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Endo > Adrenal Insufficiency & Cushing's Syndrome > Flashcards

Adrenal Insufficiency & Cushing's Syndrome Flashcards

1
Q

Adult adrenal glands

  • Weight
  • Location
  • Divisions
  • Vascularization
A
  • 4-5 g each
  • Retroperitoneum or medial to upper pole of kidneys
  • Adrenal Cortex
    • Zona glomerulosa (aldosterone)
    • Zona fasciculata/reticularis (cortisol & androgens)
  • Adrenal Weight
    • Cortex (90%)
    • Medulla (10%)
  • Highly vascularized
    • Inferior phrenic artery
    • Renal arteries
    • Aorta
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2
Q

How are the adrenal glands drained?

What are they vulnerable to?

A

R adrenal vein –> posterior aspect of vena cava

L adrenal vein –> L renal vein

venous thrombosis/non-traumatic hemorrhage

bilateral adrenal hemorrage

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3
Q

What is the hypothalamic-pituitary-adrenal axis?

How is it regulated?

A
  • Steroid production from zona fasciculata/reticularis controlled by ACTH
  • ACTH secretion regulated by hypothalamus & CNS
  • CRH stimulates ACTH in pulsatile manner
    • Peak –> decline throughout day
  • Cortisol exerts negative feedback on CRH/ACTH
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4
Q

___________ may stimulate ACTH secretion.

A
  • Stressors
  • Physical, emotional, chemical
  • Pain, trauma, hypoxia, hypoglycemia, surgery, cytokines, depression
  • Overriding glucocorticoid negative feedback & diurnal rhythm
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5
Q

How is adrenocorticotrophic hormone (ACTH) processed?

A
  • 39 aa peptide hormone
  • Processed from large precursor (POMC)
    • ACTH secreting cells in the pituitary gland corticotroph
  • Single gene + mRNA + prohormone convertase enzymes
    • Direct synthesis & processing of POMC
    • Small or biological fragments
  • Morning plasma levels of ACTH = 10-50 pg/ml
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6
Q

What is the role of alpha-MSH in ACTH genetic expression?

A
  • alpha-melanocyte secreting hormone
  • Increased skin pigmentation in patients w/ elevated ACTH
  • Example: primary adrenal insufficiency
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7
Q

What is the steroidogenic pathway of cortisol production?

A
  • Cholesterol –> Pregnenolone
    • P450scc
  • Pregnenolone –> Progesterone
    • 3β-HSD2
  • Progesterone –> 17-Hydroxyprogesterone
    • P450c17
  • 17-Hydroxyprogesterone –> 11-Deoxycortisol
    • P450c21
  • 11-Deoxycortisol –> Cortisol
    • P450c11
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8
Q

What is the steroidogenic pathway of mineralocorticoid synthesis?

A
  • Progesterone –> 11-Deoxycorticosterone
    • P450c21
  • 11-Deoxycorticosterone –> Corticosterone
    • P450c11
  • Corticosterone –> Aldosterone
    • P450c11AS
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9
Q

What is the steroidogenic pathway of adrenal androgen synthesis?

A
  • Pregnenolone –> 17-Hydroxypregnenolone
    • P450c17
  • 17-Hydroxypregnenolone –> DHEA
    • P450c17
  • DHEA –> DHEAS
    • SULT2A1
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10
Q

Bound cortisol is biologically (active/inactive).

Free cortisol is biologically (active/inactive).

A

Inactive

Active

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11
Q

How do you measure free cortisol?

A

Saliva

Hypothalamic-pituitary-adrenal axis

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12
Q

How and where is cortisol metabolized?

A
  • Cortisol binds to plasma proteins upon entering the circulation
  • CBG >> albumin
  • Hepatic metabolism
    • Metabolic conversions –> products excreted in the urine
    • Altered in chronic liver disease (decreases clearance)
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13
Q

What role do the kidneys play in cortisol metabolism?

What is the cortisol-cortisone shuttle?

