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Glucocorticoid excess. (May or may not involve mineralcorticoid excess)

Exogenous (Most common)
Iatrogenic (given as medications)

Endogenous (Rare)
* ACTH Dependent -
-Pituitary = Cushing's Disease
-Ectopic source of ACTH

* ACTH-independent
Problem withe adrenals incorrectly producing too much Glucocorticoid

3%

Immune Response - Lymphocytes are activated
Immunologic Tolerance - Lymphocytes functionally inactivated
Ignorance - Lymphocytes do not react

Central Tolerance:
Developing Lymphocytes are filtered out (bone marrow for B cells, Thymus for T cells)


Periphreal Tolerance
Mature lymphocytes -> Induced to be anergic
Regulatory T cells

Type II, III and IV.

Only Type 1 is not.

Type 2: Antibodies against cell surfaces / ECm
Type 3: Immune complexes
Type 4: Effector T cells

AI Hemolytic Anemia
IgG and IgM against RH antibodies on RBCs.
=> Complement activation & Enhanced phagocytosis
3 methods of destruction:
1) FcR+ on macrophages => Destruction
2) Binds comlement=> recruits Macrophages=>Destruction
3) Binds complement=> Complement mediated Lysis




Goodpasture's Sydnrome
IgG targets Type IV Collagen.
Antibody deposits => Kidney problems.

SLE: Immune complexes deposited in
1) Blood capillaries
2) Renal Glomeruli

Use Effector T cells:

Pancreas: T1DM
Joints: Rheumatoid Arthritis
Brain: MS

Grave's Disease: Hyperthyroidism. Ab activates. Heat intolerance, nervousness, weight loss, BULGING EYES

Baby can get. Pregnant mother needs Plasmaphoresis to remove Ab.

Hashimoto's Disease: Hypothyroidism. Ab destroys. Germinal center generation => Goiter.
Middle Aged women common

Acetylcholine receptor.

Get drooping eyes, double vision.

Binding of Ab causes internalization of AChR. which reduces total number of AChR.

Intense inflammation
TIII hypersensitivity
Formation of immune responses in resonse to DNA, histones, ribosomes. This often happens after viral infection


Glomerulonephritis is a big problem because of kidney damage from the immune complexes

90% have arthritis.
Butterfly shaped skin rash


10:1 female to male
1:700 in women
1:250 among women of African or Asian descent.

Effectors:
T cells, B cells, Macrophages & Neutrophils

Prostaglandins / Leukotrienes mediate inflammation


Lysosomal enzymes, proteinases, collagenases, TNF, IL-1, 8.

1-3% of the US.


80% have Anti-Antibodies called rheumatoid factor
Fc portion of human IgG

Main cause of neurological disability in young people
20-30 yo onset


Inflammation of CNS White Matter (myelinated)
Involves T-cell and macrophage => Axonal injury

CD4+ T cells secrete proinflammatory cytokines (TNF- and IFN-)

Relapse-remitting (RR) - cycle between acute attack and recover. Can accumulate damage

Progressive (PP) - getting worse

MS and IDDM.

From Twin studies.

Diseases not associated:
Goodpasteur's Sydnrome
MG
IDDM
Rheumatoid Arthritis 3

Cushing's Disease involves a problem with the pituitaries producing too much ACTH, resulting in excess glucocorticoid

Cushing's SYNDROME involves the production of too much glucocorticoid, regardless of etiology

Cholesterol => Pregnenelone

Ultimate products are

Mineralcorticoids (ie Aldosterone)
Glucocorticoids (ie Cortisol)
Androgens (ie Estradiol)

high

ACTH-dependent	ACTH-independent
Pituitary Dependent	Iatrogenic/ Factitious
Ectopic ACTH	Pigmented micronodular adrenal hyperplasia
Exogenous ACTH	Adrenal hyperplasia b/c of abnormal hormone receptor function

* Macronodular adrenal hyperplasia can be both

ACTH Dependent:
2/3 are Cushings: 8:1 female/male. Gradual onset. 20-40 yo. Adenoma small / occult

1/6 Ectopic ACTH/CRH: 1:3 female/male. Oat cell carcinoma. Neuroendocrine tumors that might have somatostatin receptors

ACTH-Independent
1/6 are Adrenal (ACTH Independent): NO ANDROGEN EXCESS. Autoimmune / ectopic receptor / benign or malignant growth

1) Plasma ACTH: Sensitive
2) Plasma Cortisol: bound + free cortisol
3) Urine free cortisol: don't use this. Multiple false neg/pos
4) Salivary Cortisol: free cortisol, easy test

CS will have elevated levels of free cortisol in the urine

1) Screening
- Overnight dexamethasone
- 24hr urine free cortisol


2) Confirmatory
- 2day Dexamethasone suppression test (DM is a synthetic glucocorticoid
- Dexamethasone-oCRH test
- Midnight salivary cortisol

In the presence of dexamethasone, should get diminished free cortisol over a 4 day (?) period.

Should be a stimulation test to see if you can increase the Cortisol levels.

1) ACTH
2) MRI- PIT
3) Bilateral Petrosal Sinus sampling for ACTH with oCRH

Pituitary: transsphenoidal microsurgery
Ectopic: adrenal enzyme blockers

For all of them: Rads, Medical, Bilateral adrenalectomy

Metyrapone
Ketoconazole
Aminoglutethimide
Mitotane
Etomidate


Neuromodulatory agents
- 5HT antagonists [ Cyproheptadine, Rianserin ]

Dopamine antagonists [Bromocriptine]
Somatostatin Analogues  [Octreotide]
GABA agonist - [Sodium Valproate]
Glucocorticoid Antagonist - [Mifepristone RU486]

11HSD-1 converts CORTISONE to CORTISOL, which can be used on a glucocorticoid receptor.

11HSD-2 converts CORTISOL to CORTISONE, which doesn't interact with mineralcorticoid receptors (ie in the kidney)


11HSD2 is found in kidneys and other tissues with mineralcorticoid activity

Shared	Cushing's Only
Abdominal Obesity	Osteoporosis
Insulin Resistance	Myopathy
Hypertension	Neuropyschiatric Syndromes
Glucose Intolerance
PCOS/ hyperandrogenism
Oligomenorrhea

* Polycystic ovary disease