Endocrinology 1 Flashcards
Thyroid regulation
- 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
Thyroid hormone synthesis
- 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
Thyroid PERIPHERAL FATE
- 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
Thyroid hormone metabolism
- 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
TSH
- 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
Total T4, T3
- 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
TBG ESTIMATION
- 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
T3 Resin Uptake
tell the story
FREE THYROXINE
- 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
Thyroid: AUTOANTIBODIES
- 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’
THYROGLOBULIN (TG)
- 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
HYPERTHYROIDISM
- 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
HYPOTHYROIDISM
- 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
TFT IN OTHER STATES
- 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
ADRENAL FUNDAMENTALS
- Functionally, three distinct glands in one anatomic structure
- Most adrenal disorders detected by change in function
- Most functional disorders affect only one hormone class
GLUCOCORTICOID
REGULATION
- 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
PLASMA CORTISOL
- 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
Urinary Free Cortisol
- 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
URINE METABOLITES
- 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
PLASMA ACTH
- 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
SUPPRESSION TESTS
- 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
DEXAMETHASONE SUPPRESSION TESTS
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
CORTROSYN STIMULATION
- 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
PITUITARY STIMULATION
- 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