Endocrine- Adrenal Disorders

Front 1

What are some physical features of a Cushing's patient?

Back 1

- central obesity, thin legs
- facial plethora + cheek redness
- spontaneous ecchymoses
- moon facies, supraclavicular fat pads
- hirsutism
- buffalo hump (extra fat deposit)
- wide purple striae

*proximal muscle weakness!

Front 2

Why do patients with CS (Cushing's syndrome) present with "central" obesity?

What about hypokalemic acidosis?

Back 2

GC stimulates adipogenesis. Central obesity- skinny legs (muscle atrophy). Also conversion of cortisone to cortisol in omental fat (via HSD-1)

HSD-2 is overridden by large amounts of cortisol. So it binds aldosterone receptors and increase K+ excretion.

Front 3

Why do patients with CS have plethora/ecchymoses/ striae?

What about Hirsutism?

Back 3

Catabolic effects of GC

1. Inhibit epidermal cell division (atrophy)
2. DECREASE collagen synthesis

Hirsutism- increased adrenal androgens

Front 4

What does CS do to the thyroid axis?

What is the reason for osteoporosis and muscle weakness in these patients?

Back 4

Suppresses thyroid access.

Osteoporosis- cortisol inhibits osteoblast. It also decrease intestinal Ca2+ absorption and increased renal excretion of Ca2+ causing a negative calcium balance so PTH goes into overdrive.Muscle weeakness from decreased protein synthesis (saves AA for gluconeogenesis)

Front 5

What 3 tests are used when you suspect Cushing's Syndrome?

Briefly describe.

Back 5

Suspected Cushing:

1) 1mg Dex suppresion test (DST): dex at night will decrease ACTH levels (feedback), if cortisol is still high in the morning be suspicious.

2) Urine free cortisol: measure plasma free cortisol, not affected by CBG, need acurate 24hr urine collection. Value must be 4x above normal limit.

3) Late night salivary control: cortisol in saliva is correlated with plasma free cortisol. Take midnight sample (when cortisol is normally suppressed). Loss of circadian rhythm in CS pts (just high all the time, rather than peak and nadir).

Front 6

To determine the cause of Cushing's syndrome, what blood level would you look for?

What would you expect in a ACTH independent disease vs. and ACTH-dependent disease?

Back 6

ACTH

ACTH independent= something is wrong with the adernals, get a CT! (adenoma, carcinoma, etc.)

If ACTH is detectable or slighlty elevated, suspect ACTH-dependent disease (ectopic ACTH, pituitary disease-Cushings)

Front 7

Which of the three tests for Cushing's syndrome is the most Sensitive? Which is the most Specific?

Back 7

Sensitive (pick out true positives): Dex Suppression

Specific (pick out people who aren't sick): Urine Free Cortisol

Front 8

Why is dexamethosone used for suppression tests rather than other steroids?

Back 8

1. most potent GC
2. it is not measured in the assay for bound cortisol (so it decreases noise, whereas prednisone and other's don't)

Front 9

Which is a more common cause of Cushing's: ACTH-dependent or independent diseases?

Back 9

ACTH dependent is more common (82% of all CS cases)

ex: ectopic ACTH (tumor in lung), Cushing's disease (pituitary dependent)

Front 10

What type of disorder is PPNAD?

What are some other disorders in this category?

Back 10

Primary pigmented nodular adrenocortical disease (PPNAD). Multiple, pigmented, autonomously functioning nodules.

It is a bilateral adrenal disorder (causing CS- i.e. ACTH independent). Another disorder in this category= McCune Albright, AIMAH

Front 11

What is the "Carney complex"? Why is it relevant to CS?

Back 11

It is an auto dominant disorder characterized by multiple neoplasias.

50% of PPNAD have Carney syndrome.

Other features: atrial myxomas, spotty skin pigmentation, schwannomas, testicular tumor, GH secreting tumor (acromegaly)

Front 12

What is the defect in McCune-Albright syndrome?

What signs and symptoms can result?

Back 12

Activating mutation of G-protein subunit -->constitutive steroidogenesis (i.e. endocrine hyperfunction)

"triad"
- sexual precocity *most common sxs.
- skin pigment ("Coast of Maine", jagged + respect midline)
- fibrous dysplasia

Front 13

What would the abdominal CT of a patient with AIMAH (ACTH-independent macronodular adrenal hyperplasia) look like? Why?

