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Thyroid Disease Facts

Jeffrey Medland

Lt Col, USAF, MC, SFS

Chief, Endocrinology

MGMC, Andrews AFB, MD

Capital Conference-June 2007

Outline• Thyroid Testing• Hypothyroidism

– Causes– Signs/symptoms– Treatment

• Hyperthyroidism– Causes– Signs/symptoms– Treatment

• Thyroid Nodules/ Cancer• Thyroid Disease and Pregnancy

– Hypothyroidism– Hyperthyroidism (Hyperemesis Gravidarum, Graves’)– Thyroiditis

• Factors affecting Thyroid function, LT4

Thyroid

Colloid

Apical Membrane

Basal Membrane

Thyroid Peroxidase (TPO)

“Iodination Reaction”

“Coupling Reaction”

Thyroid Testing

• TSH– Best test for screening for thyroid

dysfunction! – Log/linear response w/ FT4

• A 2-fold change in FT4 produces a 100-fold change in TSH

– Not specific for a particular thyroid disease.

• Don’t use TSH alone for diagnosis!

– Also useful in• Assessing LT4 tx in 1° hypothyroidism

• Monitoring TSH-suppressive tx in thyroid Ca

Thyroid Testing• FT4

– Testing methods: • Equilibrium dialysis • Analog assays

– Abnormal TSH check this next– Indications:

• In conjunction w/ TSH for diagnosing hyperthyroidism or hypothyroidism.

• Monitoring LT4 replacement in central hypothyroidism (TSH not helpful)

• Assessing response to tx following 131-RAIA (Graves, toxic nodules)

• Monitoring ATD tx in pregnant females

• FT3– Abnormal TSH + normal FT4, then

check this (T3 Thyrotoxicosis)

TSH

HIGH

LOW

FT4 Clinical StatusLOW Primary Hypothyroidism, Thyroiditis (stage 3)

NORMAL Subclinical Hypothyroidism

HIGH Pituitary Hyperthyroidism

HIGH Thyrotoxicosis, Thyroiditis (stage 1)

NORMAL Subclinical Hyperthyroidism, Autonomous nodules

LOW Pituitary Hypothyroidism

Overview of Thyroid Function Tests

Thyroid Testing• Thyroid Antibodies (TPO, Tg, TSI, TRAb)

– TPO• TPO + Tg Ab’s assoc w/ Hashimoto’s. TPO more sensitive.• Helpful in predicting those w/ subclinical hypothyroidism who are at

↑ risk for progression to overt hypothyroidism.– TSI

• When dx of Graves’ in question – Note: a negative test does not r/o Graves’

• Pregnant women w/ Graves’ – to determine fetal risk of thyroid dysfunction (due to transplacental

passage of stimulating or blocking Ab’s).• Suspected euthyroid ophthalmopathy.• In pt’s w/ alternating hyper- and hypothyroidism (due to fluctuations in

TSH receptor stimulating and blocking and stimulating Ab’s)• Thyroglobulin (Tg)

– Indications • Thyroid cancer recurrence• Factitious (exogenous) vs. endogenous hyperthyroidism

– Note: Most assays are not reliable in pt’s (+) for anti-Tg Ab• Interferes w/ method of Tg measurement (causing factitious low Tg)

Thyroid Testing• Radioactive Iodine Uptake and Scan (RAIU/Scan)

– 123-RAIU/Scan or 131-RAIU/Scan– Indications:

• biochemically hyperthyroid pt • No role in euthyroid or hypothyroid pt’s

– RAIU produces a number. • 4-hr (normal 10-15%)• 24-hr (normal 20-30%)

– The scan produces a picture

• Tc99m-Pertechnetate Scan– Picture only, no number

Thyroid Testing

• Fine Needle Aspiration (FNA)– provides the most direct information about a thyroid nodule– 95% sensitivity

• Ultrasound– to assess thyroid nodule size and characteristics (cystic vs. solid)– often used to guide FNA’s

• Calcitonin– h/o MTC– Thyroid nodule and (+) FHx of MTC (Familial, MEN2A, MEN2B)

• MEN2A: MTC, HyperPTH, Pheo • MEN2B: MTC, Pheo, Mucosal neuromas

F-15D

Hypothyroidism

• More common than hyperthyroidism• 99% is primary (< 1% due to TSH deficiency)• Hashimoto’s

– most common thyroid problem (4% of population) – most common cause in iodine-replete areas– aka chronic lymphocytic thyroiditis– Assoc w/ TPO Ab’s (90%), less commonly Tg Ab’s.

