Adrenal Disorders Iv- Adrenal Insufficiency

Front 1

Presentation of AI:

Back 1

*General:
Fatigue
Weakness
Weight loss
GI complaints
Low blood pressure

*Specific to cause:
Volume depletion
Hyperkalemia
Hyperpigmentation

*Dependent on patient status: SHOCK

Front 2

Variable presentation of AI:

Back 2

*Is the AI due to primary dysfunction of the adrenal gland (1˚) or secondary to hypothalamic-pituitary dysfunction (2˚)?

*Is the AI acute or chronic?

*What is the underlying cause of the AI?

Front 3

HPA axis:

Back 3

Front 4

1˚ AI vs 2˚ AI:

Back 4

1˚ Adrenal Insufficiency
*Loss of GC--General AI symptoms
*Loss of MC
-Sodium (volume) loss
-Potassium retention
*ACTH levels high
-Lack of negative feedback
-Hyperpigmentation
*Pituitary function normal

2˚ Adrenal Insufficiency
*Loss of GC because low ACTH--General AI symptoms
*MC system maintained--No hyperkalemia
*ACTH levels low--No hyperpigmentation
*Other evidence of hypopituitarism

Front 5

Hyperpigmentation in 1˚ AI:

Back 5

*Due to high ACTH

*Generalized, though more pronounced in sun-exposed areas

*Areas exposed to chronic friction or pressure

*Buccal mucosa and other mucous membranes (vaginal, vulvar, anal)

*New scars

Front 6

Back 6

Hyperpigmentation in 1˚ AI
-Pt's right hand is darker

Front 7

Back 7

Hyperpigmentation in 1˚ AI
-This is buccal mucosa

Front 8

What's the mechanism of hyperpigmentation in 1˚ AI?

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*Melanocyte stimulation occurs through activation of MC1R (melanocortin receptor type 1).

*ACTH, B lipotropin and LPH share a common sequence that is reqd to activate MC1R. These peptides are responsible for inducing skin pigmentation in addisons disease as the other melanostimulating peptides, alpha MSH and beta MSH are not produced in the pituitary.

*Local production of MSH and aCTH occurs in melanocytes and keratinocytes and is stimulated by cytokines and ultraviolet radiation.

Front 9

Causes of 1˚ Adrenal Insufficiency:

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*Autoimmune adrenalitis
*Infection
*Hemorrhage
*Metastases
*Drugs
*Genetic disorders:
-Congenital adrenal hyperplasia
-Adrenoleukodystrophy
-Adrenal hypoplasia congenita
-Familial glucocorticoid deficiency

Front 10

Autoimmune adrenalitis:

Back 10

*Major cause of AI in developed countries (70%)

*Adrenal autoantibodies present in 75%
-Test for 21-hydroxylase antibody is commercially available

*Associated with other autoimmune disease in 50% (usually autoimmune thyroid disease)

*May be part of “polyglandular autoimmune syndrome”

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Polyglandular Autoimmune Syndrome Type 1:

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*“APECED”
-Autoimmune PolyEndocrinopathy
-Chronic Mucocutaneous Candidiasis
-Ectodermal Dysplasia (dental enamel hypoplasia, pitted nails, alopecia)

*Autosomal recessive disorder due to mutation in autoimmune regulator (AIRE) gene
*Onset in infancy
*Equal gender incidence

*Classic triad of mucocutaneous candidiasis, AI hypoparathyroidism and Addison’s disease

*Other manifestations: gonadal failure, hypoplasia of dental enamel, alopecia, vitiligo, intestinal malabsorption, type 1 diabetes, pernicious anemia, hypothyroidism

Front 12

Summary chart of autoimmune polyendocrine syndrome type 1:

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Front 13

Polyglandular autoimmune syndrome Type 2:

