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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? recheck a TSH?

  • A. 1 day

  • B. 5 days

  • C. 6 weeks

  • D. None of the above.


Daily production
Daily Production recheck a TSH?

  • T4

    • 10-15 ug/kg/day

    • Or…..80 – 100 ug/day

  • T3

    • 30-40 ug/day


Thyroid hormone physiology1
Thyroid Hormone Physiology recheck a TSH?

  • Gland secretion 80% T4, 20% T3

  • Deiodinase in peripheral tissues/pituitary convert T4 to T3 and reverseT3 [rT3]


Mechanism of action
Mechanism of Action recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • 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 recheck a TSH?

  • Primary: direct problem with gland secreting end product

  • Secondary: problem with gland controlling final gland


Causes primary hypothyroidism
Causes Primary Hypothyroidism recheck a TSH?

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 recheck a TSH?

    • 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 recheck a TSH?

    • Brand names – T4, ~$14/month

      • Levoxyl

      • Synthroid

      • Unithroid

      • Levothroid

    • Brand names – T3 ~$ 35/month

      • Cytomel

      • Triostat


    Thyroid pharmacokinetics
    Thyroid Pharmacokinetics recheck a TSH?

    • T4 best absorbed in duodenum and ileum

      • 80% oral preparation absorbed

    • T3 95% absorbed

    • Both less absorbed with severe hypothyroidism


    Thyroid pharmacokinetics1
    Thyroid Pharmacokinetics recheck a TSH?

    • 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: recheck a TSH?

    • 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?? recheck a TSH?

    • 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 recheck a TSH?

    • Weight-based

    • Severity of symptoms

    • Cardiac failure

    • Coronary artery disease

    • Renal disease


    Drug interactions
    Drug Interactions recheck a TSH?

    • 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? recheck a TSH?

    • 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 recheck a TSH?

    • TSH most sensitive and cost-effective test

    • Signs and symptoms not very specific

    • T4 supplementation fairly easy

    • Hypothyroid patients do generally well with surgery


    Questions

    Questions?? recheck a TSH?


    A case of more fatigue
    A Case of More Fatigue! recheck a TSH?

    • 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 recheck a TSH?

    • TSH <0.2

    • Total T4 13 [8.5 – 12.5]

    • Total T3 222 [80 – 200]


    And the diagnosis is
    And the diagnosis is…. recheck a TSH?

    • A. Secondary hypothyroidism

    • B. Quanternary hyperthyroidism

    • C. Primary hyperthyroidism

    • D. Primary hypothyroidism

    • E. None of the above


    Primary hyperthyroidism
    Primary Hyperthyroidism recheck a TSH?

    • Causes

      • “productive”

        • Graves Disease

        • Multi- or single autonomous nodules

      • “destructive”

        • Thyroiditis: painless or subacute

      • exogenous


    Graves disease
    Graves Disease recheck a TSH?

    • Women 30-60 years old

    • Opthalmopathy ~10%

    • Dermopathy <5%

    • TSII [Thyroid Stimulating Immunoglobulin]

    • High concordance rate, 2-hit hypothesis [?Yersinia]


    Thyroiditis
    Thyroiditis recheck a TSH?

    • May be viral cause for inflammation

    • “leaky” thyroid

    • Painless form often post-partum

    • May have antecedent URI symptoms


    Drug causes
    Drug Causes recheck a TSH?

    • 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 recheck a TSH?

    • 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? recheck a TSH?

    • More hypertension

    • Higher chance tachyarrhythmias

    • ?higher catecholamine binding sites

    • Probably no increase mortality


    Treatment general
    Treatment - General recheck a TSH?

    • 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 recheck a TSH?

    • 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 recheck a TSH?

    • PTU rapidly absorbed, peak 1 hr; Tapazole variable

    • MMI ½ life = 4-6 hours

    • PTU ½ life = 1-2 hours


    Ptu mmi
    PTU/MMI recheck a TSH?

    • Immunosuppressive actions

      • Decrease TSII production

      • Decrease intrathyroidal T cells

    • PTU more protein-bound

      • Pregnancy, breast-feeding


    Ptu mmi1
    PTU/MMI recheck a TSH?

    • 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 recheck a TSH?

    • 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” recheck a TSH?

    • 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 recheck a TSH?

    • 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 recheck a TSH?

    • 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 recheck a TSH?

    • RAI vs. medical Rx vs. surgery

    • 25-30% remission rate after 2 years of medical Rx


    Autonomous nodules
    Autonomous nodules recheck a TSH?

    • Multinodular goiters

      • common in elderly

      • RAI preferred

    • Single “hot” nodules

      • RAI preferred

      • Usually euthyroid post-RAI


    Take home points hyperthyroid
    Take-home Points - Hyperthyroid recheck a TSH?

    • 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 recheck a TSH?

    • 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 recheck a TSH?

    • Blockage of T4 to T3 conversion

    • Less binding to TBG

    • “recovery phase”

    • Bottom line: no evidence to suggest replacement Rx improves outcomes


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