• Iatrogenic Hypothyroidism from 131-RAIA (following tx for Graves’)• Postpartum (silent) thyroiditis

– Silent/painless– Occurs within 6 weeks6 months postpartum– Incidence: 10-15% of all women, ≈ 25% women w/ Type 1 DM – Up to 50% are TPO Ab (+) – 70% chance of recurrence w/ subsequent pregnancies

Hypothyroidism

• Subacute thyroiditis– aka de Quervain’s, Granulomatous– Painful, often radiates to the ear– c/o malaise, pharyngitis, fatigue, fever, neck pain/swelling– Viral etiology (URI/ pharyngitis)– self-limited. Can tx inflammation w/ ASA, NSAID’s or steroids

• Suppurative/ Acute Infectious Thyroiditis– Infections of the thyroid are rare

• normally protected from infection by its thick capsule– Bacterial >> fungal, mycobacterial or parasitic– Pt’s are acutely ill w/ a painful thyroid gland

• assoc w/ fever/chills, anterior neck pain/swelling, dysphagia and dysphonia

Thyroiditis

• Clinical Course of Painful Subacute Thyroiditis, Painless Postpartum Thyroiditis, and Painless Sporadic Thyroiditis.

• Measurements of serum thyrotropin (TSH), Thyroxine(T4) and iodine-123 (123I) uptake show thyrotoxicosis during the first three months, followed by hypothyroidism for three months and then by euthyroidism.

Stage 1

Stage 2

Stage 3

Stage 4

Hypothyroidism

• Reidel’s Struma/Thyroiditis (rare)– Pt’s present w/ a painless, hard, fixed goiter– hypothyroidism occurs when entire gland becomes fibrosed– can see fibrosis of other tissues (fibrosing retroperitonitis, orbital

fibrosis, or sclerosing cholangitis)• Drug-induced

– Amiodarone– Lithium– Interferon-alpha– Interleukin-2

• Iodine deficiency– Most common cause of hypothyroidism worldwide!!

Hypothyroidism• Symptoms

– General Slowing Down– Lethargy/somnolence– Depression– Modest Weight Gain– Cold Intolerance– Hoarseness– Dry skin– Constipation (↓ peristaltic activity)– General Aches/Pains

• Arthralgias or myalgias (worsened by cold temps)

– Brittle Hair– Menstrual irregularities

• Excessive bleeding• Failure of ovulation

– ↓ Libido

Hypothyroidism

• Exam:– Dry, pale, course skin w/ yellowish tinge– Periorbital edema– Puffy face and extremities– Sinus Bradycardia– Diastolic HTN– ↓ Body Temperature – Delayed relaxation of DTRs– Megacolon (↓ peristaltic activity)– Pericardial/ pleural effusions– CHF– Myxedema (nonpitting edema)

• Bradycardia and hypothermia- think hypothyroidism!

Hypothyroidism

• Laboratory Findings– Elevated TSH– Low FT4– TPO Ab (+)

• Pregnant women w/ TPO Ab (+)– Miscarriage rate doubles– ↑ risk post partum thyroiditis (35%)

– mild anemia – ↑ CPK-MB– ↑ LDL,↑ Chol (↓ lipid clearance)– Hyponatremia

Hypothyroidism (Treatment)

Synthroid (LT4) • Initial starting dosage 1.6 mg/kg/day.

– Dose correlates better w/ lean body wt

• ≈ 80% of PO dose of LT4 is absorbed– vs. Cytomel which is 95% absorbed

• The main absorptive sites proximal and mid-jejunum.

• Food can ↓ LT4 absorption up to 40-50%.

• Serum LT4 levels rise 10-15% after ingestion, peaking at 2-4 hrs. – Serum LT3 levels don’t change due to the

slow peripheral conversion of T4 T3.

• T-1/2 LT4 is 7 days – can be given weekly in non compliant pt’s.

• Goal LT4 replacement: TSH 1.0-2.5 mU/L

Hypothyroidism (treatment in general)

Indications for LT4 replacement• Asymptomatic: TSH > 10• Asymptomatic and TPO Ab (+): TSH > 5• Symptomatic: TSH > 5• Pregnant female: TSH > 5• Goitrous: TSH > 5

Hypothyroidism (treatment in general)

Hypothyroidism + surgery• Postpone elective surgery in any hypothyroid pt until the euthyroid

state is restored, however • Urgent surgery should not be postponed in hypothyroid pt’s,

– though potential complications should be watched for.

