Thyroid Physiology and Thyroid Physiology and ThyroiditisThyroiditis

Heidi Chamberlain Shea, MDHeidi Chamberlain Shea, MDEndocrine Associates of DallasEndocrine Associates of Dallas

Case PresentationCase Presentation

23 year old female23 year old female G2P2G2P2 6 months post partum6 months post partum Palpitations that were Palpitations that were

intermittent for a couple of intermittent for a couple of weeks and now resolvedweeks and now resolved

Now with 1 month of increased Now with 1 month of increased fatigue, hair loss and 10 pound fatigue, hair loss and 10 pound weight gain weight gain

Case PresentationCase Presentation

What is her diagnosis?What is her diagnosis?

Tests that should be done?Tests that should be done?

Pathophysiology of her disease process?Pathophysiology of her disease process?

Thyroid TriviaThyroid Trivia

““Bronchocele”Bronchocele” Greek for tracheal Greek for tracheal

outpouchoutpouch

1500 AD described by 1500 AD described by Leonardo da VinciLeonardo da Vinci

1656 AD “thyroid” 1656 AD “thyroid” Thomas WhartonThomas Wharton Shield shaped cartilageShield shaped cartilage

Thyroid TriviaThyroid Trivia

Largest endocrine Largest endocrine glandgland 20 grams in adult20 grams in adult Each lobe Each lobe

2-2.5cm in width and 2-2.5cm in width and thicknessthickness

4cm in height4cm in height IsthmusIsthmus

0.5cm thick0.5cm thick

2cm height and width2cm height and width

ThyroidThyroid

Derived from endoderm Derived from endoderm at base of tongueat base of tongue

Recognizable after 1 Recognizable after 1 month of fetal lifemonth of fetal life

Isthmus lies over 2Isthmus lies over 2ndnd and and 33rdrd tracheal rings tracheal rings

2cm wide x 2 cm height x 2cm wide x 2 cm height x 0.5cm thick0.5cm thick

Adult 15-20 gramsAdult 15-20 grams

ThyroidThyroid

Largest of the endocrine glandsLargest of the endocrine glands

Blood flow 5x the weight of the gland/minuteBlood flow 5x the weight of the gland/minute

Hormones producedHormones produced 93% thyroxine (T4)93% thyroxine (T4) 7% triiodothyronine (T3)7% triiodothyronine (T3)

4x the potency of thyroxine4x the potency of thyroxine

Responsible for the basal metabolic rateResponsible for the basal metabolic rate Deficiency = 40-50% fall in metabolic rateDeficiency = 40-50% fall in metabolic rate Excess = 60-100% increase in metabolic rateExcess = 60-100% increase in metabolic rate

Thyroid HistologyThyroid HistologyMultiple closed follicles Multiple closed follicles (100-300 micrometers)(100-300 micrometers)

Cuboidal epithelial cells Cuboidal epithelial cells secrete colloid into the secrete colloid into the folliclesfollicles

Colloid = thyroglobulinColloid = thyroglobulin Large glycoprotein with 70 Large glycoprotein with 70

tyrosine amino acidstyrosine amino acids Endoplasmic reticulum Endoplasmic reticulum

and Golgi apparatus and Golgi apparatus synthesize and secretesynthesize and secrete

TRH(+)

HYPOTHALAMUS

ANTERIORPITUITARY

HYPOTHALAMIC-PITUITARY

PORTAL SYSTEM

T4, T3 (T4 --> T3)THYROID GLAND

TSH

POSTERIORPITUITARY

(-)

(-)

TRHTRH

Produced by HypothalamusProduced by Hypothalamus

Release is pulsatile, circadianRelease is pulsatile, circadian

Downregulated by TDownregulated by T44, T, T33

Travels through portal venous system to Travels through portal venous system to adenohypophysisadenohypophysis

Stimulates TSH formationStimulates TSH formation

TSHTSHProduced by Adenohypophysis ThyrotrophsProduced by Adenohypophysis Thyrotrophs

Upregulated by TRH Upregulated by TRH

Downregulated by TDownregulated by T44, T, T33

Travels through portal venous system to Travels through portal venous system to cavernous sinus, body.cavernous sinus, body.

