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Endocrine Physiology Thyroid. Bob Bing-You, MD, MEd, MBA Medical Director Maine Center for Endocrinology. A case of fatigue. 28 y.o. white female c/o 4 month h/o increasing fatigue 2 children, ages 4 and 7 Sleeping all day, weight up 15 lbs, labile moods

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endocrine physiology thyroid

Endocrine PhysiologyThyroid

Bob Bing-You, MD, MEd, MBA

Medical Director

Maine Center for Endocrinology

a case of fatigue
A case of fatigue
  • 28 y.o. white female c/o 4 month h/o increasing fatigue
  • 2 children, ages 4 and 7
  • Sleeping all day, weight up 15 lbs, labile moods
  • Dry skin, constipation, no periods for 6 mos
  • She’s worried she’s pregnant….
laboratory testing
Laboratory Testing
  • Thyrotropin Stimulating Hormone [TSH] = >100 [NR 0.27-4.2 mU/ml]
  • Free T4 = 0.4 ug% [0.7-1.8]
  • Total T3 = 70 ug% [80-200]
  • Thyroid “antibodies” [anti-thyroglobulin, anti-microsomal] “moderately positive”
diagnosis
Diagnosis?
  • A. Secondary hyperthyroidism
  • B. Primary hypothyroidism
  • C. Lab error
  • D. Fictitious hyperthyroidism
history of the thyroid
History of the Thyroid
  • 1st described 1656
  • lubricated the trachea
  • vascular shunt to the brain
  • larger size gave grace to women
  • 1700’s:no important physiological role
more history
More History
  • 1835: Graves noticed thyroid enlargement and eye problems
  • 1874: atrophy and deficiency noted
  • 1891: Murray treated 1st case with thyroid extract
thyroid hormone
Thyroid Hormone
  • Lack of thyroid secretion causes BMR to fall 40%
  • Extreme thyroid hormone excesses can cause BMR >60-100% above normal
  • Thyroid secretion under control of anterior pituitary gland
thyroid gland
Thyroid Gland
  • Composed of large number of closed follicles
  • Hormone stored with large glycoprotein Thyroglobulin
  • Traps iodide
iodine
Iodine
  • Average ingestion 1 mg. per week
  • Breads, ice cream, sea kelp
  • Iodide pump on thyroid cell membrane can concentrate in cell 40 x concentration in blood
hormone biosynthesis
Hormone Biosynthesis
  • Organification:
    • iodide oxidized to iodine
    • combines with tyrosine residues to form monoiodotyrosine and diiodotyrosine
    • MIT and DIT combine with TG to make T3 and T4
  • 5-6 T4 molecules/TG, 1 T3/3-4 TGs
  • Can store up to 3 months requirement
  • exocytosis at colloid border for release
thyroid hormone physiology
Thyroid Hormone Physiology
  • Thyroxine, Triiodothyronine
  • T3 4 x more potent than T4
  • Free components are biologically active
  • 99% protein-bound, mainly Thyroid Binding Globulin [TBG]
  • High affinity of TBG for T4
  • Half-life T4 7 days, 1 day for T3
if you were to change t4 dose how long would you wait to recheck a tsh
If you were to change T4 dose, how long would you wait to recheck a TSH?
  • A. 7 days
  • B. 3 weeks
  • C. 6 weeks
  • D. 10 weeks
how about t3 then
How about T3 then?
  • A. 1 day
  • B. 5 days
  • C. 6 weeks
  • D. None of the above.
daily production
Daily Production
  • T4
    • 10-15 ug/kg/day
    • Or…..80 – 100 ug/day
  • T3
    • 30-40 ug/day
thyroid hormone physiology1
Thyroid Hormone Physiology
  • Gland secretion 80% T4, 20% T3
  • Deiodinase in peripheral tissues/pituitary convert T4 to T3 and reverseT3 [rT3]
mechanism of action
Mechanism of Action
  • Free forms enter cells
  • T4 converted to T3 by 5’-deiodinase
  • T3 binds to nuclear receptors, RNA formation, protein synthesis
  • actions delayed by hours or days
effects of thyroid hormones
Effects of Thyroid Hormones
  • Increase metabolic rate almost all tissues [except brain, lungs, spleen]
  • Increase protein synthesis
  • Increase >100 cellular enzyme systems
  • Cell mitochondria increase size and number
growth
Growth
  • Can accelerate growth in children when in excess, and vice versa
  • Growth effect mainly through promoting protein synthesis
excess effects on metabolism
Excess Effects on Metabolism
  • Stimulates almost all aspects of carbohydrate metabolism [e.g., glycolysis]
  • Can deplete fat stores, increase FFA in blood
  • Decrease LDL
  • Weight up and down!
more effects with higher levels
More effects with higher levels
  • Increases blood flow, vasodilation
  • Need for heat elimination
  • Heart rate very sensitive index
  • Increases respiratory rate and depth
  • Increased GI motility
  • Weaken muscles due to protein catabolism
  • Fine tremor 10-15x/second
key points
Key Points
  • Iodine physiology key to thyroid hormone production
  • Thyroid hormone effects just about everything!
  • Know differences between T4 vs. T3
a case of fatigue1
A case of fatigue
  • 28 y.o. white female c/o 4 month h/o increasing fatigue
  • 2 children, ages 4 and 7
  • Sleeping all day, weight up 15 lbs, labile moods
  • Dry skin, constipation, no periods for 6 mos
  • She’s worried she’s pregnant…..
laboratory testing1
Laboratory Testing
  • Thyrotropin Stimulating Hormone [TSH] = >100 [NR 0.27-4.2 mU/ml]
  • Free T4 = 0.4 ug% [0.7-1.8]
  • Total T3 = 70 ug% [80-200]
  • Thyroid “antibodies” [anti-thyroglobulin, anti-microsomal] “moderately positive”
primary vs secondary
Primary vs Secondary
  • Primary: direct problem with gland secreting end product
  • Secondary: problem with gland controlling final gland
causes primary hypothyroidism
Causes Primary Hypothyroidism