Hypothyroidism + elderly• It is prudent to begin treatment with low dose LT4, starting at 12.5

or 25 mcg/day• Titrate to goal or less than goal if cardiac symptoms develop

despite max anti-anginal tx.

Hypothyroidism (treatment in general)

Combined LT4/LT3 tx• Bottom Line:

– most studies show combination T4/T3 therapy does not appear to be superior to LT4 alone, for the management of hypothyroid symptoms.

• If you decide to try combined T4/T3 therapy – ↓ LT4 by 50 mcg and add 12.5 mcg LT3 (cytomel) in the a.m.– ↓ LT4 by 12.5-25 mcg, and add 5 mcg LT3 in the a.m.

• Check TSH before LT3 dose– T-1/2 Cytomel is 1 day

Hyperthyroidism

• Thyrotoxicosis = “any condition that results in thyroid hormone excess”– Includes: Graves Disease, Toxic Goiter, Thyroiditis, and Excessive

Thyroxine Ingestion

• Hyperthyroidism = “Specifically hyperfunctioning of the thyroid gland”– Most Commonly caused by Graves Disease in the young– Toxic Nodular Goiter in the elderly

Hyperthyroidism

• Graves’ Disease– Due to autoAb’s directed against the TSH receptor, resulting in

continuous stimulation of the thyroid gland to secrete hormone.• Ab’s to TSH receptor (+) in ≈ 80% of Graves’ pt’s • Ab’s to TPO or Tg are (+) in ≈ 80% of Graves’ pt’s

– Female:Male (5-10:1)– Caucasian = Asian > Black

• Toxic MNG– Generally arises in the setting of a long-standing MNG– More common in the elderly, areas of iodine deficiency

• Toxic Adenoma (Plummer’s Disease)– More common in women, areas of iodine deficiency– adenomas > 3 cm are more prone to overt hyperthyroidism

Hyperthyroidism

• Iodine-induced Hyperthyroidism (jod-basedow phenomenom)– Amiodarone-induced (AIT Type 1)– IV Contrast– Diets high in iodine

• Thyroiditis– Subacute (de Quervains)

• painful

– Postpartum• painless

– Suppurative• painful

– Amiodarone-induced (AIT Type 2)

Hyperthyroidism

• Symptoms– Jittery, shaky, nervous– Difficulty concentrating– Emotional lability– Insomnia– Rapid HR, palpitations, DOE– Feeling Hot– Weight Loss (can see weight gain)– Freq BMs (hyperdefecation, not diarrhea)– Fatigue– Menses w/ lighter flow, shorter duration

Hyperthyroidism• Exam

– Eye findings (20%)– Goiter– Thyroid bruit or thrill– Tachycardia: Sinus Tach, A-Fib– Flow murmur– Systolic Hypertension– Hyperreflexia– Tremors

• UE, tongue

– Proximal muscle weakness– Thenar/ hypothenar atrophy– Acropachy– Onycholysis (<1%)

• separation of nail from the nailbed

– Dermopathy (1%)

Hyperthyroid Eye Disease• Hyperthyroidism (any cause)

– Lid lag, lid retraction and stare – Due to increased adrenergic tone

stimulating the levator palpebral muscles.

• True Graves’ Ophthalmopathy– Proptosis– Diplopia– Inflammatory changes

• Conjunctival injection• Periorbital edema• Chemosis

– Due to thyroid autoAb’s that cross-react w/ Ag’s in fibroblasts, adipo-cytes, + myocytes behind the eyes.

Hyperthyroid Eye Disease• Causes of Worsening Ophthalmopathy

– Pre-existing eye disease– Smoking– marked ↑ T3– marked ↑ TSI titers– Not letting pt get to hypothyroid state

following 131-RAIA.

Does131-RAIA worse ophthalmopathy?• Majority of cases arise in the 18 mos before

to 18 mos after the onset of thyrotoxicosis.• Thus a fair number of cases can be ex-

pected to coincide w/ timing of 131-RAIA. • Two prospective randomized trials have

shown that 131-RAIA more likely (vs. other tx modalities) to worsen ophthalmopathy.