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*HLA-related
*Multiple types of inheritance described (AD, AR, polygenic)
*Onset in adulthood
*Female predominance
*Autoimmune diseases occurring in multiple endocrine systems
*Two or more of the following:
- Primary adrenal insufficiency
- Graves’ disease
- AI thyroiditis
- Type 1 diabetes
- Primary hypogonadism
- Myasthenia gravis
- Celiac disease

Front 14

Summary chart of autoimmune polyendocrine syndrome type 2:

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Front 15

Infections of the adrenal gland:

Back 15

*Tuberculosis
-Major worldwide cause of AI
-From hematogenous spread

*Fungal (histoplasmosis, cryptococcus)

*CMV

*HIV

Front 16

Adrenal hemorrhage:

Back 16

*Adrenal gland is prone to hemorrhage, especially in patients with sepsis, coagulopathy or trauma

*Clues:
-Hypotension or shock
-Abdominal or flank pain
-Fever
-Drop in hemoglobin

*Waterhouse-Friederichson syndrome
-Adrenal hemorrhage occurring in patients with sepsis (classically meningococcal sepsis)

Front 17

Metastases to the adrenal gland:

Back 17

*40-60% of patients with disseminated breast or lung cancer have adrenal metastases at autopsy

*Frank AI is uncommon

Front 18

Drugs interfering with cortisol biosynthesis:

Back 18

Ketoconazole (antifungal)
Metyrapone
Etomidate (anesthetic)
Aminoglutethimide (antiepileptic)
Suramin (antiparasitic)

Front 19

Congenital Adrenal Hyperplasia:

Back 19

*Family of AR disorders resulting in impaired production of cortisol
*Presentation varies depending on the particular mutation and the particular enzyme involved

Front 20

Adrenoleukodystrophy:

Back 20

*X-linked recessive disorder
*Mutations in ABCD1 gene

*Defect in oxidation of fatty acids within peroxisomes
-Elevated serum levels of very-long-chain fatty acids
-Accumulation in cell membranes
-Demyelination within the nervous system

*Progressive neurologic dysfunction and adrenal insufficiency

Front 21

Discuss the 3 forms of adrenoleukodystrophy:

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1) Childhood cerebral form (30-40%)
– blind, mute, severely spastic tetraplegic

2) Adrenomyeloneuropathy (40%)
– gradual development of spastic paresis and peripheral neuropathy

3) Addison’s disease (only 7%)

Front 22

Adrenal hypoplasia congenita:

Back 22

*X-linked
*Mutation in DAX-1 gene
-Nuclear receptor of unknown function
-Expressed in adrenal cortex, gonads, and hypothalamus

*Present with congenital adrenal insufficiency and hypogonadotrophic hypogonadism

Front 23

Familial glucocorticoid deficiency:

Back 23

*Inherited unresponsiveness to ACTH
*Autosomal recessive
*Defect in MCR-2 (ACTH receptor) or in its accessory proteins
*Unlike most causes of 1˚ AI, mineralocorticoid function is intact

*Patients present in childhood
-Neonatal hypoglycemia
-Hyperpigmentation
-Enhanced growth velocity

Front 24

Causes of 2˚ Adrenal Insufficiency, long list:

Back 24

*Exogenous glucocorticoid therapy
*Hypopituitarism
*Selective removal of ACTH-secreting pituitary adenoma
*Pituitary tumors and pituitary surgery, craniopharyngioma
*Pituitary apoplexy
*Granulomatous disease (TB, sarcoid)
*Secondary tumor deposits (breast, bronchus)
*Postpartum pituitary infarction (Sheehan’s)
*Pituitary irradiation
*Isolated ACTH deficiency
*Multiple pituitary hormone deficiencies

Front 25

Causes of 2˚ Adrenal Insufficiency, short list:

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1) Exogenous glucocorticoids (DON'T FORGET IT!)
2) Hypothalamic/pituitary disease

Front 26

Describe how exogenous glucocorticoids cause 2˚ AI:

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*Chronic glucocorticoid use results in suppression of HPA axis.