Autoimmune Thyroid Disease [“Hashimoto’s Disease”]

    • Very common [5-20 per 1000]
    • Women > men
    • Age [4th-5th decade]
    • Antibodies may be positive
  • Surgery
  • Congenital
primary hypothyroidism
Primary Hypothyroidism
  • TSH is most sensitive test for diagnosis and Rx adjustment
  • Pituitary/Thyroid & Thermostat/Furnace analogy
  • Low long-term morbidity, no mortality
t4 supplementation
T4 supplementation
  • Brand names – T4, ~$14/month
    • Levoxyl
    • Synthroid
    • Unithroid
    • Levothroid
  • Brand names – T3 ~$ 35/month
    • Cytomel
    • Triostat
thyroid pharmacokinetics
Thyroid Pharmacokinetics
  • T4 best absorbed in duodenum and ileum
    • 80% oral preparation absorbed
  • T3 95% absorbed
  • Both less absorbed with severe hypothyroidism
thyroid pharmacokinetics1
Thyroid Pharmacokinetics
  • Half-life
    • T4 = 7 days
    • T3 = 1 day
  • Oral supplementation typical route; IV available, 75% of oral dosing
  • Synthetic formulation preferred vs. animal [“Armour”]
  • Brand and generic are not the same dose!
tsh is the most sensitive test for screening because
TSH is the most sensitive test for screening because:
  • A. Least expensive
  • B. Comes in a thyroid panel
  • C. Is a pituitary hormone
  • D. Changes more with small T3 changes
  • E. Involved in negative feedback
t4 vs t3
T4 vs. T3??
  • T4 is just fine
    • Long-term experience of majority of healthy patients
    • No case report of inability to convert to T3
  • T3 advocates
    • More natural, few studies showing small QOL improvement
  • Adverse effects [sx’s, a-fib, bone loss] TSH is most sensitive test for diagnosis and Rx adjustment
dosing considerations
Dosing Considerations
  • Weight-based
  • Severity of symptoms
  • Cardiac failure
  • Coronary artery disease
  • Renal disease
drug interactions
Drug Interactions
  • Malabsorption
    • Iron, sucralfate, bile acid resins, AlOH
  • Changes in TBG
    • Oral estrogen, liver inflammation [e.g. Niacin]
  • Increased clearance: phenytoin, carbamazepine
  • Anti-coagulants
    • Hypothyroidism prolong bleeding
hypothyroidism surgery
Hypothyroidism & Surgery?
  • Intraoperative hypotension; less responsive to pressor agents
  • Lower cardiac rate
  • Slow to wean from vent
  • Less fever manifestations
  • More heart failure in cardiac surgery pts.
  • More constipation, ileus; more confusion
  • No significant increase mortality
take home points hypothyroid
Take-home Points - Hypothyroid
  • TSH most sensitive and cost-effective test
  • Signs and symptoms not very specific
  • T4 supplementation fairly easy
  • Hypothyroid patients do generally well with surgery
a case of more fatigue
A Case of More Fatigue!
  • 44 y.o. white male, 2 month h/o fatigue with exertion
  • Normally runs 4-6 miles/day, more winded
  • Sweats, loose stools, resting pulse up to 88
  • Weight down 10 lbs. Aunt had “thyroid problem.”
  • Diagnosis?
laboratory testing2
Laboratory Testing
  • TSH <0.2
  • Total T4 13 [8.5 – 12.5]
  • Total T3 222 [80 – 200]
and the diagnosis is
And the diagnosis is….
  • A. Secondary hypothyroidism
  • B. Quanternary hyperthyroidism
  • C. Primary hyperthyroidism
  • D. Primary hypothyroidism
  • E. None of the above
primary hyperthyroidism
Primary Hyperthyroidism
  • Causes
    • “productive”
      • Graves Disease
      • Multi- or single autonomous nodules
    • “destructive”
      • Thyroiditis: painless or subacute
    • exogenous
graves disease
Graves Disease
  • Women 30-60 years old
  • Opthalmopathy ~10%
  • Dermopathy <5%
  • TSII [Thyroid Stimulating Immunoglobulin]
  • High concordance rate, 2-hit hypothesis [?Yersinia]
thyroiditis
Thyroiditis
  • May be viral cause for inflammation