Graves’ Dermopathy

Thyroid Dermopathy – Thickening and redness of the

dermis• Due to lymphocytic infiltration

– Distribution• Pretibial (93.3%), • Pretibial+ feet (4.3%), • Pretibial + UE (1.1%).

Graves’ Dermopathy

Localized plaque on the outer aspect of the skin. Horny form over shin and dorsum of the foot

Thyroid Acropachy

Thyroid acropachy. This is most marked in the index fingers and thumbs.

Hyperthyroidism

• Laboratory Findings– TSH nearly undetectable– Elevated FT4 or FT3– mild leukopenia, – N/N anemia, – ↑ LFT’s and alk phos, – mild ↑ Ca++, – ↓ albumin– ↓ chol

RAIU/Scan

Increased RAIU• Graves’ Disease• Toxic Nodules

– MNG– Adenoma

• hCG secreting tumors– Hydatidiform mole

– Choriocarcinoma

• TSH mediated thyrotoxicosis– Pituitary tumor

– Pituitary resistance to thyroid hormone

• Iodine Deficiency

• RAIU produces a number. 4-hr (normal 10-15%) 24-hr (normal 20-30%)

• The scan produces a picture.

RAIU/Scan

Decreased RAIU • Thyroiditis

– Chronic painless

– Postpartum

– Subacute

– Amiodarone-induced

• Thyroiditis Factitia• Iodine Excess

– Contrast dye

– Diet

– Amiodarone

• Struma ovarii: (ectopic thyroid hormone production from thyroid tissue in an ovarian teratoma)

• RAIU produces a number. 4-hr (normal 10-15%) 24-hr (normal 20-30%)

• The scan produces a picture.

Hyperthyroidism (Treatment)

1) β-blockers (symptom control)– Propranolol (Inderal ®) LA: 60-320 mg daily – Atenolol (Tenormin ®): 50-100 mg daily– Metoprolol (Lopressor ®): 50-100 mg bid– If β-blocker contraindicated then Verapamil (Calan ®) 40-80 mg tid

2) 131-RAIA (70% thyroidologists prefer)– Dosing

• Graves: 10-15 mCi• Toxic MNG/Adenoma: 20-30 mCi

– Absolute contraindications• Pregnancy and nursing moms (excreted in breast milk)!

– Pregnancy should be deferred for at least 6 months following tx w/ 131-RAIA.

– Prudent to avoid 131-RAIA in pt’s w/ active moderate severe Graves’ ophthalmopathy.

Hyperthyroidism (Treatment)

3) Antithyroid Drugs (30% thyroidologists prefer)– Propylthiouracil (PTU)

• 100 mg bid-tid to start– Tapazole (Methimazole)

• 10X more potent the PTU • 10 mg bid-tid to start

– Complications of ATD’s • Dose dependent w/ Tapazole, Idiosyncratic w/ PTU.• Agranulocytosis (1/200-500)

– usually presents w/ acute pharyngitis/ tonsilitis or pneumonia.

• Rash • Hepatic necrosis w/ PTU, Cholestatic jaundice w/ Tapazole.• Arthralgias

Hyperthyroidism (Treatment)

3) Antithyroid Drugs (30% thyroidologists prefer)– Candidates for ATD’s

• Children and adolescents• Pt’s w/ moderate severe ophthalmopathy• Thyroid Storm• Pt’s w/ mild disease: small goiter, low titers of TSI (TSH-R

Ab), low maintenance dose• Pt’s w/ severe disease prior to 131-RAIA

– stop ATD’s 5-7 days prior to 131-RAIA

• Labs– Follow TSH/FT4, CBC, LFT’s

Hyperthyroidism (Treatment)

4) Surgery (sub-total thyroidectomy)– Indications

• Pt preference• Pregnant women w/ failed ATD’s• Large or symptomatic goiters• When there is question of malignancy

– Need to be euthyroid prior to surgery • To ↓ the risk of arrhythmias during induction of anesthesia• To ↓ the risk of thyroid storm post operatively• ATD’s + β-blockers

– Risks• Permanent hypoparathyroidism• Recurrent laryngeal nerve problems• Permanent hypothyroidism