Back 13

Enlarged, bilateral nodules on the adrenal glands

Aberrant expression of hormone receptors on cells that secrete GC (receptors for other hormones like HCG-LH, catecholamines, etc.)

*not susceptible to negative feedback from cortisol

Front 14

What is Pseudo-Cushing's syndrome and what test is most useful in distinguishing it from true CS?

Back 14

Some or all of clinical features of CS with some evidence of hypercortisolism but not true CS.

Ex: alcoholism, depression, eating disorder, chronic pain all will elevate levels of cortisol due to activation of HPA axis via CRH activation. Not an ACTUAL PROBLEM with HPA axis.

Distinguish using 24-hr Urine sample- levels >4x upper limit of normal = true CS. Pseudo has only slight elevation

Front 15

What are the PITUITARY ACTH and cortisol levels if measured in a patient with:

1. ACTH secreting pituitary adenoma
2. Ectopic ACTH syndrome

Back 15

1. Adenoma- increased ACTH (not subject to neg feedback) and increased cortisol

2. Ectopic- pituitary ACTH levels are low (neg feedback from cortisol), but ectopic tissue continues to produce ACTH which stimulates cortisol production

Front 16

How does one distinguish the causes of ACTH-DEPENDENT Cushing's Syndrome?

Hint: 2 tests

Back 16

1. High Dose Dex suppression test (HDDST)-
2. CRH stimulation test

1. If pit adenoma, high dose Dex will slightly suppress ACTH secretion VS. If ectopic ACTH, high dose Dex WILL NOT suppress ACTH secretion

2. Pit adenoma is still responsive to CRH (levels should rise with CRH stim test). Ectopic ACTH is not (levels don't change much).

Front 17

What test, other than the CRH and High-dose dex suppression test helps determine if the pituitary is the source of ACTH?

Back 17

Inferior Petrosal Sinus Sampling

Take blood from Inferior petrosal sinus and from peripheral vein (internal jugular). There should be a gradient of ACTH levels (more at sinus than peripheral vein).

Front 18

What is the first-line treatment for CS due to an ACTH-secreting pit adenoma?

What are alternatives if this isn't curative?

Back 18

1. Surgery

if not curative:
- pit irradiation (can cause other hormone axis deficiencies)
- Antiadrenal agents (inhibit enzyme in steroid biosynth pathway)
- bilateral adrenalectomy

Front 19

What is a drawback of bilateral adrenalectomies?

What is Nelson's syndrome?

Back 19

- patients need lifelong GC and MC replacement

Nelson's syndrome- aggressive growth of remaining ACTH-pit adenoma because of lack of feedback. Also hyperpigmentation (occurs in adrenal insufficiency)

Front 20

What is the difference between the management of CS due to a cortisol-secreting adrenal ADENOMA and an adrenal CARCINOMA?

Back 20

Adenoma- surgery is curative
Carcinoma- surgery is primary treatment but usually not curative.

*for carcinoma- also use antiadrenal agents (ex: Mitotane- cousin of DDT, severe side effects- GI, neurologic)

Front 21

How do you manage CS due to an ectopic ACTH?

Back 21

1st- imaging, cat scan, abdomen, chest, etc. to find source of tumor

2nd- surgery, chemo to treat tumor

3rd- antiadrenal agents and bilateral adrenectomy if not curative

Front 22

What is primary aldosteronism?

What symptoms do patients with this condition present with? What is their renin level?

Back 22

Increased aldosterone secretion (adenoma or idiopathic- not dependent on renin)

- Patients present with Hypertension (Na+ retention)
- Hypokalemia (K+ secretion)- only in some!

Suppressed Renin level (negative feedback)

Front 23

What are symptoms of Hypokalemia?

When should you consider Primary Aldosteronism (PA) in patients?

Back 23

Hypokalemia- arrhythmia, fatigue, headache, muscle weakness, cramping

Consider in patients with difficult to control HTN, early onset HTN, or HTN with adrenal incidentaloma

Front 24

What are common causes of PA?

Back 24

Bilateral adrenal hyperplasia (60%)
Aldosterone-producing adenoma (35%)

Front 25

What is the defect in Glucocorticoid-remediable aldosteronism (GRA)?

Back 25

Auto dominant disorder
ACTH responsive 11B-OH gene is fused to aldosterone synthase.

So aldosterone control is under ACTH (in zona fascicula).

Front 26

How do you screen for PA? What must you tell patients on medications?