Stimulates several processesStimulates several processes Iodine uptakeIodine uptake Colloid endocytosisColloid endocytosis Growth of thyroid gland Growth of thyroid gland

Thyroid PhysiologyThyroid PhysiologyUptake of Iodine by thyroidUptake of Iodine by thyroid

Coupling of Iodine to ThyroglobulinCoupling of Iodine to Thyroglobulin

Storage of MIT / DIT in follicular spaceStorage of MIT / DIT in follicular space

Re-absorption of MIT / DITRe-absorption of MIT / DIT

Formation of TFormation of T33, T, T44 from MIT / DIT from MIT / DIT

Release of TRelease of T33, T, T44 into serum into serum

Breakdown of TBreakdown of T33, T, T44 with release of Iodine with release of Iodine

Thyroid and IodineThyroid and Iodine

50 mg of iodides are needed per year50 mg of iodides are needed per year 1 mg/week1 mg/week Iodized saltIodized salt

1 part Na iodide to 100,000 parts NaCl1 part Na iodide to 100,000 parts NaCl

Iodides are ingested and oxidized to iodine in Iodides are ingested and oxidized to iodine in the thyroidthe thyroid Nascent iodine(INascent iodine(Ioo) or I) or I33

--

Peroxidase enzyme (hydrogen peroxide)Peroxidase enzyme (hydrogen peroxide)

1/5 of ingested iodine utilized for hormone 1/5 of ingested iodine utilized for hormone synthesissynthesis

Iodide CirculationIodide Circulation

Iodine uptakeIodine uptake

NaNa++/I/I-- symport protein symport protein controls serum Icontrols serum I-- uptakeuptake

Based on NaBased on Na++/K/K++ antiport potentialantiport potential

Stimulated by TSHStimulated by TSH

Inhibited by Inhibited by PerchloratePerchlorate

Iodide PumpIodide PumpThyroid gland actively pumps iodide into Thyroid gland actively pumps iodide into the cell via the basal membrane the cell via the basal membrane (iodide trapping)(iodide trapping) Iodide 30x the concentration of bloodIodide 30x the concentration of blood Able to concentrate to 250x the concentration Able to concentrate to 250x the concentration

in bloodin blood

Rate of iodide trappingRate of iodide trapping TSH dependentTSH dependent

Thyroid Hormone SynthesisThyroid Hormone Synthesis

Tyrosine backboneTyrosine backbone

IodineIodine IodinaseIodinase enzyme (enzyme I) attaches iodine enzyme (enzyme I) attaches iodine

to thyroglobulinto thyroglobulin

Number of iodines determine activity of Number of iodines determine activity of thyroid hormonethyroid hormone Thyroxine (4 iodines)Thyroxine (4 iodines) Triiodothyronine (3 iodines)Triiodothyronine (3 iodines)

MIT / DIT FormationMIT / DIT Formation

Thyroid Peroxidase (TPO)Thyroid Peroxidase (TPO) Apical membrane proteinApical membrane protein Catalyzes iodide oxidation to reactive iodine Catalyzes iodide oxidation to reactive iodine

Binds to Tyrosine residues of ThyroglobulinBinds to Tyrosine residues of Thyroglobulin Antagonized by thionamidesAntagonized by thionamides Coupling enzymeCoupling enzyme

MIT with DIT= T3MIT with DIT= T3

Two DIT’s= T4Two DIT’s= T4

Pre-hormones secreted into follicular spacePre-hormones secreted into follicular space

Transport of T3 and T4Transport of T3 and T4

When in circulationWhen in circulation 93% thyroxine and 7% triiodothyronine93% thyroxine and 7% triiodothyronine Conversion to active (T3) is by slow Conversion to active (T3) is by slow

deiodination processdeiodination process 99% of T4 and T3 bound to plasma proteins99% of T4 and T3 bound to plasma proteins