Hyperthyroidism

Apathetic Hyperthyroidism• Elderly pt’s w/ Graves' disease may present w/ apathy, weight loss,

muscular weakness, arrhythmias (esp A-fib), CHF, + constipation.• A goiter may not be palpable in as many as 70% of pt’s• There symptoms may suggest PMR or depression• The usual hyperkinetic signs and symptoms seen in Graves’ are not

typically present in the elderly.• Check all elderly w/ new-onset atrial arrhythmias or CHF for

hyperthyroidism

HyperthyroidismThyroid Storm• A life-threatening condition characterized by an exaggeration of the

manifestations of thyrotoxicosis• Diagnostic Criteria (based on point system)

– Thermoregulatory Dysfunction: ↑ Temp (99°>104°)– CNS: +/-, mild (Agitation)/mod (delirium)/severe (seizures,

coma)– Tachycardia: (99>140 bpm)– CHF: +/-, mild (edema)/mod (rales)/severe (pulm edema)– Atrial Fibrillation: +/-– Precipitant History

• Treatment– ATD’s (PTU, Tapazole)– Iodide (Lugol’s solution)– β-blockers– Corticosteroids– Avoid ASA– Definitive Tx when euthyroid: 131-RAIA or surgery

Subclinical Hyperthyroidism

• Refers to an elevation in T4 and/or T3 within the normal range, leading to suppression of the pituitary secretion of TSH in the subnormal range (i.e. normal T4 and T3, low TSH).

• Clinical symptoms and signs are frequently absent or nonspecific.• Usually found in the elderly• Often due to an autonomously functioning MNG or adenoma.• Studies have linked subclinical thyrotoxicosis to

– Accelerated bone loss in postmenopausal women

– A higher incidence of atrial dysrhythmias (esp atrial fibrillation)

• Recent studies suggest an increase in cognitive impairment and all-cause mortality (esp CV disease).

• A TSH below the lower limit of normal, but above 0.1 mIU/mL are less likely to result in such complications.

• If pt’s are not treated, then careful f/u.

Thyroid Nodules

• Structural disorders of the thyroid (i.e. nodules- simple or multiple) are more common than functional disorders.

• Prevalence– Palpable: 5%– Non-Palpable: 40-50%– Cancer in nodules: 5%

• Risks– Women > Men– Smoking– h/o XRT to head/neck (esp children) – Iodine deficiency

• Most are Euthyroid and Asymptomatic• Less than 1% with thyrotoxicosis

Thyroid Nodules

Red Flags concerning for Cancer• Male• Extremes of age (<20 or >60)• Rapid Growth• > 4 cm• Symptoms of local invasion

– hoarseness, dysphagia• h/o XRT to the head/neck (esp children)• Family history of Thyroid Ca

– (PTC or MTC)• Hard, fixed lesion• (+) LN• h/o familial adenomatous polyposis

Thyroid NodulesFNA Results:• Benign (69%)

– f/u 6-12 months– Surgery if

• MNG w/ compressive Symptoms• Growth of Nodule• Recurrence of cystic nodule after

aspiration• Insufficient (17%)

– Repeat FNA 3-4 months• Indeterminate/ Suspicious (10%)

– follicular neoplasm • 85% benign adenomas

– 123-RAIU/Scan– Surgery

• Malignant (5%)– Surgery– 131-RAIA if PTC or FTC

Thyroid Nodules “Mimickers”

• Thyroid Hemiagenesis– Agenesis of one lobe of the thyroid, w/

hypertrophy of the other presenting as a mass in the neck mimicking a nodule.

– Occurs in 1/2500 people– Usually the left lobe that fails to develop

w/ hypertrophy in the right lobe.• 95% of the time

• Parathyroid gland• Thyroglossal duct remnants

Thyroid Cancer

• Papillary Thyroid Ca (PTC): 75%• Follicular Thyroid Ca (FTC): 15-20%• Medullary Thyroid Ca (MTC): < 5%• Anaplastic: < 5 %• Lymphoma: rare

– Hashimoto’s is a risk factor• Metastatic to thyroid: rare

– Breast, Renal cell, melanoma and lung Ca

MTC• FMTC• MEN2A

– MTC, HyperPTH, Pheo• MEN2B

– MTC, Pheo, Mucosal neuromas

Thyroid Disease in Pregnancy

Four factors alter thyroid function in pregnancy1) Transient ↑ in hCG, during the 1st trimester can stimulate the TSH-R

- Gestational Transient Thyrotoxicosis (GTT)

- Hyperemesis gravidarum

2) E2-induced ↑ in TBG during the 1st trimester, which is sustained during pregnancy.

3) Alterations in immune function leading to onset, exacerbation, or amelioration of an underlying autoimmune thyroid disease.

