ThyroidThyroid diseasesdiseases:: hyperthyroidismhyperthyroidism

Dr habDr hab. . Jacek Jacek DaroszewskiDaroszewski Department of Department of EndocrinologyEndocrinology, , DiabetesDiabetes

and and IsotopeIsotope TherapyTherapy

jacek.daroszewski@umed.wroc.pljacek.daroszewski@umed.wroc.pl

Jacek Daroszewski

THE THYROID GLAND

Jacek Daroszewski

REGULACJA WYDZIELANIA HORMONÓW TARCZYCY Hypothalamus

Pituitary

Thyroid

Thyroid Disease Spectrum TSH measurement is the first step in assessment of function

0 10 5

TSH, IU/mL

Mild Thyroid Failure TSH >4.0 IU/mL, Free T4 Normal

Overt Hypothyroidism TSH >4.0 IU/mL, Free T4 Low

Euthyroid TSH 0.4-4.0 IU/mL, Free T4 Normal

Thyrotoxicosis TSH <0.4 IU/mL, Free T3/T4 Normal or Elevated

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.

Spectrum of thyroid dysfunction

TSHTSH

FTFT44

Euthyroidism

overt

Hypothyroidism

mild

overt

Hyperthyroidism

mild

Thyroid Disease Spectrum

0 10 5

TSH, IU/mL

Mild Thyroid Failure TSH >4.0 IU/mL, Free T4 Normal

Overt Hypothyroidism TSH >4.0 IU/mL, Free T4 Low

Euthyroid TSH 0.4-4.0 IU/mL, Free T4 Normal

Thyrotoxicosis TSH <0.4 IU/mL, Free T3/T4 Normal or Elevated

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A Fundamental and Clinical Text. 8th ed. 2000.

Canaris GJ, et al. Arch Intern Med. 2000;160:526-534.

Vanderpump MP, et al. Clin Endocrinol (Oxf). 1995;43:55-68.

Alteration in structure and dysfunction not always goes together

AlteredAltered morphologymorphology MechnismsMechnisms of of dysfunctiondysfunction ((mainlymainly hyperthyroidismhyperthyroidism))

GoiterGoiter 1. 1. tissuetissue autonomyautonomy

TThhyroiditisyroiditis 2. 2. tissuetissue destructiondestruction

Single nodule Single nodule autommunityautommunity ((inflammationinflammation))

rarerare:: drugdrug--inducedinduced

AtrophyAtrophy 3. 3. pathologicalpathological stimulationstimulation

AgenesisAgenesis ((hemihemi--)) TRAbTRAb ––TSI (Graves’)TSI (Graves’)

DyshormonogenesisDyshormonogenesis ββ--hCGhCG, , TSHTSH--omaoma

4. 4. exogenousexogenous thyroxinthyroxin ingestioningestion

Prevalence of Thyrotoxicosis

• In a cross-sectional study of urban and rural adults, the prevalence of thyrotoxicosis ranged from

– 1.9% to 2.7% in women

– 0.16% to 0.23% in men

Tunbridge WMG, et al. Clin Endocrinol. 1977;7:481-493. Jacek Daroszewski

Effects of Thyroid Hormone

• Fetal brain and skeletal maturation

• Increase in basal metabolic rate

• Inotropic and chronotropic effects on heart

• Increases sensitivity to catecholamines

• Stimulates gut motility

• Increase bone turnover

• Increase in serum glucose, decrease in serum cholesterol

Jacek Daroszewski

Effects of Thyroid Hormone

• Fetal brain and skeletal maturation

• Increase in basal metabolic rate

• Inotropic and chronotropic effects on heart

• Increases sensitivity to catecholamines

• Stimulates gut motility

• Increase bone turnover

• Increase in serum glucose, decrease in serum cholesterol

Jacek Daroszewski

THYROID HORMONES IN THE BLOODTHYROID HORMONES IN THE BLOOD

• Approximately 99.98% of T4 is bound to 3 serum proteins: Thyroid binding globulin (TBG) ~75%; Thyroid binding prealbumin (TBPA or transthyretin) 15-20%; albumin ~5-10%

• Only ~0.02% of the total T4 in blood is unbound or free.

• Only ~0.4% of total T3 in blood is free.