Causes slow release of hormone to tissueCauses slow release of hormone to tissue

Thyroxine-binding globulin (TBG)Thyroxine-binding globulin (TBG)

Tyroxine-binding prealbumin and albuminTyroxine-binding prealbumin and albumin

Secretion of Thyroid HormoneSecretion of Thyroid HormoneStimulated by TSHStimulated by TSH

Endocytosis of colloid on apical membraneEndocytosis of colloid on apical membrane

Coupling of MIT & DIT residuesCoupling of MIT & DIT residues Catalyzed by TPOCatalyzed by TPO MIT + DIT = TMIT + DIT = T33

DIT + DIT = TDIT + DIT = T44

Hydrolysis of ThyroglobulinHydrolysis of Thyroglobulin

Release of TRelease of T33, T, T44

Release inhibited by LithiumRelease inhibited by Lithium

Thyroid HormonesThyroid Hormones

Thyroglobulin StorageThyroglobulin Storage

Thyroglobulin moleculeThyroglobulin molecule 30 thyroxine molecules30 thyroxine molecules Few triiodothyronineFew triiodothyronine

Sufficient supply for 2-3 Sufficient supply for 2-3 monthsmonths

Deiodinase enzyme Deiodinase enzyme recycles iodine when recycles iodine when thyroglobulin utilizedthyroglobulin utilized

Thyroid Hormone Thyroid Hormone

Metabolic effect of thyroxine noticed 2-3 Metabolic effect of thyroxine noticed 2-3 days after releasedays after release

Steady state of thyroid hormone 10-12 Steady state of thyroid hormone 10-12 days after ingestiondays after ingestion

Half life of 15 daysHalf life of 15 days

Due to steady state, thyroid hormone is Due to steady state, thyroid hormone is typically adjusted every 4-6 weekstypically adjusted every 4-6 weeks Check T4 vs. TSH in the short term Check T4 vs. TSH in the short term

assessmentassessment

Thyroid HormoneThyroid Hormone Majority of circulating hormone is TMajority of circulating hormone is T44

98.5% T98.5% T44

1.5% T1.5% T33

Total Hormone load is influenced by serum Total Hormone load is influenced by serum binding proteins binding proteins

Thyroid Binding Globulin 70%Thyroid Binding Globulin 70%Albumin 15%Albumin 15%Transthyretin 10%Transthyretin 10%

Regulation is based on the free component of Regulation is based on the free component of thyroid hormonethyroid hormone

Hormone Binding FactorsHormone Binding Factors

Increased TBGIncreased TBG High estrogen states (pregnancy, OCP, HRT, Tamoxifen)High estrogen states (pregnancy, OCP, HRT, Tamoxifen) Liver disease (early)Liver disease (early)

Decreased TBGDecreased TBG Androgens or anabolic steroidsAndrogens or anabolic steroids Liver disease (late)Liver disease (late)

Binding Site CompetitionBinding Site Competition NSAID’sNSAID’s Furosemide IVFurosemide IV Anticonvulsants (Phenytoin, Carbamazepine)Anticonvulsants (Phenytoin, Carbamazepine)

Hormone DegradationHormone Degradation

TT44 is converted to T is converted to T33 (active) by (active) by 5’ deiodinase5’ deiodinase

TT44 can be converted to rT can be converted to rT33 (inactive) by (inactive) by 5 deiodinase5 deiodinase

TT33 is converted to rT is converted to rT22 (inactive)by (inactive)by 5 deiodinase5 deiodinase

rTrT33 is inactive but measured by serum tests is inactive but measured by serum tests