*Secondary adrenal insufficiency occurs when steroids are withdrawn, especially if they are withdrawn suddenly.

*Recovery of HPA axis may take as long as 9-12 months, or maybe never.

Front 27

H-P disease classes resulting in 2˚ adrenal insufficiency: 5

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Tumors
Hemorrhage
Infarction
Infiltrative disorders
Traumatic brain injury

Front 28

Tumors resulting in 2˚ adrenal insufficiency:

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*Space-occupying lesions cause hypopituitarism by destroying the pituitary gland or by disrupting the hypothalamic-hypophyseal portal venous system

- Pituitary adenomas
- Other CNS tumors (meningioma, epidermoid tumors)
- Metastases (breast cancer)

Front 29

Pituitary hemorrhage resulting in 2˚ adrenal insufficiency:

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*Often due to bleeding into a previously undiagnosed pituitary adenoma

*Severe headache and visual changes may be prominent

*Often called “Pituitary apoplexy” -- requires immediate surgery!

Front 30

Pituitary infarction resulting in 2˚ adrenal insufficiency:

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*Most commonly occurring peripartum (“Sheehan’s syndrome”)

*Hypotension along with vasospasm of the hypophyseal arteries compromise arterial perfusion of the anterior pituitary

Front 31

Infiltrative disease resulting in 2˚ adrenal insufficiency: 3

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*Langerhan’s histiocytosis
-Infiltration of multiple organs by well-differentiated histiocytes
-Diabetes insipidus, anterior pituitary hormone deficiency

*Sarcoidosis
- Multisystem granulomatous disorder characterized by the presence of noncaseating granulomas in involved organs
- Diabetes insipidus, anterior pituitary hormone deficiency

*Hemochromatosis
- Excessive iron deposition in the tissues
- Hypogonadotropic hypogonadism
- Deficiency of TSH, GH and ACTH later in the course of disease

Front 32

Talk about pituitary and hypothalamic problems arising from TBI:

Back 32

*Prevalence of hypopituitarism - up to 68.5% of TBIs

*Mechanisms:
- compression of the pituitary gland and/or hypothalamic nuclei due to edema
- direct mechanical injury to the hypothalamus, pituitary stalk (hypophysial vessels, portal capillaries) or the gland

*GH deficiency – most common pituitary deficit; can get 2˚ AI.

Front 33

How do we test the adrenal gland?

Back 33

*Cortrosyn stimulation testing (CST)
-Injection of cosyntropin 250 mcg (synthetic ACTH)
-Measure cortisol response in 30-60 minutes [Normal peak > 18-20 mg/dl]
-Patients with 1˚ AI have subnormal response
-Most but not all patients with 2˚ AI have subnormal response

*Normal CST does not prove that HPA axis is normal*

Front 34

CST in 2˚ Adrenal Insufficiency:

Back 34

*Why is the CST abnormal in 2˚ AI if the problem is not in the adrenal gland?
-Chronic ACTH stimulation is necessary to maintain normal function of zona fasciculata cells
-In the absence of chronic ACTH stimulation in 2˚ AI, the zona fasciculata cells “shut down”

*Why is the CST not abnormal in all patients with 2˚ AI?
-“Shut down” process takes WEEKS.
-Some patients can have sufficient ACTH secretion to maintain the fasciculata cells but insufficient H-P function to respond to stress

Front 35

What if CST is normal but you suspect 2˚ Adrenal Insufficiency?

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*Need tests that require the function of the ENTIRE HPA axis:

-Insulin-induced hypoglycemia test
-Metyrapone test

Front 36

Describe the Insulin tolerance test:

Back 36

*Use if CST is normal but you suspect 2˚ Adrenal Insufficiency

*Hypoglycemia is a major stress and a potent stimulus of entire HPA axis

*Give IV insulin to cause serum glucose < 40 mg/dl with hypoglycemic symptoms, then check cortisol level

*Some level of risk and discomfort, and needs to occur in a monitored setting

*CI: history of seizures, or cardiovascular or cerebrovascular disease or in elderly patients (>65 y/o).

