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Adrenal Insufficiency & Cushing's Syndrome Flashcards

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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?

Study These Flashcards
A

Know figure on page 18 of handout

22
Q

How are morning cortisol levels used to diagnose adrenal insufficiency?

Study These Flashcards
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?

Study These Flashcards
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?

Study These Flashcards
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
Patients receiving medications (**estrogen**,oral contraceptives) will have significant increase in _______ rather than alteration of adrenal function.
**CBG**
26
Measurement of adrenal _________ production is a sensitive marker of adrenal reserve.
**androgen (DHEAS)**
27
What are the causes of **Primary Adrenal Insufficiency**?
* Autoimmune * Malignancy * Adrenal Hemorrhage (bilateral) * Infectious * Genetic * Infiltrative disorders * Drugs * **Ketoconazole** * **Metyrapone** * **Mitotane** * **Etomidate **
28
What are the causes of **Secondary Adrenal Insufficiency**?
* Withdrawal from exogenous corticosteroid therapy * Primary/Hypothalamic disease * Hypophysitis * Autoimmune * Granulomatous * Drug-Induced (**Ipilimumab**)
29
How is **Chronic** Primary Adrenal Insufficiency treated?
* **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
How is **Acute Adrenal Crisis** treated?
* 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
In patients w/ Primary Adrenal Insufficiency, how is steroid coverage done for **surgery**?
* 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
What is the **treatment** for Secondary Adrenal Insufficiency?
* **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
What are the most prominent cause of **Cushing Syndrome**?
* 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
What is the cause of **ACTH Dependent** Cushing Syndrome? What are its properties?
* **ACTH-secreting neoplasm** * Higher set pt for glucocorticoid negative feedback * Diurnal rhythm disrupted * Lack of nadir of cortisol secretion late at night
35
What is the cause of **ACTH Independent** Cushing Syndrome? What are its properties?
* **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
What are the causes of **Physiological Hypercortisolism**?
* Stress * Alcohol * Neuropsych Disorders * Starvation
37
What are the **signs & symptoms** of Cushing Syndrome?
* **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
What are some **clinical diagnoses** that would make you suspect Cushing Syndrome? (3)
* Diabetes/HTN/Metabolic Syndrome (0.5-1%) * Osteoporosis (3%) * Adrenal nodules (10-30%)
39
What is the process of **biochemical diagnosis** of Cushing Syndrome?
know flow chart on **page 27** of handout
40
What **diagnostic testing** is used for Cushing Syndrome?
* **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
What is the **differential diagnosis** of ACTH Dependent Cushing Syndrome?
Excess ACTH despite glucocorticoid negative feedback ACTH-secreting pituitary tumor (**Cushing’s disease**) Non-pituitary ACTH secreting tumor (**ectopic ACTH**)
42
What is the **differential diagnosis** of ACTH Independent Cushing Syndrome?
* 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
What is the process of diagnosing Cushing Syndrome, beginning w/ measurement of plasma ACTH?
know flow chart on **page 30** of handout
44
What are the **treatment** options for Cushing Syndrome?
Surgery Radiotherapy Medication
45
What kind of **surgery** is performed to treat Cushing Syndrome? How effective is it?
* **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
How and when is **radiotherapy** used to treat Cushing Syndrome?
* 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
What _3 classes of medications_ are used to treat Cushing Syndrome?
* **pituitary-directed** * **adrenal steroid inhibitors** * **glucocorticoid receptor antagonists**
48
What medications are used in pituitary-directed therapy of Cushing Syndrome? What are their side effects?
* **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
\_\_\_\_\_\_\_\_\_\_\_ is the adrenal steroid inhibitor used to treat Cushing Syndrome.
**Metyrapone** available w/ compassionate use 11ß-hydroxylase inhibitor
50
\_\_\_\_\_\_\_\_\_\_\_ is the glucocorticoid receptor antagonist used to treat Cushing Syndrome.
**Mifepristone** potent inhibitor of glucocorticoid & progesterone receptor

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