Hypothyroidism Hypothyroidism SymptomsSymptoms

Nervous systemNervous system Forgetfulness and Forgetfulness and

mental slowingmental slowing ParesthesiasParesthesias Carpal tunnelCarpal tunnel Ataxia and decreased Ataxia and decreased

hearinghearing Tendon jerk slowed Tendon jerk slowed

with prolonged with prolonged relaxation phaserelaxation phase

CardiovascularCardiovascular BradycardiaBradycardia Decreased cardiac Decreased cardiac

outputoutput Pericardial effusionPericardial effusion Reduced voltage on Reduced voltage on

EKG and flat T wavesEKG and flat T waves Dependent edemaDependent edema

HypothyroidismHypothyroidismSymptomsSymptoms

GastrointestinalGastrointestinal ConstipationConstipation Achlorhydria with Achlorhydria with

pernicious anemiapernicious anemia Ascitic fluid with high Ascitic fluid with high

proteinprotein

Renal Renal Reduced excretion of Reduced excretion of

water loadwater loadHyponatremiaHyponatremia

Decreased renal blood Decreased renal blood flow and glomerular flow and glomerular filtrationfiltration

PulmonaryPulmonary Responses to hypoxia and Responses to hypoxia and

hypercapnia are decreasedhypercapnia are decreased Pleural effusions high Pleural effusions high

proteinprotein

MusculoskeletalMusculoskeletal ArthralgiaArthralgia Joint effusionsJoint effusions Muscle crampsMuscle cramps CK can be elevatedCK can be elevated

AnemiaAnemia Normochromic normocyticNormochromic normocytic MegaloblasticMegaloblastic

Pernicious anemiaPernicious anemia

HypothyroidismHypothyroidismSymptomsSymptoms

Skin and hairSkin and hair Loss of lateral eye browsLoss of lateral eye brows Dry, cool skinDry, cool skin Facial featuresFacial features

Coarse and puffyCoarse and puffy Orange skinOrange skin

CaroteneCarotene

Reproductive systemReproductive system Menorrhagia from Menorrhagia from

anovulatory cyclesanovulatory cycles HyperprolactinemiaHyperprolactinemia

No inhibition of thyroid No inhibition of thyroid hormonehormone

MetabolismMetabolism HypothermiaHypothermia Intolerance to coldIntolerance to cold Increased cholesterol Increased cholesterol

and triglycerideand triglycerideDecreased lipoprotein Decreased lipoprotein receptorsreceptors

Weight gainWeight gain

Thyroid HormoneThyroid Hormone

Metabolic effect of thyroxine noticed 2-3 Metabolic effect of thyroxine noticed 2-3 days after releasedays after release

Steady state of thyroid hormone 10-12 Steady state of thyroid hormone 10-12 days after ingestiondays after ingestion

Half life of 15 daysHalf life of 15 days

Due to steady state, thyroid hormone is Due to steady state, thyroid hormone is typically adjusted every 4-6 weekstypically adjusted every 4-6 weeks Check T4 vs TSH in the short term Check T4 vs TSH in the short term

assessmentassessment

HypothyroidismHypothyroidismEtiologiesEtiologies

ThyroiditisThyroiditis

Thyroid ablationThyroid ablation

External radiotherapyExternal radiotherapy

Pharmacologic agentsPharmacologic agents

Infiltrative disordersInfiltrative disorders

Embryologic variantsEmbryologic variants

ThyroiditisThyroiditisDecreased uptake on Decreased uptake on uptake scanuptake scanTransientTransient

Euthyroidism returns with Euthyroidism returns with time time

Lead to chronic thyroid Lead to chronic thyroid dysfunctiondysfunction

EtiologyEtiology InfectiousInfectious Post-partumPost-partum Auto-immuneAuto-immune