What Confirmatory testing can be done in patients who screen positive?

Back 26

Measure Aldosterone/plasma renin ratio. If pt is on aldosterone antagonist, diuretic, ACE inhibitor, AII-receptor blocker, etc. they must stop for 6 wks.

Confimatory test= salt loading and measure aldosterone. Lack of aldo suppression after salt loading = problem
(oral salt- measure urine aldo, IV saline- measure plasma aldo)

Front 27

Once you have confirmed primary aldosteronism, what is the next step?

How does age play a role in this next step?

Back 27

Adrenal CT must be done
1. If normal adrenals and b/l abnormalities or Age >40, do further testing (adrenal vein sample) -- age >40 may have non pathologic adrenal nodules

2. If adrenal CT shows unilateral nodule >1cm and pt <40, need to remove via adrenalectomy

*imaging correlates with dx in <50% of pts

Front 28

What is the treatment for a patient with PA bilateral abnormalities (nodules <1cm) with no lateralization on CT?

What about a patient with unilateral hyperplasia or a single adrenal adenoma?

Back 28

1. Medical treatment (Mineralocorticoid Antagonists)- Spironolactone

2. Surgery (unilateral= laproscopic, results in improvement and eukalemia restoration)

Front 29

What side effects make spironolactone less desirable to males? What could you prescribe instead and why?

Back 29

Spironolactone block MR receptor AND androgen receptor (gynecomastia, decreased libido, erectile dysfunction can result)

- Eplerenone acts on MR receptor more specifically but is $$$

Front 30

How does a patient who has PA and Glucocorticoid-Remediable Aldosteronism get treated?

What are they at risk for?

Back 30

1. Dex (low dose) at bedtime. It will suppress ACTH secretion.
2. MR receptor agonist as well.

At risk for HPA axis suppression and 2ndary adrenal insufficiency.

Front 31

What is the difference between primary aldosteronism and mineralocorticoid hypertension?

Back 31

In MR hypertention both aldosterone and renin are low.

Can be genetic or acquired

Front 32

How do the following syndromes result in Mineralocorticoid hypertension (say whether they are genetic, congenital, or acquired):

-Liddle's syndrome
-Syndrome of apparent MR excess
-Glucocorticoid resistance

Back 32

- Liddle's: genetic AD disorder of Na channel in distal kidney, Na+ reabsorbed and K+ secreted in absence of aldo

- Syndrome of apparent MR excess: genetic AR deficiency of HSD-2 so cortisol not inactivated and binds to MR increasing activity

- GC-resistance: AR defect in GC-receptor causing increase in ACTH and cortisol which overwhelms HSD-2 and cortisol binds to MR. No evidence of Cushings (no receptor binding due to defect)

Front 33

How is CAH a cause of mineralocorticoid hypertension?

What is the difference between 11-OH deficiency CAH and 17a-OH deficiency?

Back 33

AR enzyme defect causes accumulation of cortisol precursor DOC that has mineralocorticoid receptor activity.

17a-OH earlier in pathway, no androgen conversion, females have delayed puberty. Males- phenotypic female.

11-OH deficiency- later in pathway, conversion of precursor to androgens. Virilized female, precocious puberty in male.

Front 34

What are 2 acquired forms of MR hypertension?

Back 34

1. Cushing's syndrome (Ectopic ACTH, more cortisol, HSD-2 overwhelmed, cortisol binds MR)

2. Chronic licorice ingestion (blocks HSD-2 so cortisol not inactivated)

Front 35

What is a pheochromocytoma? How does this differ from a Paraganglioma?

Back 35

Catecholamine producing tumor

Pheo= 80-85%- adrenal pheo
Paraganglioma= 15-20% extra-adrenal pheo

Front 36

What are classic signs and symptoms of Pheos?

Back 36

"Classic triad"= Headache, Palpitations, Sweating

- Spells/Paroxysms can result (15 min - hrs)
- BP effects vary (sometimes hypertension, sometimes hypo, etc.)
-Pallor (due to vasoconstriction)
- Hyperglycemic (because Catecholamines suppress insulin)

Front 37

What is the defect in MEN Type 2?

How does Type 2A differ from Type 2B?

Back 37

RET proto-oncogene AD mutation: RET is a tyrosine kinase, mutation causes ligan-independent activation

Type2A: medullary thyroid CA, pheo, hyperparathyroid

Type 2B: medullary thyroid CA, pheo, MUCOSAL neuroma, MARFANOID

Front 38

What is the defect in VHL syndrome?