A
  • Cortisol –> cortisone [11ß-HSD2]
    • Kidney
    • Protects mineralocorticoid receptor on the tubules of the distal nephron from the action of cortisol
    • Cortisol has the same affinity for the mineralocorticoid receptor as aldosterone
  • Cortisone –> cortisol [11ß-HSD1]
    • Liver & visceral fat
    • Redundant system helps protect against cortisol deficiency
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14
Q

What is the mechanism of action of cortisol?

A
  • Intracellular glucocorticoid receptor (GR)
  • Cortisol binds & activates GR
  • Dissociation of HSP from receptor
  • Dimerization
  • Cortisol-bound GR dimers translocate to the nucleus & activate GRE in DNA
    • Can also transrepress inflammatory genes
    • AP-1, NF-B
  • Enhanced transcription of glucocorticoid-related genes
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15
Q

High dose potent ____________ agents may occupy the glucocorticoid receptor.

What are 2 examples?

A
  • Progesterone
  • Megestrol acetate
    • Stimuluation of appetite in cancer patients
    • Suppression of ACTH & cortisol
  • Mifepristone
    • Treatment of endogenous hypercortisolism
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16
Q

What is adrenal insufficiency?

What is the difference between primary, secondary & tertiary adrenal insufficiency?

A
  • Inadequate production of cortisol from the adrenal cortex
  • Primary AI
    • Disease process in adrenal gland
    • Aldosterone absent
    • Plasma ACTH always elevated
  • Secondary AI
    • Disease of pituitary gland
    • Low cortisol
    • Low or inappropriately normal ACTH
  • Tertiary AI
    • Disease of hypothalamus
    • Low cortisol
    • Low or inappropriately normal ACTH
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17
Q

What are the signs & symptoms of adrenal insufficiency?

A
  • Fatigue, malaise, lack of energy
  • Nausea, vomiting, anorexia: weight loss
  • Hypotension: dizziness, orthostasis
  • Increased skin pigmentation, salt craving (primary)
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18
Q

____________ is the predominant lab abnormalitiy in adrenal insufficiency.

A

Hyponatremia

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19
Q

What are some examples of drugs that cause adrenal insufficiency?

A
  • Withdrawal from corticosteroids
    • Oral, inhaled, topical, parenteral
  • Narcotics
    • Suppress CRH, ACTH
    • Common cause of tertiary adrenal insufficiency
  • Adrenostatic/lytic
    • Ketoconazole, Etomidate, Mitotane
  • Glucocorticoid receptor antagonist
    • Mifepristone
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20
Q

What are some genetic causes of adrenal insufficiency?

A
  • Congenital Adrenal Hyperplasia
  • Adrenoleukodystrophy
    • X-linked disorder
    • LCFAs in adrenal glands & brain
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21
Q

What is the algorithm for management of adrenal insufficiency?

A

Know figure on page 18 of handout

22
Q

How are morning cortisol levels used to diagnose adrenal insufficiency?

A
  • Mean: 11-12 µg/dL
  • Normal: 6-18 µg/dL
  • Indicates adrenal insufficiency: <5 µg/dL
  • Excludes adrenal insufficiency: >14 µg/dL
23
Q

What do you do if morning cortisol levels are between 5-14 µg/dL?

A
  • Administer synthetic ACTH
    • **Cosyntropin 250 mcg **
  • Given following basal level
  • Followed by cortisol sampling at 30 and/or 60 min
  • Normal cortisol response to ACTH
    • >18 µg/dL
  • If peak cortisol response <18 µg/dL or basal morning cortisol <5 µg/dL, plasma ACTH should be measured to determine primary from secondary adrenal insufficiency
24
Q

How do plasma ACTH levels distinguish between primary & secondary adrenal insufficiency?

A
  • **Plasma ACTH is ALWAYS elevated in patients w/ primary adrenal insufficiency **
  • Plasma ACTH levels may be low or normal (inappropriately not increased) in patients w/ secondary adrenal insufficiency
25
Q

Patients receiving medications (estrogen,oral contraceptives) will have significant increase in _______ rather than alteration of adrenal function.