TransientTransientChronicChronic

DrugDrug

ThyroiditisThyroiditisThyrotoxic phaseThyrotoxic phase Short phaseShort phase Increased T3 and T4Increased T3 and T4 Symptoms of Symptoms of

hyperthyroidismhyperthyroidism Thionamides not Thionamides not

effectiveeffectiveThyroid synthesis lowThyroid synthesis low

Can use beta-blockersCan use beta-blockers

Hypothyroid phaseHypothyroid phase Transient or permanentTransient or permanent Symptomatic patients Symptomatic patients

need replacementneed replacement Can check for recovery Can check for recovery

with stopping after 3-6 with stopping after 3-6 monthsmonths

ThyroiditisThyroiditisTime CourseTime Course

Williams Text of Endocrinology, Fig 11.50

Infectious ThyroiditisInfectious Thyroiditis

EtiologyEtiology Bacterial 90%Bacterial 90% FungalFungal MycobacterialMycobacterial ParasiticParasitic SyphiliticSyphilitic

SymptomsSymptoms Thyroid pain and Thyroid pain and

tendernesstenderness FeverFever DysphagiaDysphagia Dysphonia Dysphonia

TreatmentTreatment Treat the infectionTreat the infection

Autoimmune ThyroiditisAutoimmune ThyroiditisChronic LymphocyticChronic Lymphocytic

Silent ThyroiditisSilent Thyroiditis Hashimoto’sHashimoto’s

Women 3.5/1000Women 3.5/1000Men 0.8/1000Men 0.8/1000Frequency increases with Frequency increases with ageageFamilial historyFamilial historyAssociated with Associated with autoimmune diseasesautoimmune diseases

AntibodiesAntibodies Thyroid peroxidaseThyroid peroxidase

More specificMore specific ThyroglobulinThyroglobulin

Elevated in many types of Elevated in many types of thyroid inflammationthyroid inflammation

ThyroiditisThyroiditisPostpartum thyroiditisPostpartum thyroiditis 2-21% of pregnancies2-21% of pregnancies Can occur up to one Can occur up to one

year post partumyear post partum Usually transient and Usually transient and

returns to euthyroid returns to euthyroid statestate

Treat Treat HypothyroidismHypothyroidism

Symptoms with Symptoms with ‘hyperthyroidism’‘hyperthyroidism’

Presence of TPO AB Presence of TPO AB increases risk of long increases risk of long term hypothyroidismterm hypothyroidism

Transient/Destructive ThyroiditisTransient/Destructive Thyroiditis

SubacuteSubacute 20% of thyrotoxic cases20% of thyrotoxic cases De Quervain’s thyroiditisDe Quervain’s thyroiditis Giant cell thyroiditisGiant cell thyroiditis Pseudogranulomatous Pseudogranulomatous

thyroiditisthyroiditis Subacute painful thyroiditisSubacute painful thyroiditis

SymptomsSymptoms PainPain FeverFever Increased ESRIncreased ESR Hoarseness or dysphagiaHoarseness or dysphagia

TreatmentTreatment ASA, NSAIDASA, NSAID Steroid rarelySteroid rarely

Comparison of ThyroiditisComparison of ThyroiditisCharacteristicCharacteristic Silent thyroiditisSilent thyroiditis Subacute thyroiditisSubacute thyroiditisAge of onset (yr)Age of onset (yr) 5-935-93 20-6020-60

Sex ratio (F:M)Sex ratio (F:M) 2:12:1 5:15:1

EtiologyEtiology AutoimmuneAutoimmune ViralViral

PathologyPathology Lymphocytic infiltrationLymphocytic infiltration Giant cells, granulomasGiant cells, granulomas

ProdromeProdrome PregnancyPregnancy Viral illnessViral illness

GoiterGoiter Non-painfulNon-painful PainfulPainful

Fever/malaiseFever/malaise NoNo YesYes

TPO/thyroglobulin ABTPO/thyroglobulin AB High and risingHigh and rising Low, absent or transientLow, absent or transient