What about Neurofibromatosis?

Back 38

1. AD disorder- VHL tumor suppressor mutation- can't degrade HIP- increases VEGF and growth factors. Pts with hemangiomas, pheos, renal-cell cysts and CA.

2. NF1- also tumor suppressor gene mutation, neurofibromin usually turns off ras. now ras constitutively active- multiple fibromas, cafe au lait, freckling, pheos <5%

Front 39

How does Familial paraganglioma present?

Why is important to know the location of the tumor in these individuals?

Back 39

AD disorder, extra-adrenal pheos. Mutations in subunits of succinate dehydrogenase (mitochondria- tumor suppressor). Pts have pheos as well as paragangliomas, other tumors also

SDHD subunit- typically head and neck tumors
SDHB subunit- typically abdomen, pelvis, mediastinum tumors
*helps determine which mutation to look for

Front 40

What two genetic mutations do we want to look at when someone comes in with bilateral adrenal pheos?

Back 40

MEN-type 2
VHL

Front 41

What is the definition of Resistant hypertension?

Back 41

The patient is on 3+ drugs to treat it (including diuretic) and is still symptomatic

Front 42

What two metabolites of catecholamines are typically checked when suspecting pheos?

What is the biochemical test for Pheo?

Back 42

Metanephrine and Normetanephrine

1. 24hr urine collection- high sensitivity and specificity
2. Plasma metanephrines- continuously released (very good sensitivity but lots of false positives).

*confirm screening of plasma mets with 24hr urine (more specific)

Front 43

Why is it not recommended that a patient on antipsychotics or on tri-cyclic antidepressents undergoes pheo testing?

Back 43

They interfere with catecholamines and raise met levels. Ask pt to stop meds for 2 weeks.

Front 44

What is the Clonidine suppresion tests and the Glucagon stimulation test used for?

Which is more fatal?

Back 44

1. Clonidine suppresses catecholamines. Failure to suppress = pheo

2. Glucagon stimulates NE levels to rise 3x. Not recommended, test can be fatal.

Front 45

T or F

Do not perform imaging studies unless there is "compelling" biochemistry

Back 45

True!

Can do CT or MRI (safer but more costly)

Front 46

What is the characteristic finding on MRI that indicates a Pheo?

How does the MIBG test for pheo work?

Back 46

Light bulb sign (bright on T2-weighted MRI)

- MIBG looks like NE and is uptaken by catecholamine tumors. Can be visualized and tell us size of tumor.

*other tests= Octreotide scan, PET

Front 47

Preoperative management of a Pheo patient undergoing removal is...

Back 47

1. Alpha blockade (ex: Phenoxybenzamine- inhibition of alpha adrenergic receptors)- risk of hypotension, syncope!

2. Beta blocker (propranolol, atenolol, yo-mama lol)

Front 48

Why do you always give Alpha-blockade BEFORE Beta-blockade?

Back 48

Alpha- vasoconstrictive
Beta- vasodilation

If beta before alpha, you can get unopposed alpha-adrenergic vasocontriction causing hypertensive crisis.

Front 49

What is Labetolol?

What is Metyrosine and how does it work?

Back 49

Labetolol- combined alpha and beta blocker

Metyrosine (tyrosine hydroxylase inhibitor- blocks rate limiting step of catecholamine synthesis)

Front 50

Why do you salt load patients preoperatively before a removal of their Pheochromocytoma?

What type of surgery has lowest associated mortality?

Back 50

Salt load to reduce hypotension from phenoxybenzamine (drug) + post operative hypotension (due to dec. catecholamine)

Laproscopic

Front 51

What post surgical risks are of concern in patients undergoing Pheochromocytoma surgery?

Back 51

Risk of hypotension (phenoxybenzamine still active- alpha blockade). Reduce risk with salt loading!

Risk of hypoglycemia (insulin levels rebound)

Front 52

What are the manifestations of MEN Type 1?

Back 52

MEN1 codes for tumor suppressor protein

Three P's
- hyperParathyroidism
-Pituitary adenoma
- Pancreatic Neuroendocrine tumor (Gastinoma, insulinoma, nonfunctional= 3 most common)

Front 53

What is Carcinoid Syndrome?

