10/6- Diseases of the Anterior Pituitary 2 Flashcards Preview

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Flashcards in 10/6- Diseases of the Anterior Pituitary 2 Deck (56):
1

What does the HPA axis refer to?

Hypothalamo-pituitary-adrenal axis

2

Describe the HPA axis in terms of cortisol

- Hypothalamus CRH (corticotropin releasing hormone)

- Pituitary ACTH (adreno-corticotropic hormone)

- Adrenal cortisol

3

What is ACTH?

- Half life

- Source

- Other products

Adrenocorticotropin

- 39 AA peptide

- Plasma half life

- Derived from POMC (pro-opiomelanocortin)

Other POMC products:

- a-MSH

- B-MSH

- Lipotropins

- Etc 

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4

Cortisol is a glucocorticoid.

What are some synthetic glucocorticoids?

- Prednisone

- Methylprednisone

- Dexamethasone

5

What is Cushing's syndrome?

- Manifestation of glucocorticoid (cortisol) excess

- Multiple systems affected through the widespread effect of glucocorticoids on gene expression

  • Receptors present in every cell in the body

6

What is the basic model of steroid receptors?

- Conformation change

- Nuclear translocation

- Dimerization

- DNA binding 

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7

What are common signs/symptoms of Cushing's disease?

- Truncal obesity (96%)

- Moon facies (82%)

- Diabetes or IGT (80%)

- Gonadal dysfunction (74%)

- Hirsutism/acne (72%)

- Hypertension (68%)

- Muscle weakness/atrophy (64%)

- Skin atrophy and bruising (62%)

- Phenomenal striae (where there has been fat gained) Many others; most are non-specific

- None are pathognomonic

8

What is seen here, characteristic of Cushing's disease?

Q image thumb

- Cushingoid facies

- Round, red face (plethora)

9

What is seen here, characteristic of Cushing's disease? 

Q image thumb

- Truncal obesity with supraclavicular and dorsocervical fat pads

10

What is the characteristic body mass/distribution in Cushing's?

Central adiposity with peripheral muscle wasting

- Weight gain and fat redistribution

  • Increased appetite
  • Increased central fat deposition (deposition in the abdomen, dorsocervical and supraclavicular areas as well as retrorobital and face)

- Muscle wasting and weakness catabolic

  • Degradation of proteins

11

What are skin changes in Cushing's?

Skin atrophy

Ecchymoses

- Catabolism of proteins making up underlying subcutaneous connective tissue

- Leads to fragility and easy bruising (thin skin and fragile blood vessels)

Striae (> 1 cm in width)

- Caused by weight gain

- Violacious color due to thinning of subcutaneous layers of the skin (can see venous blood underneath)

Hyperpigmentation

- "Dusky"

- Light or trauma exposed areas: pro-opiomelanocortin, ACTH

Acanthosis

- Insulin resistance

- Diabetes mellitus 

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12

What glucose level changes are seen in Cushing's?

Elevated glucose

- Increased hepatic glucose output

  • More muscle AAs available as a substrate to make glucose (gluconeogenesis)

- Decreased glucose uptake into tissues (insulin resistance)

13

What affect does Cushing's syndrome have on the adrenals?

Hyperandrogenism

- Adrenal androgen synthesis is increased by ACTH

14

How does Cushing's cause hypertension?

Cortisol can activate the aldosterone receptor

- normally endogenous cortisol is inactivated by an enzyme in the kidney (11-b-hydroxy-dehydrogenase type 2). High levels of cortisol overwhelm the enzyme.

May be accompanied by

- hypokalemia

- hypernatremia

- metabolic alkalosis

Increased vascular reactivity to vasoconstrictors

15

What is seen in Cushing's in regards to gonadal function?

Gonadal dysfunction:

- Decreased sex hormone production

  • GnRH pulsatility affected
  • androgen feedback in women?

- Oligo- and amenorrhea Impotence/decreased libido

16

With glucocorticoid therapy, there is an increased fracture risk when?

- Due to what?

- How does this tie in with renal effects?

With glucocorticoid therapy, there is an increased fracture risk at 3 - 6 mo

- Increased bone resorption

  • Positive effects on osteoclast activity
  • Decreased gonadal hormones

- Decreased bone formation

  • Inhibit osteoblasts
  • Increased osteoblast apoptosis
  • Muscle weakness

Decreased intestinal Ca absorption

Increased renal Ca excretion

- increased calcium mobilization from bone

- direct effects on kidney

- nephrolithiasis

17

T/F: Cushing's syndrome involves increased infections

True

18

How does Cushing's syndrome cause increased infections?

Inhibition of inflammatory cytokines

- Decreased fever, signals to fight infection

Fungal/yeast, bacterial

Phagocytes

- Decreased neutrophil adhesion molecules so less accumulation at sites of infection

- Decreased macrophage phagocytosis

T cells

- Opportunistic infections (PCP, TB)

19

What are some psychiatric disorders seen in Cushing's syndrome?

