endocrine physiology thyroid bob bing-you, md, med, mba medical director maine center for...
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Endocrine PhysiologyThyroid
Bob Bing-You, MD, MEd, MBA
Medical Director
Maine Center for Endocrinology
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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….
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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”
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Diagnosis?
• A. Secondary hyperthyroidism
• B. Primary hypothyroidism
• C. Lab error
• D. Fictitious hyperthyroidism
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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
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More History
• 1835: Graves noticed thyroid enlargement and eye problems
• 1874: atrophy and deficiency noted
• 1891: Murray treated 1st case with thyroid extract
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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
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Thyroid Gland
• Composed of large number of closed follicles
• Hormone stored with large glycoprotein Thyroglobulin
• Traps iodide
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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
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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
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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
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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
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How about T3 then?
• A. 1 day
• B. 5 days
• C. 6 weeks
• D. None of the above.
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Daily Production
• T4 – 10-15 ug/kg/day– Or…..80 – 100 ug/day
• T3– 30-40 ug/day
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Thyroid Hormone Physiology
• Gland secretion 80% T4, 20% T3
• Deiodinase in peripheral tissues/pituitary convert T4 to T3 and reverseT3 [rT3]
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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
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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
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Growth
• Can accelerate growth in children when in excess, and vice versa
• Growth effect mainly through promoting protein synthesis
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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!
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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
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Key Points
• Iodine physiology key to thyroid hormone production
• Thyroid hormone effects just about everything!
• Know differences between T4 vs. T3
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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…..
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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”
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Primary vs Secondary
• Primary: direct problem with gland secreting end product
• Secondary: problem with gland controlling final gland
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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
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Primary Hypothyroidism
• TSH is most sensitive test for diagnosis and Rx adjustment
• Pituitary/Thyroid & Thermostat/Furnace analogy
• Low long-term morbidity, no mortality
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T4 supplementation
• Brand names – T4, ~$14/month– Levoxyl– Synthroid– Unithroid– Levothroid
• Brand names – T3 ~$ 35/month– Cytomel– Triostat
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Thyroid Pharmacokinetics
• T4 best absorbed in duodenum and ileum– 80% oral preparation absorbed
• T3 95% absorbed
• Both less absorbed with severe hypothyroidism
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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!
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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
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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
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Dosing Considerations
• Weight-based
• Severity of symptoms
• Cardiac failure
• Coronary artery disease
• Renal disease
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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
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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
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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
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Questions??
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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?
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Laboratory Testing
• TSH <0.2
• Total T4 13 [8.5 – 12.5]
• Total T3 222 [80 – 200]
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And the diagnosis is….
• A. Secondary hypothyroidism
• B. Quanternary hyperthyroidism
• C. Primary hyperthyroidism
• D. Primary hypothyroidism
• E. None of the above
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Primary Hyperthyroidism
• Causes– “productive”
• Graves Disease
• Multi- or single autonomous nodules
– “destructive”• Thyroiditis: painless or subacute
– exogenous
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Graves Disease
• Women 30-60 years old
• Opthalmopathy ~10%
• Dermopathy <5%
• TSII [Thyroid Stimulating Immunoglobulin]
• High concordance rate, 2-hit hypothesis [?Yersinia]
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Thyroiditis
• May be viral cause for inflammation
• “leaky” thyroid
• Painless form often post-partum
• May have antecedent URI symptoms
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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
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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]
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Hyperthyroidism & Surgery?
• More hypertension
• Higher chance tachyarrhythmias
• ?higher catecholamine binding sites
• Probably no increase mortality
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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
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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
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Pharmacokinetics
• PTU rapidly absorbed, peak 1 hr; Tapazole variable
• MMI ½ life = 4-6 hours
• PTU ½ life = 1-2 hours
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PTU/MMI
• Immunosuppressive actions– Decrease TSII production– Decrease intrathyroidal T cells
• PTU more protein-bound– Pregnancy, breast-feeding
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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
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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
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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
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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
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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
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Graves Disease Treatment
• RAI vs. medical Rx vs. surgery
• 25-30% remission rate after 2 years of medical Rx
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Autonomous nodules
• Multinodular goiters– common in elderly– RAI preferred
• Single “hot” nodules– RAI preferred– Usually euthyroid post-RAI
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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
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Euthyroid Sick Syndrome
• Low, normal, or mildly high TSH
• Low Total T4
• Normal Free T4 [watch out for heparin]
• Low TT3 and Free T3
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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