Front 37

Describe the Metyrapone test:

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*Use if CST is normal but you suspect 2˚ Adrenal Insufficiency
*Test should raise 11-deoxycortisol levels and suppress cortisol

Front 38

What's your next step as soon as AI is diagnosed?

Back 38

-Check ACTH

-ACTH invariably high in patients with primary AI

-ACTH low or “inappropriately normal” in patients with secondary AI

Front 39

Flowchart of testing and conclusions for suspected adrenal insufficiency:

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Front 40

Additional evaluation for 1˚ AI:

Back 40

*Adrenal imaging with CT or MRI

*Check antibodies to 21-hydroxylase

*If autoantibodies negative in a young man, consider evaluation VLCFA for adrenoleukodystrophy

Front 41

Additional evaluation for 2˚ AI:

Back 41

*Assess for use of glucocorticoids or other drugs with GC-activity

*Assess other pituitary function

Front 42

Glucocorticoid therapy in AI:

Back 42

*Life-saving treatment for AI

*Used in a wide variety of illnesses for anti-inflammatory and immunosuppressive effects

*Common: Taken by 4-5 million adults in US daily

*Serious side effects from chronic use

*Patients may also experience problems when steroids are withdrawn

Front 43

SEs of corticosteroid therapy:

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Front 44

Describe the effects of chronic GC therapy:

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Chronic GC use results in suppression of HPA axis.

Secondary adrenal insufficiency occurs if steroids are withdrawn suddenly.

While patient remains on exogenous GC, unable to mount an adrenal GC response to stress.

Front 45

Commonly Used Glucocorticoids for AI:

Back 45

most used: hydrocortisone (short acting can mimic circadian rhythm), prednisone (more potent), methylprednisone, dexamethasone

Front 46

Mineralocorticoid therapy for AI:

Back 46

*Fludrocortisone (9-alpha-flurohydrocortisone)
Potent synthetic mineralocorticoid

*Some glucocorticoid drugs have mineralocorticoid properties at high doses (e.g. Hydrocortisone)

Front 47

Describe recommendations for maintenance therapy for Glucocorticoid replacement:

Back 47

*Current recommendations are in the 15-25 mg/day range
e.g. Hydrocortisone 15 mg AM, 5 mg afternoon

*No good method for biochemical monitoring; follow patient clinically

*If patient develops Cushing’s, lower the dose

Front 48

Describe recommendations for maintenance therapy for Mineralocorticoid replacement:

Back 48

*Fludrocortisone 0.05 to 0.2 mg daily
*Adjust based on serum potassium
*Not needed in 2˚ adrenal insufficiency
*Liberal salt intake

Front 49

Acute management of patients with AI:

Back 49

*Serious illness or surgery:
-Hydrocortisone 100 mg IV every 8 hours
-Doses tapered as patient status improves
-Don't need to give mineralocorticoid with high doses of hydrocortisone

*Outpatient febrile illness
-Take two to four times the usual replacement dose
(Give pt a rule like “Take three times the dose for three days or more”)
-Emergency room if can’t keep down pills
-Some doctors prescribe injectable steroid to take as a single dose on the way to the ER

*All patients should wear Medic-alert bracelet!!

Front 50

What is an adrenal crisis?

Back 50

*Acute presentation of AI

*Hypotensive shock unresponsive to fluid resuscitation and pressors

*Variety of patient scenarios:
-Sudden loss of HPA function
-Abrupt withdrawal from steroids
-Omission of adrenal replacement therapy in known AI
-Failure to increase adrenal replacement when necessary for acute stress

*More common in patients with 1˚ AI because of combined GC and MC deficiency

Front 51

Chart describing treatment of an adrenal crisis:

Back 51

*3 and 4 are most important