Back 53

Tumor secretes vasoactive peptides (histamine, kinins) and serotonin

-flushing
-diarrhea
- wheezing

Test= 24 hr urine excretion of 5-IAHH (for iodine)

Front 54

What do patients with an Insulinoma present with?

What is the clinical presentation of patients with a VIPoma that secretes VIP?

Back 54

Insulinoma- too much insulin so HYPOglycemic

Vaso active intestinal peptide --> "WDHA syndrome"
- watery diarrhea (gastric motility)
- hypokalemia (K secretion into bowel)
- achlorhydria (inhibit HCL secretion)

Front 55

What are the signs of a glucagonoma? What about a somatostatinoma?

What is the appropriate testing in these patients?

Back 55

Functional NET secreting glucagon- necrolytic migratory erythema, HYPER glycemia,.

Somatostatinoma: diabetes (inhibits insulin secretion), gallbladder disease (inhibits gallblader motility), Diarrhea

*Get glucagon and somatostatin levels.

Front 56

What is Zollinger-Ellison syndrome?

What test do you do for this?

Back 56

1. Abdominal pain- peptic ulcer disese of Gastroesophageal reflux
2. Diarrhea

Gastrinoma (gastrin stimulates HCL secretion)

Testing= Secretin test- (secretin controls levels of gastric acid)
normal: Gastrin decrease. Gastrinoma: Gastrin increases

Front 57

Why do patients have hyperpigmentation in primary Adrenal Insufficiency (AI)?

Back 57

ACTH able to bind to melanocortin receptor in melanocytes and stimulate melanin synthesis (MCR-1) . Remember common precursor POMC.

* typically on mucosal surface, sun-exposed, places with friction/pressure

Front 58

What is the most common cause of Primary AI in the USA?

What about worldwide?

Back 58

US: Autoimmune adrenalitis

Worldwide: Infectious (tuberculosis- developed countries)

Front 59

What test looks for adrenal antibodies when suspecting autoimmune adrenalitis? Will you always find them?

Back 59

Test for 21-hydroxylase antibody

75% of time adrenal antibodies are present in these cases

Front 60

What is the classic presentation of Polyglandular Autoimmune Syndrome Type 1?

What is the defect in this case?

Back 60

AR Mutation in AIRE (autoimmune regulator)

Triad= Mucocutanoues Candidiasis, AI hypoparathyroidism, Addison's disease

*also occurs in INFANCY (unlike Type 2)- can get ectodermal dysplasia as well

Front 61

What is the classic presentation of Polyglandular Autoimmune Syndrome Type 2?

What is the defect in this case?

Back 61

Antibodies against many different things- HLA related

onset in ADULTHOOD. multiple endocrine systems affected (thyroiditis, graves, myasthenia gravis, celiac, Addison's disease, etc.)

Front 62

What is Waterhouse Friedrichson syndrome?

What are clues of adrenal hemorrhage?

Back 62

Syndrome occurs in septic patients (usually N. meningitidis)- causes adrenal hemorrhage.

- hypotension/shock
- abdominal/flank pain
- Fever

Front 63

What are some drugs that interfere with cortisol biosynthesis and cause Primary AI?

What is the problem in adrenoleukodystrophy?

Back 63

Ketoconazole (antifungal)
Metyrapone
Suramin (antiparasitic)

ALD- mutation in ABCD1 gene (x linked)- defective oxidation of fatty acids in peroxisomes. VLCFA build up in cell membrane, cause neurological problems and adrenal insufficiency.

Front 64

What is the mutation in Adrenal hypoplasia congenita?

Back 64

DAX-1 (X linked)- nuclear receptor of unknown significance

Expressed in adrenal cortex, gonads, hypothal. Can present with CAH and hypogonadotrophic hypogonadism.

Front 65

Why do patients with Familial glucocorticoid deficiency have intact mineralocorticoid function?

How do these patients typically present and at what age?

Back 65

They have MCR-2 mutation (ACTH receptor) so unresponsive to ACTH but Renin/Angiotensin is ok and MR respond to that.

Patients present in childhood:
- neonatal hypoglycemia (low cortisol, high insulin)
- hyperpigmentation (high ACTH- bind to MCR-1)
- enhanced growth velocity

Front 66

What is the most common cause of secondary adrenal insufficiency?

What is the treatment?

Back 66

Exogenous GCs that are abruptly stopped (there is downregulation of HPA axis and it takes a while for it to recover. Do not abruptly stop!)