Jacek Daroszewski

Benign Thyroid Disease

• Benign Nontoxic Conditions – Diffuse and Nodular Goiter

• Benign Toxic Conditions – Graves’ Disease – Toxic Multinodular Goiter – Toxic Adenoma

• Inflammatory Conditions – hypothyroidism (sometimes transial hyper-) – Chronic Autoimmune (Hashimoto’s) Thyroiditis – Subacute (De Quervain’s) Thyroiditis – Riedel’s Thyroiditis

Autoimmune Thyroid Disease (ATD) :

Graves Disease, Chronic Thyroiditis, autoimmune subacute thyroiditis

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AutoimmuneAutoimmune thyroidthyroid diseasedisease (ATD)(ATD)

Graves’

Disease

Hashitoxicosis Hashimoto

Thyroiditis

Thyroid function Jacek Daroszewski

humoral reaction

cytotoxic reaction

Hyperthyroidism Underlying Causes (1)

Signs and symptoms can be caused by any disorder that results in an increase in circulation of thyroid hormone

Mechanisms of thyrotoxic states

– Tissue autonomy

– Pathological stimulation (TSI, TSH, β-hCG)

– Tissue destruction (autoimmune, painful thyroiditis, IF-α, I)

– Excessive ingestion of thyroid hormones

Jacek Daroszewski

HyperthyroidismHyperthyroidism -- uunderlyingnderlying ccausesauses (2)(2)

• Signs and symptoms are similar irrespectively of the mechanism

• Graves disease (toxic diffuse goiter)

•Toxic uninodular or multinodular goiter

•Toxic adenoma

•Painful subacute thyroiditis

•Silent thyroiditis, postpartum thyroiditis

•Iodine and iodine-containing drugs and radiographic contrast agents

•Trophoblastic disease, including hydatidiform mole

•TSH secreting pituitary adenoma

•Thyroxin overtreatment

Jacek Daroszewski

Symptoms of hyperthyroidism

Symptom Frequency (%)

NervousnessNervousness 8080––9595

PalpitationsPalpitations 6565––9999

SweatingSweating 5050––9090

Heat intolerance Heat intolerance 4040––9090

Weight lossWeight loss 5050––8585

FatigabilityFatigability 4545––8585

DyspneaDyspnea 6565––8080

FatigueFatigue 5050––8080

OligomenorrheaOligomenorrhea 4545––8080

IncreasedIncreased appetiteappetite 1010––6565

DiarrheaDiarrhea 1010––3030

Graves Disease:

• Common(2%F) 5-times more often than M males

• Females (20-40 y)

• Autoimmune etiology with familial predisposition

• Big life events may trigger

Jacek Daroszewski

Graves’ Disease

extrathyroidal symptoms

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Laboratory diagnostics Clinical signs or symptoms of hyperthyroidism

• TSH – (n) euthyroid

• TSH : FT4 – (n) FT3

• TSH FT4 or FT3 overt

• TSH FT4 and FT3 (n) subclinical

Jacek Daroszewski

Diagnostics for the cause

• Immunology:

TPO-Ab, TSHR-Ab, (TG-Ab)

• US

• Scintigraphy

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TreatmentTreatment of of HyperthyroidismHyperthyroidism

Antithyroid drugs (ATD) Inhibit the synthesis of T4 and T3

Surgical resection Remove hyperplastic and adenomatous tissues Restore normal thyroid function May lead to permanent hypothyroidism

Radioactive iodine therapy Iodine 131 taken up by functioning thyroid tissue can

decrease thyroid hormone production May lead to permanent hypothyroidism

Symptomatic treatment β-blockers (propranolol – non-selective) Steroids

Braverman LE, et al. Werner & Ingbar’s The Thyroid. A

Fundamental and Clinical Text. 8th ed. 2000. Jacek Daroszewski

Indications for antithyroid drugs (ATD)

1. Graves Disease – first episode

duration of treatment 18-24 months

titration

„block and replace” (not recommended)

2. Thyroid autonomy-MNG, toxic adenoma

Preparation to surgery

Contraindication to surgery & 131I

3. Thyroid crisis (comprehensive therapy).

Jacek Daroszewski

ATD: adverse reactions

Pruritic maculopapular rash is the most common

adverse reaction

The severe adverse reaction is agranulocytosis

Long-term use leads to thyroid hyperplasia

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131-I treatment

• Simpson SL, „Major Endocrine Disorders”, Second Edition, Oxford University Press, 1948

• Poland, Poznań 1957

• Radiation – fotons 364 keV

Radiation – fotons 606 keV , penetration range of 0.4-2 mm

DNA damage

Vassels obliteratrion

Thyroid atrophy

• T1/2 8,02 days

Jacek Daroszewski

131I treatment: indications

• Hyperthyrotic states

– GD-recurrence, pure prognosis for remission, concomitant diseases (CVD, diabetes…)

– Thyroid autonomy-MNG, toxic adenoma

– Contraindication for surgery

• Euthyroid states

– MNG (tracheal compression)

Jacek Daroszewski

131-I treatment: contraindications

absolute

•• PregnancyPregnancy

•• LLactationactation

relative

•• Young Young ageage

•• Big Big goitergoiter

•• ActiveActive orbitopathyorbitopathy

Jacek Daroszewski

131-I treatment: complications

•• HHyypothyropothyroidismidism (? (? -- thisthis isis an an aimaim))

•• ReactivationReactivation of of orbitopathyorbitopathy ((steroidssteroids))

•• ThyroiditisThyroiditis -- „„subacutesubacute––likelike””

FinalFinal assessmentassessment of of thyroidthyroid functionfunction afterafter 66--8 8 monthsmonths

Jacek Daroszewski

TSH < 0,01

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TSH – 1,23uIU/ml

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Surgery: indications

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•Thyroid malignancy (usually euthyroid)

• Tracheal compression • GD - recurrence, pure prognosis for remission •GD – active and severe

orbitopathy (??)