26
Q

Measurement of adrenal _________ production is a sensitive marker of adrenal reserve.

A

androgen (DHEAS)

27
Q

What are the causes of Primary Adrenal Insufficiency?

A
  • Autoimmune
  • Malignancy
  • Adrenal Hemorrhage (bilateral)
  • Infectious
  • Genetic
  • Infiltrative disorders
  • Drugs
    • Ketoconazole
    • Metyrapone
    • Mitotane
    • **Etomidate **
28
Q

What are the causes of Secondary Adrenal Insufficiency?

A
  • Withdrawal from exogenous corticosteroid therapy
  • Primary/Hypothalamic disease
    • Hypophysitis
      • Autoimmune
      • Granulomatous
      • Drug-Induced (Ipilimumab)
29
Q

How is Chronic Primary Adrenal Insufficiency treated?

A
  • Hydrocortisone
    • 10-15 mg AM, 5-10 mg in afternoon
    • Monitor sense of well-being
    • Plasma ACTH should remain elevated
    • Injectable hydrocortisone (Solu-Cortef) for emergency
  • Fludrocortisone
    • 50-100 mcg daily
    • Monitor electrolyte composition
    • Plasma renin (<5 ng/mL/min)
  • Patient Education
    • Identification card/medical bracelet
    • Sick day management: 3x3
30
Q

How is Acute Adrenal Crisis treated?

A
  • Administer hydrocortisone
    • 100 mg IV every 6 hrs for 24 hrs
  • When stable, decreased to 50 mg every hr & then taper to maintenance as clinically warranted
  • Support w/ isotonic, glucose containing IV fluids to replace volume
31
Q

In patients w/ Primary Adrenal Insufficiency, how is steroid coverage done for surgery?

A
  • Correct electrolytes, BP, hydration if necessary
  • Hydrocortisone 100 mg IM or IV on call to OR
  • Hydrocortisone 50 mg every 6-8 hrs for 24 hrs then taper judiciously to maintenance
32
Q

What is the treatment for Secondary Adrenal Insufficiency?

A
  • Hydrocortisone
  • 7.5-15 mg daily in divided doses
  • Lower doses than primary adrenal insufficiency
  • Mineralocorticoid replacement NOT needed b/c renin-angiotensin-aldosterone system & zone glomerulosa intact
  • Sick-day management, adrenal crisis, surgical steroid coverage still apply
33
Q

What are the most prominent cause of Cushing Syndrome?

A
  • Pathologic hypercortisolism
    • Pituitary or ectopic ACTH secreting neoplasm
    • Benign or malignant adrenal tumors
  • Majority of patients have had hypercortisolism for many years before diagnosis
  • Onset of symptoms indolent
34
Q

What is the cause of ACTH Dependent Cushing Syndrome?

What are its properties?

A
  • ACTH-secreting neoplasm
  • Higher set pt for glucocorticoid negative feedback
  • Diurnal rhythm disrupted
  • Lack of nadir of cortisol secretion late at night
35
Q

What is the cause of ACTH Independent Cushing Syndrome?

What are its properties?

A
  • Solitary benign or malignant tumor
  • Bilteral adrenal nodular disease
  • ACTH low
    • Cortisol negative feedback
    • Contralateral adrenal small
  • Mild hypercortisolism
  • Osteoporosis, HTN, obesity, DM due to mild hypercortisolism for decades (10-40 yrs)
36
Q

What are the causes of Physiological Hypercortisolism?

A
  • Stress
  • Alcohol
  • Neuropsych Disorders
  • Starvation
37
Q

What are the signs & symptoms of Cushing Syndrome?