  • “leaky” thyroid
  • Painless form often post-partum
  • May have antecedent URI symptoms
drug causes
Drug Causes
  • Amiodarone
    • Long half-life, can cause productive or destructive picture, hypothyroidism
    • Blocks T4 to T3, uptake not helpful
  • Lithium
    • More hypo- than hyperthyroidism
  • Iodinated contrast agents
evaluation
Evaluation
  • TSH for screening
  • T 4 and T3 needed for severity
  • 24 hour iodine uptake
    • Productive vs. destructive
  • TSII [TSH-like antibodies]
    • Other antibodies non-specific [I.e., anti-thyroglobulin, anti-microsomal]
hyperthyroidism surgery
Hyperthyroidism & Surgery?
  • More hypertension
  • Higher chance tachyarrhythmias
  • ?higher catecholamine binding sites
  • Probably no increase mortality
treatment general
Treatment - General
  • Beta-blockers
    • Propanolol 80-180 mg/day
      • Better inhibition of T4/T3 conversion
    • Good for adrenergic sx’s
    • Can’t use in asthma and heart failure
  • Hydration
anti thyroid medications
Anti-thyroid Medications
  • Propylthiouracil, Methimazole [Tapazole]
  • 1928: rabbits fed cabbage developed goiters
  • Thioamides developed 1940’s
  • Concentrated in thyroid, inhibit biosynthesis by blocking organification of iodine
  • PTU also blocks T4/T3 conversion
pharmacokinetics
Pharmacokinetics
  • PTU rapidly absorbed, peak 1 hr; Tapazole variable
  • MMI ½ life = 4-6 hours
  • PTU ½ life = 1-2 hours
ptu mmi
PTU/MMI
  • Immunosuppressive actions
    • Decrease TSII production
    • Decrease intrathyroidal T cells
  • PTU more protein-bound
    • Pregnancy, breast-feeding
ptu mmi1
PTU/MMI
  • Dosing depends on severity
    • MMI can be once a day
  • Adverse effects
    • Pruritis, GI 2-5%
    • Metallic taste
    • Rare [1/600] agranulocytosis, hepatocellular damage
other agents
Other agents
  • Saturated Solution Potassium Iodide [SSKI] 5-10 drops several times daily – also decreases vascularity pre-op
  • Lithium 300 mg qid
  • Glucocorticoids
    • Block T4/T3 conversion
    • Prednisone 50-60 mg/day
thyroid storm
Thyroid “Storm”
  • Life-threatening, usually with underlying major illness [e.g., acute infection]
  • Fever, tachycardia, N/V, acute abdomen, cardiac failure, agitation….continuum
  • Rx = hydration, high doses of PTU and IV glucocorticoids, then SSKI few hours later
radioactive iodine
Radioactive Iodine
  • I131 for beta particles
  • Usually one-time dose
  • Goal= ablation with subsequent hypothyroidism
  • No long-term side effects in 50 years
  • ~$1,000/treatment
thyroiditis treatment
Thyroiditis Treatment
  • 24 hour iodine uptake <5%
  • Symptomatic treatment only [beta-blockers]
  • Hypothyroid phase possible, lasting 2-3 mos, may need LT4
  • ~20% permanently hypothyroid
graves disease treatment
Graves Disease Treatment
  • RAI vs. medical Rx vs. surgery
  • 25-30% remission rate after 2 years of medical Rx
autonomous nodules
Autonomous nodules
  • Multinodular goiters
    • common in elderly
    • RAI preferred
  • Single “hot” nodules
    • RAI preferred
    • Usually euthyroid post-RAI
take home points hyperthyroid
Take-home Points - Hyperthyroid
  • Graves disease vs. thyroiditis differentiation
  • TSH still best screening lab
  • Medical Rx 1st option for treatment over surgery
  • Cardiovascular effects biggest concern peri-operatively
euthyroid sick syndrome
Euthyroid Sick Syndrome
  • Low, normal, or mildly high TSH
  • Low Total T4
  • Normal Free T4 [watch out for heparin]
  • Low TT3 and Free T3
euthyroid sick syndrome1
Euthyroid Sick Syndrome
  • Blockage of T4 to T3 conversion
  • Less binding to TBG
  • “recovery phase”
  • Bottom line: no evidence to suggest replacement Rx improves outcomes
ad