  1. NR0B1 gene (aka DAX1)
    located on the X chromosome
    results in failure of fetal adrenal cortical development and deficiency in adrenocortical steroids.
  2. Deficiency in aldosterone and cortisol results. All adrenocortical steroids are deficient or low, even after cosyntropin stim test
39
Q

classic/nonclassic congenital adrenal hyperplasia
1. enzyme affected
2. labs?
3. due to pathogenic variants in what gene?
4. clinical presentation (classic vs nonclassic)
5. treatment/monitoring

A
  1. 21 hydroxylase
  2. elevated 17 hydroxyprogesterone
  3. CYP21A2
  4. classic - saltwasting (some) and simple virilizing
    nonclassic - no cortisol deficiency; hyperandrogenism later in life
    -females - genital ambiguity. Males may present with FTT and dehydration
  5. monitor tx with 17OHP (in kids), clinically in adults. Also androstenedione and PRA (nl range for age and sex). If untreated –> rapid postnatal growth and sexual precocity
40
Q

11 beta hydroxylase deficiency
1. labs?
2. due to pathogenic variants in what gene?
3. clinical presentation
4. treatment/monitoring

A
  1. increased 11-deoxycortisol, deoxycorticosterone, adrenal androgens
    - decreased cortisol, corticosterone
  2. CYP11B1 deficiency
  3. 2/3 with early onset HTN, hypokalemia d/t excess mineralocorticoid –> suppression RAAS (decreased PRA and aldosterone)
    also androgen excess
    females with genital ambiguity
  4. goal of treatment is to reduce mineralocorticoid and adrenal androgen synthesis –> glucocorticoids, spironolactone, correct hypoK
41
Q

3 beta hydroxysteroid dehydrogenase deficiency
1. labs?
2. due to pathogenic variants in what gene?
3. clinical presentation
4. testing with cosyntropin

A
  1. high 17-hydroxy pregnenolone, pregnenolone, DHEAS. Aldosterone and cortisol synthesis are impaired
  2. HSD3B2 gene
  3. salt-wasting with hypotension, hyponatremia, hyperkalemia, ambiguous genitalia
  4. for NONCLASSIC 3BHSD deficiency (which is extremely rare), 17-pregnenolone should be > 5000 ng/dl after cosyntropin
42
Q

Ki67 proliferation index
1. significance of this?
2. percentages for low-grade and high-grade tumors?

A
  1. determines tumor grade
  2. < 10% for low; greater than 10% for high
43
Q

Diagnostic approach for pheochromocytoma

tx prior to sx?

A
  1. confirm clinically/biochemially. Legit pheos have metanephrine/normetanephrine levels that are 4 times or higher than the ULN.
  2. obtain imaging: CT abdomen for adrenal pheos or PGLs. On unenhanced CT (> 10 HU, poor delayed contrast washout) or MRI (hyperintensity on T2, NO loss of signal on out-of-phase sequences).

tx prior to surgery: alpha block, salt load for +orthostatic HOTN, BB

44
Q

Post-op management of adrenal Cushing syndrome

A

long duration taper (wks to months) of supplemental glucocorticoid therapy
NO mineralocorticoid needed since aldo production is regulated by angiotensin II and potassium in addition to ACTH

post-op, pt will develop SECONDARY AI d/t low ACTH and low cortisol

45
Q

What are the goals of MR antagonist therapy in primary aldosteronism (3)?
MOA?

A
  1. normalize BP to < 138/80
  2. K > 4.0 mEq/L
  3. nonsuppressed renin

MOA - blocks MR in the principal cell of the distal nephron –> decreased Na reabsorption by epithelial sodium channels –> decreased potassium excretion –> intravascular volume contraction –> relative renal hypoperfusion –> increase renin secretion (becomes UNsuppressed)

46
Q

Most common culprit medications that result in a false-negative screen for primary aldosteronism

A
  • spironolactine and eplerenone (MOA mineralocorticoid receptor antagonists)
  • amiloride and triamterene (epithelial sodium channel inhibitors)

stop these meds for at least 3 weeks prior to screening

47
Q

What are the 2 indications for adrenal biopsy?

A
  1. confirmation of an extra-adrenal metastasis to determine staging and consequent management
  2. confirmation of an invasive infectious infiltration of the adrenal glands.

both can be either unilteral or bilateral

48
Q

DDX of bilateral adrenal abnormalities

A
  1. Bilateral adrenal macronodular hyperplasia (BMAH)
    - germline mutation in ARMC5
    - cortisol excess (may be subtle)
    - positive for finding on adrenal CT
  2. Primary pigmented nodular adrenal hyperplasia (PPNAD)
    - small adrenal nodules, not typically seen on imaging (as opposed to BMAH) - rather, string of beads is seen
  3. Carney complex
    - PPNAD present
49
Q

How to interpret adrenal vein sampling? (3)
Selectivity indices?
Lateralization index?

