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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
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