Endocrinology 1 Flashcards
1
Q
Thyroid regulation
A
- Hypothalamus makes TRH at relatively constant rate
- Pituitary TSH response to TRH inversely related to cellular T3
- At least 50% of pituitary T3 produced within cell from T4
2
Q
Thyroid hormone synthesis
A
- All steps activated by TSH; normally, TSH rate limiting
- T4 predominant (90-95%) product
- When TSH high, iodine rate limiting and progressively more T3 made
- T3, active hormone, mostly produced in cells using it; circulating T3 mostly from liver
3
Q
Thyroid PERIPHERAL FATE
A
- Protein bound in blood (99.97% T4, 99.7% T3); free hormone active, regulated by TSH
- Protein bound inactive, unregulated
- Altered T4/T3 levels may be due to changes in production rate or binding protein levels
- Changes in binding proteins common
4
Q
Thyroid hormone metabolism
A
- Most T3 produced peripherally (liver, kidney) by action of monodeiodinases
- Type 1 3’,5’ monodeiodinase produces T3; enzyme labile, low in very young and old, acute illness, starvation
- Pituitary type 2 monodeiodinase not affected in these states, so sees normal T3
5
Q
TSH
A
- Most important thyroid test; TSH changes logarithmically, even before T4/T3 outside reference range (more sensitive)
- Almost all disorders are primary in thyroid
- Test must distinguish low normal from suppressed (usually < 0.05 mIU/L)
- TRH stimulation no longer used
6
Q
Total T4, T3
A
- Still performed by many labs
- Affected both by thyroid function and binding proteins
- Normal results (central 75%) effectively rule out thyroid disease
- Abnormal results require estimation of binding protein levels
7
Q
TBG ESTIMATION
A
- Required if total T4 assays used and results outside central 75%
- Two competing formats: resin uptake and T-uptake
- Results of each have exactly opposite relation to TBG capacity from the other
8
Q
T3 Resin Uptake
A
tell the story
9
Q
FREE THYROXINE
A
- Measure small amount of FT4 with large amount of protein bound T4
- Cannot significantly disturb normal equilibrium between bound, free
- Equilibrium constant considered “gold standard”; falsely high with acute illness
- Most labs use other FT4 assays; may be falsely low or high with acute illness
10
Q
Thyroid: AUTOANTIBODIES
A
- Anti-TPO - seen in Graves’, Hashimoto’s in high titers, other forms of thyroiditis in low levels
- TSH receptor antibodies found in Graves’ (stimulatory), atrophic thyroiditis (blocking)
- TSI – measure cAMP production when thyroid cells incubated with IgG fraction; specific for Graves’
11
Q
THYROGLOBULIN (TG)
A
- Produced only by thyroid; related to mass, inflammation
- After removal, used as marker of thyroid tumor metastases (after TSH stimulation, usually)
- Anti-TG often present, interferes; test for Ab’s with TG assay, don’t report if positive
- Loss of anti-TG implies lack of antigen; good prognosis
12
Q
HYPERTHYROIDISM
A
- Suppressed TSH first finding
- T3 elevated before T4 (in Graves), free before total; nL T3 suggests other cause
- Total T4, T3, T3RU all high, T-uptake low
- With recovery, T4 normalizes first, then T3, TSH last (may take months); persistently low TSH – high risk of recurrence
13
Q
HYPOTHYROIDISM
A
- Separated into subclinical (high TSH, Nl FT4, no symptoms), clinical
- Incidence increases with age (5% at age 60, 20% at age 80)
- Most with subclinical hypothyroidism progress; controversy about screening, treatment
- Increased TSH first; usually > 50 mU/L when symptoms begin, lesser degree of elevation in elderly; NL-sl increased with pituitary disease (reduced bioactive TSH)
- Low free, total T4, low T3RU occur later than high TSH
- T3 normal in 30-40% (more T3 made by failing thyroid); not helpful
14
Q
TFT IN OTHER STATES
A
- Acute illness: decreased T3 (low peripheral conversion), normal total/free T4, TSH
- High TBG caused by estrogen (pregnancy, OC), phenothiazines, opiates, active liver injury: high total T4 (and T3), low T3RU, normal TSH, free T4
- Low TBG caused by cirrhosis, nephrotic syndrome, congenital deficiency; low total T4(and T3), high T3RU, normal TSH, free T
15
Q
ADRENAL FUNDAMENTALS
A
- Functionally, three distinct glands in one anatomic structure
- Most adrenal disorders detected by change in function
- Most functional disorders affect only one hormone class
16
Q
GLUCOCORTICOID
REGULATION
A
- Hypothalamic CRH, pituitary ACTH
- Cyclic production (highest on waking, lowest in early sleep)
- Stress stimulates (IL-6, serotonin), minimizes cyclic production
- Cortisol only endogenous steroid inhibiting ACTH production
17
Q
PLASMA CORTISOL
A
- Simplest to measure, difficult to evaluate because of diurnal changes, stress effects
- Highest on waking (5-25 g/dL), low early sleep (1-7 g/dL)
- Some synthetic steroids cross react (not dexamethasone)
- Protein bound, affected by binding proteins
- Free cortisol better, not widely used
18
Q
Urinary Free Cortisol
A
- Normally, little unmetabolized (free) cortisol excreted
- When binding capacity exceeded, increases exponentially (e.g., recent case, plasma 2x normal, urine 50x normal)
- Most sensitive direct test of cortisol production
19
Q
URINE METABOLITES
A
- 17-ketosteroids - measure of androgen production (does not include testosterone)
- 17-hydroxysteroids - measures cortisol, precursor, and metabolites
- Colorimetric assays outmoded, non-specific; replaced by assays for specific metabolites in most cases
20
Q
PLASMA ACTH
A
- Episodic bursts of release make single levels difficult to interpret unless cortisol highly abnormal
- Unstable; requires special handling to prevent loss
- Because adrenal dysfunction both primary and central, not as useful as TSH
21
Q
SUPPRESSION TESTS
A
- Dexamethasone, a potent steroid, should suppress ACTH production
- Dose required for suppression gives information on state of pituitary ACTH production
- Used when cortisol excess (Cushing’s syndrome) suspected
22
Q
DEXAMETHASONE SUPPRESSION TESTS
A
TEST DOSE USES EXPECTED RESULTS
OVERNIGHT 1 mg AT 11 p.m.