A
  • Weight gain (unexplained) in truncal distribution
  • Increased supraclavicular & dorsocervical fat accumulation
  • Facial rounding & plethora
  • Proximal muscle weakness
  • Hirsutism/androgen excess in women
  • Wide violaceous striae
  • Cutaneous wasting (skin fold thickness in dorsum of hand < 2mm)
    • Easy bruising
  • Neuropsychiatric problems
    • Cognitive difficulty, depression, psychosis
  • Growth retardation (children)
38
Q

What are some clinical diagnoses that would make you suspect Cushing Syndrome? (3)

A
  • Diabetes/HTN/Metabolic Syndrome (0.5-1%)
  • Osteoporosis (3%)
  • Adrenal nodules (10-30%)
39
Q

What is the process of biochemical diagnosis of Cushing Syndrome?

A

know flow chart on page 27 of handout

40
Q

What diagnostic testing is used for Cushing Syndrome?

A
  • Late night salivary cortisol
    • Biologically active free cortisol
    • 11pm-midnight
    • Sensitive/specific
  • **Overnight low-dose (1 mg) dexamethasone suppression test **
    • 1 mg orally at 11pm
    • Measurement of cortisol following morning
    • Normal suppression = cortisol <1.8 µg/dL
    • Sensitive in patients w/ adrenal nodules
  • **24 hr urine free cortisol **
    • Reflects daily cortisol secretion
    • Poor sensitivity
41
Q

What is the differential diagnosis of ACTH Dependent Cushing Syndrome?

A

Excess ACTH despite glucocorticoid negative feedback

ACTH-secreting pituitary tumor (Cushing’s disease)

Non-pituitary ACTH secreting tumor (ectopic ACTH)

42
Q

What is the differential diagnosis of ACTH Independent Cushing Syndrome?

A
  • Primary increase in glucocorticoid activity w/ suppressed ACTH due to negative feedback
  • Exogenous glucocorticoid therapy
    • Oral, intra-articular, dermal, inhaled
    • Most common cause
  • Adrenal adenoma or carcinoma
  • Nodular adrenal hyperplasia
43
Q

What is the process of diagnosing Cushing Syndrome, beginning w/ measurement of plasma ACTH?

A

know flow chart on page 30 of handout

44
Q

What are the treatment options for Cushing Syndrome?

A

Surgery

Radiotherapy

Medication

45
Q

What kind of surgery is performed to treat Cushing Syndrome?

How effective is it?

A
  • Remove offending tumor (pituitary/adrenal)
    • 70-85% remission
    • 10-20% recurrence
  • Laproscopic surgery of benign adrenal tumors
  • **Bilateral adrenalecotmy **
    • Patients who failed other modalities
    • Decreased quality of life issues due to life-long dependence on steroid support
    • Re-growth of tumor (Nelson’s syndrome)
46
Q

How and when is radiotherapy used to treat Cushing Syndrome?

A
  • Pituitary Cushing
    • Adjunctive therapy after failed surgery
  • 15-50% success rate
  • Remission of hypercortisolism
  • Hypopituitarism w/i 5-10 yrs after radiation
  • Not indicated in adrenal Cushing
47
Q

What 3 classes of medications are used to treat Cushing Syndrome?

A
  • pituitary-directed
  • adrenal steroid inhibitors
  • glucocorticoid receptor antagonists
48
Q

What medications are used in pituitary-directed therapy of Cushing Syndrome?

What are their side effects?

A
  • Pasireotide
    • SST receptor analog (agonist)
    • Patients for whom pituitary surgery is not an option
    • Side effects
      • Diarrhea
      • Nausea
      • Hyperglycemia
      • Headache
  • Cabergoline
    • Dopamine receptor agonist
49
Q

___________ is the adrenal steroid inhibitor used to treat Cushing Syndrome.

A

Metyrapone

available w/ compassionate use

11ß-hydroxylase inhibitor

50
Q

___________ is the glucocorticoid receptor antagonist used to treat Cushing Syndrome.

A

Mifepristone

potent inhibitor of glucocorticoid & progesterone receptor

Endo (18 decks)

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