Endocrine PhysiologyThyroid

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

• Dry skin, constipation, no periods for 6 mos

• She’s worried she’s pregnant….

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?

• A. Secondary hyperthyroidism

• B. Primary hypothyroidism

• C. Lab error

• D. Fictitious hyperthyroidism

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

• 1835: Graves noticed thyroid enlargement and eye problems

• 1874: atrophy and deficiency noted

• 1891: Murray treated 1st case with thyroid extract

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

• Composed of large number of closed follicles

• Hormone stored with large glycoprotein Thyroglobulin

• Traps iodide

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

• 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

• 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?

• A. 7 days

• B. 3 weeks

• C. 6 weeks

• D. 10 weeks

How about T3 then?

• A. 1 day

• B. 5 days

• C. 6 weeks

• D. None of the above.

Daily Production

• T4 – 10-15 ug/kg/day– Or…..80 – 100 ug/day

• T3– 30-40 ug/day

Thyroid Hormone Physiology

• Gland secretion 80% T4, 20% T3

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

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

• 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

• Can accelerate growth in children when in excess, and vice versa

• Growth effect mainly through promoting protein synthesis

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

• 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

• Iodine physiology key to thyroid hormone production

• Thyroid hormone effects just about everything!

• Know differences between T4 vs. T3

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

• 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: direct problem with gland secreting end product

• Secondary: problem with gland controlling final gland

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

• TSH is most sensitive test for diagnosis and Rx adjustment

• Pituitary/Thyroid & Thermostat/Furnace analogy

• Low long-term morbidity, no mortality

T4 supplementation

• Brand names – T4, ~$14/month– Levoxyl– Synthroid– Unithroid– Levothroid

• Brand names – T3 ~$ 35/month– Cytomel– Triostat

Thyroid Pharmacokinetics

• T4 best absorbed in duodenum and ileum– 80% oral preparation absorbed

• T3 95% absorbed

• Both less absorbed with severe hypothyroidism

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:

• 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 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

• Weight-based

• Severity of symptoms

• Cardiac failure

• Coronary artery disease

• Renal disease

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?

• 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

• 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??

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 Testing

• TSH <0.2

• Total T4 13 [8.5 – 12.5]

• Total T3 222 [80 – 200]

And the diagnosis is….

• A. Secondary hypothyroidism

• B. Quanternary hyperthyroidism

• C. Primary hyperthyroidism

• D. Primary hypothyroidism

• E. None of the above

Primary Hyperthyroidism

• Causes– “productive”

• Graves Disease

• Multi- or single autonomous nodules

– “destructive”• Thyroiditis: painless or subacute

– exogenous

Graves Disease

• Women 30-60 years old

• Opthalmopathy ~10%

• Dermopathy <5%

• TSII [Thyroid Stimulating Immunoglobulin]

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

Thyroiditis

• May be viral cause for inflammation

• “leaky” thyroid

• Painless form often post-partum

• May have antecedent URI symptoms

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

• 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?

• More hypertension

• Higher chance tachyarrhythmias

• ?higher catecholamine binding sites

• Probably no increase mortality

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

• 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

• PTU rapidly absorbed, peak 1 hr; Tapazole variable

• MMI ½ life = 4-6 hours

• PTU ½ life = 1-2 hours

PTU/MMI

• Immunosuppressive actions– Decrease TSII production– Decrease intrathyroidal T cells

• PTU more protein-bound– Pregnancy, breast-feeding

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

• 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”

• 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

• 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

• 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

• RAI vs. medical Rx vs. surgery

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

Autonomous nodules

• Multinodular goiters– common in elderly– RAI preferred

• Single “hot” nodules– RAI preferred– Usually euthyroid post-RAI

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

• Low, normal, or mildly high TSH

• Low Total T4

• Normal Free T4 [watch out for heparin]

• Low TT3 and Free T3

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