4) ↑ urinary iodide excretion, which can cause impaired thyroid hormone production in areas of marginal iodine deficiency (<50 µg/d).

- ↑ risk of goiter and hypothyroidism

Thyroid Disease in Pregnancy

• Women need more LT4 during pregnancy – ↑ in TBG (2- to 3-fold) due to E2

• resulting in a 30-100% increase in total T4 and total T3, but• and ↓ in FT4 and FT3

– ↑ renal LT4 clearance – Transfer of LT4 to the fetus

Known Hypothyroidism already on LT4• ↑ dose by 30% (25-50 µg) taking an extra pill 2 days a week as soon

as pregnancy is confirmed.• Make further dose changes based on serum FT4 + TSH levels

measured every 4 weeks until it is normal, and then measure the TSH once per trimester.

Thyroid Disease in Pregnancy

• Frequency of various clinical presentations of postpartum thyroid dysfunction– Hypothyroid (postpartum exacerbation of Hashimoto’s): 40%– Hyper-/Hypothyroid (postpartum thyroiditis): 25%– Hyperthyroid Thyroiditis (postpartum thyroiditis): 24%– Hyperthyroid Graves’: 20%

Stage 1

Stage 2

Stage 3Stage 4

Thyroid Disease in Pregnancy

• Glycoprotein hormones – LH, FSH, TSH + hCG– Share a similar alpha subunit (α-SU)– Beta subunit (β-SU) are

immunologically + biologically unique.

– There is considerable homology between β-SU’s of hCG and TSH.

• Distinct 1st trimester increase in hCG– 10-20% of normal pregnant women have

low TSH concentrations at peak hCG.

hCG Peak: 10-12 wks

Thyroid Disease in Pregnancy

Hyperemesis Gravidarum (HG)• Hyperthyroidism is assoc w/ severe vomiting (“toxic vomiting”) +

> 5% wt loss• Hyperemesis is assoc w/ elevated T4 + low TSH in > 50% of

affected woman.– Usu transient w/ normal TFT’s by 2nd trimester

– In transient cases, no goiter, (-) Thyroid Ab’s, + few manifestations of hyperthyroidism

• Due to elevated hCG levels – > 75,000-100,000 IU/L

• Treatment is controversial• ATD’s do not reduce vomiting despite normalization of TFT’s• Consider ATD’s if hyperthyroxinemia extends into the 2nd trimester.

Thyroid Disease in Pregnancy

Hyperemesis Gravidarum vs. Graves’• Can be a difficult distinction if pt actively vomiting• Clues pointing to Graves’ Disease

– Goiter– Thyroid bruit– Ophthalmopathy– Onycholysis– Pre-existing thyroid c/o prior to pregnancy– (+) TSI– Elevated FT3 levels

• See ↓ T4T3 conversion w/ HG (assoc w/ ↓ in nutrition) • Diagnostic123-RAI or 131-RAI scanning contraindicated!!!

– At 12 weeks gestation the fetal thyroid has 20-50x the avidity for iodine than does the maternal thyroid.

Thyroid Disease in Pregnancy

Graves’ (Treatment)• PTU, Tapazole and β-blockers all cross the placenta.• ATD’s still mainstay of tx

– PTU preferred (crosses placenta < Tapazole)– Tapazole may be assoc w/ aplasia cutis– The lowest possible dose should be given

• Goal of tx w/ ATD: maintain the mothers FT4 or FT3 in the high-normal range.– TSH levels often remain suppressed w/ FT4 or FT3 in these

ranges + can’t be accurately used for titrating ATD.• If unable to use ATD- surgery (subtotal thyroidectomy) can be done

during 2nd trimester. – 1st trimester: ↑ risk of miscarriage– 3rd trimester: ↑ risk of preterm labor

Causes of Increased LT4 requirement

• Post menopausal therapy: – Estrogen

• Drugs known to interfere with absorption: – FeSO4 – Calcium carbonate – Cholestyramine (and probably colestipol) – Sodium polystryene sulfonate (Kayexalate) – sulcrafate (Carafate) – Aluminum hydroxide (Amphogel) – soy-based feeding formulas (infants, post-menopausal women)

– Raloxifene (Evista)

• Separate LT4 and other medications or supplements at least 2-4 hrs apart!