Insomnia

- Lack of diurnal rhythm

Cognitive impairment

Depression

- Family history at higher risk

Emotional lability

Euphoria, hypomania

Psychosis

20

Long term glucocorticoid excess may cause what?

- Cataracts

- Glaucoma

- Gastritis and peptic ulcer disease

21

What is exogenous hypercortisolism/what causes it?

Medication induced CS

- Exogenous corticosteroids (glucocorticoids)

  • Iatrogenic: oral, IM, IA, inhaled, topical eye and skin
  • Megestrol acetate (Megace)

- Surreptitious glucocorticoid use (synthetic glucocorticoids in urine by HPLC/gas chromatography)

- "Herbal" medications

22

What can cause endogenous hypercortisolism (broad categories)?

ACTH- dependent

- Pituitary (65-75%)

- Ectopic (10-15%)

ACTH- independent

- Adrenal (15-20%)

23

Ectopic ACTH (and or CRH), what are the common tumor sources? Uncommon?

Neuroendocrine (common)

- Bronchial & thymic carcinoid

- Small cell lung cancer

- Medullary

- Thyroid Cancer

- Pheochromocytoma

- Pancreatic islet tumors

- Gastrinoma

Uncommon

- Neuroblastoma

- Breast

- Prostate

- Ovarian ca

24

What can produce ACTH independent Cushing's?

- Adrenal adenoma

- Adrenocortical carcinoma

- Macronodular hyperplasia

- Micronodular disease

  • Primary pigmented nodular adrenocortical disease (Carney complex)

25

T/F: Imaging should be one of the first things done to help diagnose with Cushing's.

False

- Pituitary adenomas are found in 10-20% of people; not conclusive

26

What are some tests for Cushing's (clinical features)?

Decreased feedback inhibition -> O/N 1 mg Dexamethasone (synthetic steroid) suppression test

- "Low dose DST"

- Problems include pt variation in: absorption, compliance, and clearance

Over production -> 24 hr urine free cortisol (1 to 3x)

- Cyclical Cushing's

- Cortisol in urine means it's spilled over its protein binder; have very high amounts

Lack of diurnal rhythm -> midnight serum cortisol

- (not low at midnight)

- Salivary

27

T/F: AM or random cortisol can be used if other tests are not available

False!

Unless extremely high, this really can't help; diurnal variation is too great

28

When is serum cortisol lowest?

Midnight

29

Describe the 2 day low dose dex suppression test

- 48 hrs of Dex (0.5 mg every 6 hrs) will suppress cortisol

- To "pass" test, cortisol should be

30

What is Pseudo-Cushing's?

- Symptoms

Depression

- Abnormal CRH secretion

- Abnormal Circadian rhythms -> hypercortisolism

Obesity

- Overnight DST positives

Alcohol

- Interference with metabolism and steroidogenic pathways (11B-HSD)

31

What test can be done to distinguish Cushing's and Pseudo-Cushing's?

Dexamethasone suppressed CRH stimulation test

- 48 hrs of Dex (0.5 mg q 6hrs) will suppress normally in most Pseudo-Cushing's pts so there is no stimulation by 100 ug of CRH IV

- A CD patient will still respond to CRH because of aberrant feedback inhibition

- Serum cortisol > 1.4 ng/dL

32

What do you think/do if:

- Hypercortisolism is confirmed

- Am ACTH is undetectable

- Low ACTH levels

Image adrenals

- Adrenal CT (4 mm)

33

What do you think/do if:

- Hypercortisolism is confirmed

- Am ACTH is > 20 pg/mL

- High ACTH levels

Image pituitary

- MRI pituitary protocol (Gad enhanced)

34

How to determine pituitary vs. ectopic ACTH?

ACTH dependent causes you to do MRI; possible results:

- > 5mm adenoma

  • Likely Cushing's disease
  • NSx referral

- > 5 mm adenoma

  • "Ectopic presentation"

- Normal or equivocal (under 5mm)

  • Further testing! 

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35

Treatment for Cushing's disease?

Transphenoidal resection

36

Next step for ectopic Cushing's?

Image thorax, neck, abdomen

37

Describe CRH stimulation

- Injection of 1 mcg/kg CRH (to max 100 mcg) at time 0

- Test ACTH and cortisol levels 0, 15, 30, 45, 60 minutes

- A variety of cutoffs in the literature

  • Human vs Ovine CRH
  • Depending on sensitivity and specificity
  • 50% rise in ACTH is often used with smaller responses by cortisol.

38

48 hours of Dex (2 mg every 6 hrs) will do what to cortisol? ACTH?

Suppress

- Cortisol to

- ACTH to

39

Cushing's disease confirmed if it ___ with CRH and ___ with high dose dexamethasone

Cushing's disease confirmed if it stimulates with CRH and suppresses with high dose dexamethasone

40

Ectopic Cushing's disease though if it ____ with CRH and ___ with high dose dexamethasone

Ectopic Cushing's disease though if it cannot be stimulated with CRH and does not suppress with high dose dexamethasone

41

What should you do if you get discordant results?