Screen Plasma cortisol < 2.5 g/dL
LOW DOSE 0.5 mg q6H x 2d
Confirmation of Cushing’s syndrome
Urine cortisol < lower reference limit
HIGH DOSE 2.0 mg q6H x 2d OR 8 mg AT 11 p.m.
Differential diagnosis - Cushing’s disease shows fall in cortisol
Urine cortisol < 20% of basal
Or
Plasma cortisol < 50% of basal
23
Q
CORTROSYN STIMULATION
A
- Uses synthetic fragment (1-24) of ACTH; has same effects,
- Typical dose (250 ug) produces equivalent of > 1,000 x normal ACTH levels
- Lower dose (1 ug) used by some
- Cortisol should be > 18 ug/dL at 30 min
24
Q
PITUITARY STIMULATION
A
- Insulin hypoglycemia most sensitive but rarely used; cortisol should be > 18 ug/dL
- Metyrapone blocks 11-hydroxylase; normal response is for cotrisol to fall, but ACTH and 11-deoxycortisol to rise (the latter by at least 7 ug/dL
- Less commonly used, but asked on boards
25
CUSHING'S - CLINICAL
- Relatively rare (5/million/yr)
- Due to excess cortisol/androgens
- Obesity, hypertension, poor wound healing, hyperglycemia, hypokalemia, alkalosis due to cortisol excess
- Acne, hirsutism, menstrual problems due to androgen excess
26
CUSHING'S - ETIOLOGY
- Pituitary ACTH overproduction (Cushing's disease) - 70%
- Adrenal adenoma or carcinoma - 15%
- Ectopic ACTH production (usually lung small cell or carcinoid tumors) - 15%
27
EVALUATION FOR CUSHING'S SYNDROME
make image of this slide - 1089
28
ADRENAL INSUFFICIENCY -
| FEATURES
- Much more common than Cushing's
- Mineralocorticoid - dehydration, decreased Na+, elevated
K+, metabolic acidosis
- Glucocorticoid - weakness, wt. loss, vomiting, hypoglycemia, decreased Na+ (due to SIADH, not volume depletion)
- May be due to pituitary, adrenal pathology
29
ADRENAL INSUFFICIENCY -
| DIAGNOSIS
- Plasma cortisol inappropriately low for illness; if < 3 ug/dL confirms diagnosis
- Lack of response in stimulation tests
- ACTH helpful to distinguish primary from secondary
30
ADRENOGENITAL
| SYNDROMES
- Normal genital development:
- External - female unless androgen present
- Internal - female unless Y chromosome present
- Excess or deficient androgen leads to different genetic, apparent sex
- 21-hydroxylase deficiency causes 95% of congenital adrenal hyperplasia
- Deficient cortisol, aldosterone; often low normal with high 17-OH progesterone
- Genetic females have ambiguous genitalia
- Mild deficiency may present with hirsutism after puberty
31
Stimulate Adrenals
- decreased blood flow
- decreased urine Na
- diuretics
- hyperkalemia
32
Inhibit Adrenals
- ANP / BNP
- NSAIDS
- Beta Blockers
- ACE inhibitors
- Hypokalemia
- Heparin
- Adrenal disease
- AR Blockers
33
HYPERALDOSTERONISM
- May be up to 5-10 % of hypertension
- Hypokalemia, metabolic alkalosis; hypokalemia may not be present with low sodium diet
- Adenoma - unilateral, cured by surgery
- Hyperplasia - bilateral, not cured by surgery
34
Hyperaldosteronism laboratory test
- Plasma catecholamines - affected by stress, not routinely done
- Total metanephrines, VMA - metabolites, measure total production
- Fractionated catecholamines, metanephrines - can detect tumors making only epinephrine
- HVA - dopamine metabolite
- Fractionated metanephrines in plasma most sensitive but less specific
35
PHEOCHROMOCYTOMA
- Adult tumor, rare cause of hypertension
- "10% tumor" - 10% bilateral, familial, extraadrenal, malignant; recent data suggest that up to 1/3 actually have germ line genetic mutations (VHL, RET, SDH2)
- May cause episodic HTN, sweating, tachycardia, hyperglycemia, feeling of doom
36
NEUROBLASTOMA
- Infantile medulla tumor, Dx as abdominal mass
- Malignant; spread to certain sites (skin, liver, BM) not associated with worse prognosis
- N-myc amplification poor prognosis
- VMA, HVA used to follow Rx
37
INCIDENTAL MASS
- Common finding on imaging
- If asymptomatic, limited workup usually performed (DST, urine catecholamines or fractionated metanephrines; ? plasma metanephrines)
- "Subclinical" Cushing's – some progress, treatment controversial; surgery suggested if > 2-3 cm in diameter, ACTH low, DM/HTN