CauseCause of of thyrotoxthyrotox TRabTRab Thyroid USThyroid US CFDCFD RAIURAIU Other featuresOther features

Graves' diseaseGraves' disease ++ HypoechoHypoecho.. patternpattern

IncreasedIncreased IncreasedIncreased OOrbitorbito-- , , dermopathydermopathy,, acropachyacropachy

Toxic nodular goiterToxic nodular goiter -- Multiple Multiple nodulesnodules

____ “Hot” “Hot” nodulesnodules

Toxic adenomaToxic adenoma -- Single noduleSingle nodule ____ “Hot” “Hot” nodulenodule

Subacute thyroiditisSubacute thyroiditis -- HeteroHetero// hypohypo Reduced/absReduced/abs.. LowLow Neck painNeck pain--fever and fever and elevatedelevated inflammatory indexinflammatory index

Painless thyroiditisPainless thyroiditis -- HypoechoicHypoechoic LowLow

AmiodaroneAmiodarone induced induced thyroiditisthyroiditis

-- DiffuseDiffuse//nodular nodular goitergoiter//normalnormal

AllAll possibpossib LowLow High urinary iodineHigh urinary iodine

Central hyperthyroidismCentral hyperthyroidism -- DiffuseDiffuse//nodular nodular goitergoiter//normalnormal

Normal/increasedNormal/increased IncreasedIncreased Inappropriately Inappropriately normal or high TSHnormal or high TSH

Trophoblastic diseaseTrophoblastic disease -- Diffuse or Diffuse or nodular goiternodular goiter

Normal/increasedNormal/increased IncreasedIncreased

Factitious thyrotoxicosisFactitious thyrotoxicosis -- VariableVariable Normal/increasedNormal/increased LowLow Low serum Low serum thyroglobulinthyroglobulin

Struma Struma ovariiovarii -- VariableVariable Normal/increasedNormal/increased LowLow Abdominal RAIUAbdominal RAIU

Differential diagnosis of thyrotoxicosis

TSH 0.1 mU/L

TSH

> 0.1 – 0.4 mU/L

Consequences of Mild Thyrotoxicosis

Atrial Fibrillation

Adapted from: Sawin CT, et al. N Engl J Med. 1994;331:1249-1252.

30

25

20

15

10

5

0 0 1 2 3 4 5 6 7 8 9 10

Inci

de

nce

of

Atr

ial F

ibri

llati

on

(%

)

Years

Normal TSH

(> 0.4 – 5.0 mU/L)

N=2007 pts > 60

Jacek Daroszewski

• 1191 UK persons

• 60 years

• No thyroid meds • Assessments

• Serum TSH in 1988-89

• 10-year mortality • Results

• Low TSH in 6%

• TSH correlated with CV mortality

• Hazard ratio for TSH <0.5 at 2 years:

• All-cause death: 2.1

• CV death: 3.3

Parle JV, et al. Lancet. 2001;358:861-865.

Consequences of Mild Thyrotoxicosis

Cardiovascular Mortality

<0.5 <0.5

2.1–5.0 1.3–2.0 0.5–1.2

100

95

90

85

80

75

70

65

0

1 2 3 4 5 6 7 8 9 10 0

Years of Follow-up

Surv

ival

fro

m C

ircu

lato

ry D

isea

se

TSH (mU/L)

2.1–5.0

1.3–2.0

0.5–1.2

Jacek Daroszewski

Thyroid Storm

•• Acute Acute thyrotoxicosisthyrotoxicosis: beta: beta--blockers, blockers, barbiturates, barbiturates, corticosteroidscorticosteroids

•• Thyroid storm: manage aggressively with betaThyroid storm: manage aggressively with beta--blockers, calcium channel blockers, PTU, blockers, calcium channel blockers, PTU, methimazolemethimazole, sodium iodide, digitalis or , sodium iodide, digitalis or diuretics for heart failure, fluid and electrolyte diuretics for heart failure, fluid and electrolyte managementmanagement

Jacek Daroszewski

ThyroidThyroid diseasesdiseases:: hyperthyroidismhyperthyroidism

Dr habDr hab. . Jacek Jacek DaroszewskiDaroszewski Department of Department of EndocrinologyEndocrinology, , DiabetesDiabetes

and and IsotopeIsotope TherapyTherapy

jacek.daroszewski@umed.wroc.pljacek.daroszewski@umed.wroc.pl

Jacek Daroszewski