Cushing's/ectopic is unclear; IPSS (Inferior Petrosal Sinus Sampling) should be used

- Central ACTH: peripheral ACTH > 2 baseline or > 3 CRH stimulated

- Lateralization > 1.4 (left)

Pearl: a normal person may show similar ratios.... only useful in proven hypercortisolism where ACTH should be suppressed at the pituitary level

42

Pearl for MRI in diagnosis of Cushing's

Gad enhanced mRI is max 60% sensitive in identifying a pituitary adenoma in suspected CD

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43

What are treatment options for Cushing's disease?

Surgical removal

- Transsphenoidal

- Craniotomy for larger invasive tumors

Adrenalytic Rx

- Ketoconazole

- Metyrapone (available only on compassionate grounds)

- Aminoglutethamide (not available anymore in US)

- Mitotane (destroys adrenal tissue – adrenocortical carcinoma)

- NEW!!! Mifipristone (RU486) – glucocorticoid receptor antagonist

Radiation

- EBRT

- Gamma knife

Adrenalectomy

- Risk for Nelson's disease (radiation of sella first)

44

What is Nelson's disease?

- Uncontrolled growth of residual ACTH producing pituitary tumor due to lack of feedback by cortisol

- Hyperpigmentation

45

What can cause hypopituitarism?

Vascular:

- Peripartum hypoTN with infarction (Sheehan's)

- Pituitary apoplexy

Iatrogenic

- External beam radiation

Infectious/Inflammatory/Infiltrative:

- Granulomatous diseases (Sarcoidosis, eosinophilic)

- Langerhan's cell histiocytosis

- TB

- Fungal infections

- Hemachromatosis

Neoplastic

- Pituitary adenoma

- Craniopharyngiomas

- Metastastic carcinoma

- Meningiomas

- Germinomas

- Hematologic (leukemia, lymphoma infiltration)

Congential

- Mutations of pituitary developmental TFs

Autoimmune

- Lymphocytic hypophysitis

Trauma/surgery

- Car accident

- Craniotomy

- Transphenoidal resection of pituitary adenoma

46

What is pituitary apoplexy? Cause?

Hemorrhage into pituitary (often a lesion such as an adenoma that is already there)

- Acute, catastrophic (30% of "hemorrhagic" adenomas)

  • Headache (90%)
  • Visual disturbance (75%)
  • N/V (60%)

- Silent asymptomatic (70% of "hemorrhagic" adenomas)

  • Spontaneous "cures"
  • Empty sella
  • Cysts

47

Treatment for pituitary apoplexy?

- ICU Care

- IV fluids

- High dose IV corticosteroids – assume adrenal insufficiency

- Craniotomy and decompression of pituitary fossa (save vision!!!!)

- Post-op evaluation for pituitary hormone deficiencies (ITT) and appropriate hormone replacement.

48

What are endocrine manifestations of post-pituitary apoplexy?

(by percent deficiency)

1. GH (88% deficient)

2. H-P-Adrenal (66%)

3. Reproductive: sex steroids (85%), gonadotropins LH/FSH (58%)

4. H-P-thyroid (42%)

5. ADH- diabetes insipidus (3%, rare b/c lesion in anterior pituitary)

6. Prolactin (?%)

49

What are ways to assess pituitary hormone deficiencies: H-P-A axis

- Insulin Tolerance Test (ITT)

- ACTH stimulation test, cortisol levels

50

What are ways to assess pituitary hormone deficiencies: GH axis

- ITT

- GHRH-arginine stimulation

- Glucagon stimulation

51

What are ways to assess pituitary hormone deficiencies: H-P-G axis?

- LH, FSH

- Testosterone or estrogen

52

What are ways to assess pituitary hormone deficiencies: H-P-T axis?

- TSH

- T4

53

What are ways to assess pituitary hormone deficiencies: Prolactin

Prolactin

54

What is the insulin tolerance test (ITT) and how does it work?

Test for pituitary hormone deficiencies in the H-P-A axis

- Based on the counter-regulatory roles of insulin vs. cortisol and GH

- Need physician supervision and no history of seizure disorder

Run labs for:

- Cortisol

- GH

- (ACTH)

Give pt dextrose or PO orange juice 

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55

How should ITT be interpreted?

- Plasma glucose should be 35-45 mg/dL

- Cortisol should be > 18-22 mcg/dL

- (ACTH should be > 150)

- GH should be > 5.1 ng/mL (9 ng/mL)

Glucagon stimulation (3 hrs) and GH should be > 3 ng/mL

56

How should hormone replacement be managed for hypo-pituitary function?

- Adrenal: hydrocortisone divided doses (e.g. 20 mg in the morning, 10 mg in the afternoon)

- Thyroid: daily T4 replacement

- Gonadal

  • Testosterone (patch, gel, injection)
  • Estrogen/progesterone

- GH (case by case basis)

- Diabetes insipidus: DDAVP