Treatment = cortisol

Front 67

What are some examples of Hypothalamic/Pituitary diseases that can result in Secondary AI?

Back 67

1. Tumors (adenomas, other CNS tumors)
2. Hemorrhage or Pituitary apoplexy (WHOL and visual changes)
3. Pit infarct (Sheehan's)
4. Infiltrative disease (Langerhan's histocytosis, Sarcoidosis)
5. Hemochromatosis (excessive iron deposition in tissue)

Front 68

What is Sheehan's syndrome?

Back 68

Sheehan's syndrome- pregnant women have enlarged pituitary glands due to increased metabolic demands. prone to any form of hypotension.

Hypotension can cause vasospasm of arteries and also cause decrease flow to anterior pit.

Front 69

In a patient who sustains traumatic brain injury, what syndrome can likely occur- Hyper or Hypo pit?

What will they most commonly present with?

Back 69

Hypopit (direct mechanical injury to hypothalamus)

GH deficiency is most common presentation in TBI

Front 70

What would you suspect ACTH and cortisol levels to be in a patient with:

- Primary AI
- Secondary AI

Back 70

Primary AI= problem with gland itself, low cortisol, high ACTH

Secondary AI= problem with H-P, low ACTH, low cortisol

Front 71

What is the Cortrosyn stimulation test?

Will all patients with Secondary AI have subnormal cortisol responses?

Back 71

CST = ACTH analogue
Injection should increase cortisol production. Cortisol measured and if <18, likely primary AI.

2ndary AI= If chronic problem, then zona fasciculata cells, which lack ACTH stimulation will shut down. However not ALL patients with Secondary AI will have low cortisol responses- downregulation process takes time!

Front 72

If CST is normal but you suspect secondary Adrenal insufficiency, what two tests would you conduct?

Back 72

1. Insulin tolerance (insulin causes hypoglycemic stress, check to see if cortisol levels have risen.

Contraindications for sz, cardiovasc disease, elderly pts.

2. Metyrapone test (blocks 11-deoxycortisol --> cortisol). Lack of cortisol should stimulate ACTH increase. But in hypopit disorder, ACTH levels low (measure the 11-deoxy which correlates with ACTH levels).

Front 73

What is the treatment for primary and secondary AI?

What are commonly used drugs in this category?

Back 73

Administration of cortisol

Glucocorticoids: Prednisone (more potent), Hydrocortisone (some MR activity)

Mineralocorticoid: Fludrocortisone

Front 74

What times of the day should GC replacement be taken?

Do patients with Secondary AI need MR replacement?

Back 74

GC replacement should follow normal circadian rhythm (morning, afternoon)

No! Secondary AI MR function is ok because not under control of ACTH

Front 75

What should be done for a patient with AI who is acutely ill?

Back 75

They need to take an even greater dose of steroids aka stress dosing 2-4x normal (injectible, more pills, etc.)

*always wear a bracelet in case they go into adrenal crisis!

Front 76

What happens in Adrenal crisis?

What two things do you want to do to treat it?

Back 76

Sudden loss of HPA function, decreased blood pressure, fluids lost.

1. fluids (volume load)
2. steroids STAT

Front 77

Define the following terms often used in discussion of ambiguous genetalia:

- clitoromegaly
- microphallus
- bifid scrotum
- hypospadias
- chordee
- cryptorchidism
- UG sinus

Back 77

clitoromegaly: >1 cm
microphalus <2.5 cm
bifid scrotum: fused, but clefted, scrotum
hypospadias: urethral opening on ventral surface of phallus
chordee: ventral curvature of phallus
cryptorchidism: failure of testicular descent
UG sinus- common urethral/vaginal opening (abnormal in girls)

Front 78

What is the most common genetic defect in CAH cases? What is its inheritance pattern?

What is the fundamental pathophys defect in CAH?

Back 78

- 21-hydroxylase deficiency
- AR disorder

Cortisol synthesis decreases, lack of feeback causes ACTH and CRH increase

Front 79

What is the effect of 21-OH CAH in XX patients?

What about in XY?

Back 79

XX- prenatal virilization of girls (clitoromegaly)

XY- rapid growth and early epiphyseal fusion (in both XX and XY)- because estrogen levels increase

Front 80

What is the Prader staging used for?

Back 80

To stage ambiguous genetalia (from 1-5 more virilized).

Front 81

Why do females become virilized and have normal mullerian structures (fallopian tubes, uterus, cervix, 1/3 upper vagina)?