Causes of Increased LT4 requirement

• Drugs that increase LT4 metabolism in the liver by inducing microsomal enzymes: – Rifampin – Carbamazepine (Tegretol) – Phenytoin (Dilantin) – Phenobarbitol

• Increased clearance: – Nephrotic syndrome – Pregnancy

• Drugs with unknown mechanism: – Sertraline (Zoloft) – Lovastatin (Mevacor)- 1 case report

Causes of Increased LT4 requirement

• Malabsorptive States: – High fiber diets – Intestinal diseases: celiac disease, inflammatory bowel disease,

short bowel syndromes, protein losing enteropathy – Pancreatic exocrine insufficiency – Hepatic cirrhosis

• Weight gain• Progression of the hypothyroid disease process itself!

Drugs Affecting Thyroid Function

Somatostatin, Glucocorticoids

Dopamine

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

TSH

Amiodarone Effect on Thyroid Function

The End!

Amiodarone and the ThyroidIodine Effect• Inability to “Escape” from the Wolff-Chaikoff effect results in an

increased goiter or Hypothyroidism. • Jod-Basedow phenom could occur in someone with occult MNG (AIT

type 1)Direct Toxic Effect• Thyroiditis (AIT type 2)

“Innocent Changes”• “Innocent” changes in TFT’s can occur in > 50% of pt’s• Due to a Decreased conversion of T4 T3 (Inhibition of Type’s I + II 5’-

deiodinase) • T4 levels Increase 20-40% during the 1st month, then gradually fall

towards baseline • T3 levels Decrease by up to 30% within the 1st few weeks of tx and

remain at this level • rT3 levels Increase by 20% soon after initiation of tx and remain at this

level • TSH levels initially Increase, then return to NL in 2-3 mos

Jod-Basedow phenomenon (Historical)

• Definition- Hyperthyroidism induced by excess Iodine.

• Coindet (French physician) in 1821 published his cases about Hyperthyroidism.

• In the English speaking world this became known as Graves’ disease (1835), and in the German speaking world as von Basedow’s disease (1840).

• Coindet’s cases of hyperthyroidism were actually Iodine-induced, hence it came to be known as the Iodine-Basedow phenom.

• Jod is German for Iodine, hence the Jod-Basedow phenom!• Coindet was deprived of credit for not only describing Hyper-

thyroidism, but also the variant of hyperthyroidism caused by excess Iodine

• The credit was given to Dr “Jod” who never existed!

Conditions affecting Thyroid Function

Somatostatin, Glucocorticoids

Dopamine

Block Synthesis of new T4 + T3LithiumIodinePTU + MethimazoleAmiodarone

Block peripheral T4 T3 ConversionProparanololGlucocorticoidsPTU (Propylthiouracil)AmiodaroneNa+ ipodate (iopanic acid)

Thyroid Disease in Pregnancy

Euthyroid women, (+) TPO Ab’s• Euthyroid pregnant women w/ (+) TPO Ab’s develop impaired thyroid

function• Tx w/ LT4 reduces the risk of miscarriage and prematurity in TPO Ab

(+) women • LT4 doses

– 0.5 mcg/kg/d for TSH < 1 mU/L– 0.75 mcg/kg/d for TSH 1-2 mU/L– 1 mcg/kg/d for TSH > 2 mU/L or TPO Ab titers > 1:1500

• Is it reasonable to screen all pregnant women for TPO Ab’s and TSH?

Negro R, et al. JCEM 2006

Autoimmune Polyglandular Syndromes 2• Classic Triad:

– Adrenal Insufficiency – Autoimmune thyroid disease (hypo or hyperthyroidism) – Type 1 DM

• Only 2 of the 3 are required for diagnosis • F:M 3:1 • Age of onset tends to be between 20 and 30 years• Other components of APS-2

– Primary Hypogonadism – Myasthenia Gravis – Celiac disease – Pernicious Anemia – Alopecia – Vitiligo – Serositis – Stiffman Syndrome – ITP – IgA deficiency/ Goodpasture’s syndrome

Hyperthyroidism

Hypokalemic Periodic Paralysis• Reported in conjunction w/ thyrotoxicosis• More common in Asian men• Symptoms sudden

– Muscle stiffness/cramps– Flaccid paralysis

• Due to shift of K+ intracellularly• Treatment

– K+ for hypokalemia– Β-blockers– Rapid reduction in thyroid hormone

Hyperthyroid Eye Disease

• Does 131-RAIA worsen ophthalmopathy?• The natural course of Graves’ disease is such that 15-20% have

significant ophthalmopathy.• The majority of cases arise in the 18 mos before to 18 mos after the

onset of thyrotoxicosis.• Thus a fair number of cases can be expected to coincide w/ the

timing of 131-RAIA.• Two prospective randomized trials have shown that 131 RAIA is

more likely than other tx modalities to worsen ophthalmopathy.• Prudent to avoid 131-RAIA in pt’s w/ active moderate severe

Graves’ ophthalmopathy.• Tx others at ↑ risk (esp smokers) w/ course of oral corticosteroids.