ESRESR NormalNormal HighHigh

RAIURAIU <5%<5% <5%<5%

RelapseRelapse CommonCommon RareRare

Permanent Permanent hypothyroidismhypothyroidism

CommonCommon InfrequentInfrequent

Drug Induced Thyroid DysfunctionDrug Induced Thyroid Dysfunction

LithiumLithium Inhibits thyroid hormone Inhibits thyroid hormone

secretionsecretion HypothyroidismHypothyroidism 3.4% prevalence3.4% prevalence

Interferon-Interferon-αα Hyper/HypothyroidismHyper/Hypothyroidism Transient thyroiditisTransient thyroiditis TPO AB increases risk of TPO AB increases risk of

thyroid dysfunctionthyroid dysfunction

Interleukin-2Interleukin-2

AminoglutethimideAminoglutethimide

EthionamideEthionamide

SulfonamidesSulfonamides

Drug Induced Thyroid DysfunctionDrug Induced Thyroid Dysfunction

AmiodaroneAmiodarone 75 mg iodine/200 mg75 mg iodine/200 mg HypothyroidismHypothyroidism ThyrotoxicosisThyrotoxicosis

Type I and Type IIType I and Type II Increased blood flow vs. Increased blood flow vs.

decreased blood flowdecreased blood flow

Not responsive to thionamidesNot responsive to thionamides

HypothyroidismHypothyroidismInfiltrative DisordersInfiltrative Disorders

Riedel’s thyroiditisRiedel’s thyroiditis Invasive Fibrous ThyroiditisInvasive Fibrous Thyroiditis Thyroid tissue replaced by Thyroid tissue replaced by

fibrous tissuefibrous tissue Rapidly enlarging neck Rapidly enlarging neck

massmass Compressive symptomsCompressive symptoms Surgical removalSurgical removal Steroids and tamoxifenSteroids and tamoxifen

AmyloidosisAmyloidosis

SarcoidosisSarcoidosis

HemochromatosisHemochromatosis

CystinosisCystinosis

Pneumocystis cariniiPneumocystis carinii

LymphomaLymphoma

Thyroid Hormone ReplacementThyroid Hormone Replacement1.3 ug/kg/day1.3 ug/kg/day

75-100 ug per day75-100 ug per day

Elderly or patients with Elderly or patients with anginaangina

12.5-25 ug/day 12.5-25 ug/day Carefully increase every Carefully increase every monthmonth

IV dosingIV dosing Use 60% of oral doseUse 60% of oral dose

LevothyroxineLevothyroxine SynthroidSynthroid LevoxylLevoxyl UnithroidUnithroid

Armour ThyroidArmour Thyroid T3/T4 preparationT3/T4 preparation Dessicated pig thyroidDessicated pig thyroid Not a consistent amount of Not a consistent amount of

T3/T4T3/T4

Most T3 preparations give Most T3 preparations give higher than 1:11 ratio of higher than 1:11 ratio of T3:T4T3:T4

Case PresentationCase Presentation

23 year old female23 year old female G1P1G1P1 6 months post partum6 months post partum Palpitations that were Palpitations that were

intermittent for a intermittent for a couple of weeks and couple of weeks and now resolvednow resolved

Now with 1 month of Now with 1 month of increased fatigue, hair increased fatigue, hair loss and 10 pound loss and 10 pound weight gain weight gain

Case PresentationCase Presentation

What is her diagnosis?What is her diagnosis? Post partum thyroiditisPost partum thyroiditis

Tests that should be done?Tests that should be done? TSH 15 uIU/ml, Free T4 1.2 ng/dlTSH 15 uIU/ml, Free T4 1.2 ng/dl TPO AB negativeTPO AB negative

Pathophysiology of her disease process?Pathophysiology of her disease process? TransientTransient

TreatmentTreatment Levothyroxine therapyLevothyroxine therapy Recheck every 6-8 monthsRecheck every 6-8 months After 3-6 months may be able to wean replacementAfter 3-6 months may be able to wean replacement

Post Partum ThyroiditisPost Partum ThyroiditisTime CourseTime Course

Williams Text of Endocrinology, Fig 11.51

Changes in free T4

Williams Text of Endocrinology, Fig 12.6