Back 81

They do not have a Y chromosome or SRY gene so no AMH synthesis.

*at 7 weeks they get exposed to high androgens and thus can have external genetalia virilization (some parents are told on ultrasound that they have a boy!)

Front 82

What are some signs of 21-OH deficiency in newborn boys (XY)?

Back 82

No ambiguity, more subtle!
- Scrotal hyperpigmentation
- macropenis

Front 83

What is a VCUG test used for?

Back 83

Urogenital sinus screening. Catheterize baby girl urethra and inject dye + take images.

Testosterone is needed to maintain a single UG sinus. The further up the connection between vagina and urethra, the more severe.

Front 84

What is the difference between classical and non-classical 21-OH deficiency?

Back 84

Classical=
A. salt wasting (60-70%)
B. simple virilizing (25%)

Non-classical: Late onset CAH

Front 85

Why is it that patients with simple virilizing CAH have normal Aldosterone whereas patients with salt-wasting CAH have decreased aldosterone?

Back 85

Simple-virilizing still have 1% 21-OH activity so there is enough to make a little aldosterone. Whereas the other patients have 0% wildtype 21-hydroxylase.

Front 86

Who gets diagnosed earlier: the patient with salt-wasting CAH or simple virilizing CAH?

Which is more common?

Back 86

Salt wasting- typically newborn-6 mo (more noticeable symptoms, virilization especially in males can be difficult to identify).

Salt wasting more common

Front 87

Which is more frequent Classic or Non-Classic CAH?

What are some signs and symptoms of Non-Classical CAH?

Back 87

Non-classic is more common (1:100 incidence instead of 1:12000)

Signs= premature pubic hair, acne, hirsutism, menstrual irregularity, infertility

Front 88

What is the key diagnostic maneuver to determine 21-OH deficiency?

What do you expect the results to be in Classic vs. Non-classic CAH?

Back 88

IV injection of ACTH and measure 17-OHP levels

In both cases it should be elevated but Classical (up to 100,000) > Non-Classical (1500-10,000)

Front 89

A young boy with hyponatremia, hyperkalemia, and metabolic acidosis comes to the ER.

What is his plasma renin activity like? What about his cortisol (in the setting of stress)?

Back 89

Classic triad for Salt-Wasting CAH (H+ is not secreted so it builds up --> acidosis)

Renin levels will be high because aldosterone is low. Cortisol will be low in the setting of stress (normally should be higher but he can't make cortisol)

Front 90

What would you expect if a boy with salt-wasting test was given an ACTH or Cortrosyn IV bolus test?

Back 90

ACTH should normally increase cortisol but in this case he would NOT mount a cortisol response.

Front 91

If a 5 year old boy with an enlarged penis and pubic hair came in to see you, how could you tell if he had precocious puberty or simple virilizing CAH?

What about if a 6 yr old girl came in with pubic hair and acne?

Back 91

5 year old boy- testes enlargement = central precocious puberty

6 yr old girl- breast enlargement= central precocious puberty

*remember breast development and testicular enlargement are the 1st signs of puberty

Front 92

For patients with suspected premature adrenarche what level would you want to check?

Back 92

morning 17-OHP

Front 93

What is the most common cause of irregular menses and hirsutism in women?

What is a differential diagnosis for this presentation?

Back 93

- PCOS (polycystic ovary syndrome) = most common

-differential= Non-classical CAH

Front 94

Where is the 21-hydroxylase gene located?

What types of gene mutations are associated with Salt wasting, Simple virilizing, and non-classical CAH?

Back 94

Located on short arm of Chromosome 6

1) deletion/non-sense = salt wasting
2) missense = simple virilizing
3) V281L and P30L mutations that produce enzymes with partial activity= non-classical CAH

Front 95

What is the treatment for Salt-wasting CAH?

What should you counsel the patient about in terms of if they get sick or a fever?

What levels should be monitored in these patients?

Back 95

Salt wasting- give cortisol (hydrocortisone or fludrocortisone, and NaCl tablet- salt load).

In high stress/sick situations 2x the maintenance dose. Levels: 17-OHP, androstenedione, testosterone

Front 96

What treatment options are available for 46XX girls with simple virilizing CAH?

Back 96

Corrective surgery- Vaginoplasty for urogenial sinus (separate vagina and urethra)- can be done early or in adolescence.

Controversial- clitoral reduction/recession (some say let child decide)