Cutis Aplasia

Cutis Aplasia Keloid Cutis Aplasia

Congenital absence of the skin, particularly on the scalp, larger defects may extend to the dura or meninges. Generally isolated lesions, but can also be associated with a variety of other genetic disorders. Heals as a flat scar or keloid lump.

Thyroid Binding Globulin (TBG)

• Hepatitis/ Biliary Cirrhosis• OCP’s• Pregnancy• Estrogens

(also Tamoxifen + Raloxifene)

• Drugs (Narcotics/Heroin, Methadone, Clofibrate, Major Tranquilizers, 5-FU)

• Steroids/Glucocorticoids• Hypoalbuminemia• Androgens

(Testosterone, Danazol)

• Nephrotic syndrome• Acromegaly

• Drugs (Niacin, L-asparginase)

Increased TBG Decreased TBG

Thyroid Regulation

Somatostatin, Glucocorticoids

Dopamine

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

TSH

Myxedema

Hyperthyroid Eye Disease

Lid Lag

T4 binds tightly to TBG, but weakly to albuminT3 also binds to these proteins but not as strongly

Thyroid Disease in Pregnancy

• 1st trimester increase in hCG• Glycoproteins

– LH/FSH, TSH + hCG• Share a similar alpha subunit (α-SU)• Beta subunit (β-SU) are immunologically + biologically distinct

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

T = Tyrosyl ring(aka Inner ring)P = Phenolic ring(aka Outer ring)

Amiodarone the Thyroid

• “Innocent” changes in TFT’s can occur in > 50% of pt’s• Due to a Decreased conversion of T4 T3 (Inhibition of

Type’s I + II 5’- deiodinase) • T4 levels Increase 20-40% during the 1st month, then

gradually fall towards baseline

• T3 levels Decrease by up to 30% within the 1st few weeks of tx and remain at this level

• rT3 levels Increase by 20% soon after initiation of tx and remain at this level

• TSH levels initially Increase, then return to NL in 2-3 mos

Amiodarone Effects on Thyroid

• 37% of Amiodarone’s mass is Iodine (contains 2 iodine molecules).

• Dietary Recommendations for Daily Iodide (World Health Organization) for Adults – 150 mcg. – Avg US intake: 240- 700 mcg

• Each 200mg tab contains 75 mg Iodine

• 10% (7mg) as free is released iodine, almost 50x’s the daily recommended allowance!

• Accumulates in the Liver and Adipose Tissue

• T-1/2 ~ 100 days. Total body Iodine stores can remain elevated for up to 9 months after stopping the drug

Amiodarone Effects on Thyroid

• Pt’s with underlying thyroid disease often have defects in the autoregulation of Iodine.

• National Health + Nutrition Examination Study: 11.3% positive for Anti-TPO Ab’s

Iodine Effect• Inability to “Escape” from the Wolff-

Chaikoff effect results in an increased goiter or Hypothyroidism.

• Jod-Basedow phenom could occur in someone with occult MNG (AIT type 1)

Direct Toxic Effect• Thyroiditis (AIT type 2)

Thyroid Hormone

• There is no absorption from the stomach. Absorption occurs in the small bowel.

• The main absorptive sites appear to be the proximal and mid-jejunum.

• Progressively decreasing degrees of absorption occur along the distal bowel and proximal colon.

• Hypothyroidism can lead to a slight increase in absorption.

Images obtained from technetium-99m-pertechnetate (TcO4) thyroid scintigraphy show abnormally increased homogeneous radiotracer uptake throughout the thyroid, which is normal in size. The intensity of thyroid gland uptake exceeds the uptake in both salivary glands (arrows), background activity is markedly decreased, and the pyramidal lobe is clearly visible. All of these findings indicate a hyperfunctioning gland. There is no focal photopenic or focal hot area to suggest a nodule.