A
  1. Does the patient have primary aldosteronism?
  2. Are the catheters located in the adrenal veins? Selectivity index = “adrenal vein” cortisol/peripheral vein cortisol
    Selectivity index >2 without cosyntropin
    Selectivity index >3 with cosyntropin
  3. What is the ratio of aldosterone/cortisol ratios?
    Lateralization index >4 (very stringent)
50
Q

The recommended functional evaluation of an incidentally discovered adrenal mass includes? (3)

A
  1. measurement of plasma or urinary metanephrines to exclude pheochromocytoma
  2. overnight dexamethasone suppression test to exclude hypercortisolemia
  3. measurement of plasma renin and serum aldosterone to exclude primary aldosteronism (only in hypertensive patients)
51
Q
  1. Overt, clinically manifested excess of more than one active steroid, such as glucocorticoid and androgen excess, is characteristic of?
  2. Adrenal carcinomas tend to be relatively deficient in?
A
  1. adrenal cancer

2. 11 beta-hydroxylase activity –> elevated 11-deoxycortisol and upstream intermediates

52
Q

the elevation of DHEA-S in parallel to testosterone and the 11-deoxycortisol elevation is almost pathognomonic for?

A

adrenocortical carcinoma

53
Q

Macronodular adrenocortical hyperplasia:

  1. typical manifestation?
  2. DHEA-S is typically?
A
  1. pure cortisol excess. Mineralocorticoid excess is due to cortisol and parallels cortisol production
  2. normal (rather than suppressed)
54
Q

In ovarian hyperthecosis:

  1. typical timeline?
  2. How are testosterone and DHEAS levels affected?
A
  1. onset is more insidious than adrenocortical carcinoma.

2. Testosterone levels are not as elevated as ACC. More importantly, DHEA-S is usually not significantly elevated

55
Q
  1. In primary hyperaldosteronism, effective MR antagonist therapy should result in?
  2. biomarkers suggestive of adequate renal MR blockade in primary aldosteronism include?
A
  1. contract intravascular volume to lower blood pressure, decrease glomerular hyperfiltration, and minimize urinary potassium excretion
  2. decreased blood pressure, increased serum potassium, increased renin activity from suppressed to unsuppressed, and decreased estimated glomerular filtration rate
56
Q

What is the best parameter for diagnosing nonclassic 3beta-hydroxysteroid dehydrogenase/isomerase deficiency?

A

17-hydoxypregnenolone-to-cortisol ratio

57
Q

primary aldosteronism:

  1. for aldosterone-to-renin ratio, what is a clearly positive screen?
  2. what is a normal screen?
A
  1. > 20
  2. < 4
  • when the renin level is low (<1), the aldosterone-to-renin ratio is generally valid
  • prior to screening, it is important to correct for hypOkalemia since low K impairs aldosterone production
58
Q

Congenital Adrenal Hyperplasia:
What is elevated in 17 alpha-hydroxylase deficiency?
Gene?

A

High mineralocorticoids. Deficient androstenedione and estradiol.
CYP17A1

59
Q

Congenital Adrenal Hyperplasia:
What is elevated in 11 beta-hydroxylase deficiency?
Gene?

A

High 11-deoxycortisol and 11-deoxycorticosterone

CYP11B1

60
Q

Congenital Adrenal Hyperplasia:
What is LOW in 3 beta-hydroxysteroid dehydrogenase deficiency?
Gene?

A

LOW cortisol, aldosterone, androstenedione (all layers).

HSD3B2

61
Q

Congenital Adrenal Hyperplasia:
What is elevated in 21 hydroxylase deficiency?
Gene?

A

High 17 alpha-hydroxyprogesterone.

CYP21A2

62
Q

Distinguishing between an ACTH-secreting pituitary adenoma vs an ectopic source of ACTH (i.e., a neuroendocrine tumor) can be done with?

A

high (8 mg) dose dex suppression test
- suppression increases the likelihood of an ACTH-secreting pituitary adenoma, since ACTH-secreting pituitary adenomas usually express glucocorticoid receptors and can therefore suppress

63
Q

Patient presents in adrenal crisis with no previous dx of AI. What diagnostic test do you perform?

A

ACTH and cortisol
(so you can determine whether AI is primary vs secondary)

Endocrinology (8 decks)

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