Endocrine Physiology Thyroid

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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
• Shes worried shes pregnant.

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Laboratory Testing

• Thyrotropin Stimulating Hormone TSH gt100 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
• 1700sno 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
  gt60-100 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 gt100 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
• Shes worried shes pregnant..

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Laboratory Testing

• Thyrotropin Stimulating Hormone TSH gt100 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 Hashimotos
  Disease
• Very common 5-20 per 1000
• Women gt 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 sxs, 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 lt0.2
• 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 lt5
• 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 sxs
• Cant 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 1940s
• 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 lt5
• 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