Thyroid Physiology and Thyroiditis

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Thyroid Physiology and Thyroiditis

• Heidi Chamberlain Shea, MD
• Endocrine Associates of Dallas

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Case Presentation

• 23 year old female
• G2P2
• 6 months post partum
• Palpitations that were intermittent for a couple
  of weeks and now resolved
• Now with 1 month of increased fatigue, hair loss
  and 10 pound weight gain

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Case Presentation

• What is her diagnosis?
• Tests that should be done?
• Pathophysiology of her disease process?

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Thyroid Trivia

• Bronchocele
• Greek for tracheal outpouch
• 1500 AD described by Leonardo da Vinci
• 1656 AD thyroid
• Thomas Wharton
• Shield shaped cartilage

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Thyroid Trivia

• Largest endocrine gland
• 20 grams in adult
• Each lobe
• 2-2.5cm in width and thickness
• 4cm in height
• Isthmus
• 0.5cm thick
• 2cm height and width

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Thyroid

• Derived from endoderm at base of tongue
• Recognizable after 1 month of fetal life
• Isthmus lies over 2nd and 3rd tracheal rings
• 2cm wide x 2 cm height x 0.5cm thick
• Adult 15-20 grams

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Thyroid

• Largest of the endocrine glands
• Blood flow 5x the weight of the gland/minute
• Hormones produced
• 93 thyroxine (T4)
• 7 triiodothyronine (T3)
• 4x the potency of thyroxine
• Responsible for the basal metabolic rate
• Deficiency 40-50 fall in metabolic rate
• Excess 60-100 increase in metabolic rate

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Thyroid Histology

• Multiple closed follicles (100-300 micrometers)
• Cuboidal epithelial cells secrete colloid into
  the follicles
• Colloid thyroglobulin
• Large glycoprotein with 70 tyrosine amino acids
• Endoplasmic reticulum and Golgi apparatus
  synthesize and secrete

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TRH

• Produced by Hypothalamus
• Release is pulsatile, circadian
• Downregulated by T4, T3
• Travels through portal venous system to
  adenohypophysis
• Stimulates TSH formation

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TSH

• Produced by Adenohypophysis Thyrotrophs
• Upregulated by TRH
• Downregulated by T4, T3
• Travels through portal venous system to cavernous
  sinus, body.
• Stimulates several processes
• Iodine uptake
• Colloid endocytosis
• Growth of thyroid gland

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Thyroid Physiology

• Uptake of Iodine by thyroid
• Coupling of Iodine to Thyroglobulin
• Storage of MIT / DIT in follicular space
• Re-absorption of MIT / DIT
• Formation of T3, T4 from MIT / DIT
• Release of T3, T4 into serum
• Breakdown of T3, T4 with release of Iodine

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Thyroid and Iodine

• 50 mg of iodides are needed per year
• 1 mg/week
• Iodized salt
• 1 part Na iodide to 100,000 parts NaCl
• Iodides are ingested and oxidized to iodine in
  the thyroid
• Nascent iodine(Io) or I3-
• Peroxidase enzyme (hydrogen peroxide)
• 1/5 of ingested iodine utilized for hormone
  synthesis

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Iodide Circulation
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Iodine uptake

• Na/I- symport protein controls serum I- uptake
• Based on Na/K antiport potential
• Stimulated by TSH
• Inhibited by Perchlorate

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Iodide Pump

• Thyroid gland actively pumps iodide into the cell
  via the basal membrane (iodide trapping)
• Iodide 30x the concentration of blood
• Able to concentrate to 250x the concentration in
  blood
• Rate of iodide trapping
• TSH dependent

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Thyroid Hormone Synthesis

• Tyrosine backbone
• Iodine
• Iodinase enzyme (enzyme I) attaches iodine to
  thyroglobulin
• Number of iodines determine activity of thyroid
  hormone
• Thyroxine (4 iodines)
• Triiodothyronine (3 iodines)

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MIT / DIT Formation

• Thyroid Peroxidase (TPO)
• Apical membrane protein
• Catalyzes iodide oxidation to reactive iodine
• Binds to Tyrosine residues of Thyroglobulin
• Antagonized by thionamides
• Coupling enzyme
• MIT with DIT T3
• Two DITs T4
• Pre-hormones secreted into follicular space

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Transport of T3 and T4

• When in circulation
• 93 thyroxine and 7 triiodothyronine
• Conversion to active (T3) is by slow deiodination
  process
• 99 of T4 and T3 bound to plasma proteins
• Causes slow release of hormone to tissue
• Thyroxine-binding globulin (TBG)
• Tyroxine-binding prealbumin and albumin

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Secretion of Thyroid Hormone

• Stimulated by TSH
• Endocytosis of colloid on apical membrane
• Coupling of MIT DIT residues
• Catalyzed by TPO
• MIT DIT T3
• DIT DIT T4
• Hydrolysis of Thyroglobulin
• Release of T3, T4
• Release inhibited by Lithium

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Thyroid Hormones
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Thyroglobulin Storage

• Thyroglobulin molecule
• 30 thyroxine molecules
• Few triiodothyronine
• Sufficient supply for 2-3 months
• Deiodinase enzyme recycles iodine when
  thyroglobulin utilized

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Thyroid Hormone

• Metabolic effect of thyroxine noticed 2-3 days
  after release
• Steady state of thyroid hormone 10-12 days after
  ingestion
• Half life of 15 days
• Due to steady state, thyroid hormone is typically
  adjusted every 4-6 weeks
• Check T4 vs. TSH in the short term assessment

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Thyroid Hormone

• Majority of circulating hormone is T4
• 98.5 T4
• 1.5 T3
• Total Hormone load is influenced by serum binding
  proteins
• Thyroid Binding Globulin 70
• Albumin 15
• Transthyretin 10
• Regulation is based on the free component of
  thyroid hormone

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Hormone Binding Factors

• Increased TBG
• High estrogen states (pregnancy, OCP, HRT,
  Tamoxifen)
• Liver disease (early)
• Decreased TBG
• Androgens or anabolic steroids
• Liver disease (late)
• Binding Site Competition
• NSAIDs
• Furosemide IV
• Anticonvulsants (Phenytoin, Carbamazepine)

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Hormone Degradation

• T4 is converted to T3 (active) by 5 deiodinase
• T4 can be converted to rT3 (inactive) by 5
  deiodinase
• T3 is converted to rT2 (inactive)by 5 deiodinase
• rT3 is inactive but measured by serum tests

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Hypothyroidism Symptoms

• Nervous system
• Forgetfulness and mental slowing
• Paresthesias
• Carpal tunnel
• Ataxia and decreased hearing
• Tendon jerk slowed with prolonged relaxation phase

• Cardiovascular
• Bradycardia
• Decreased cardiac output
• Pericardial effusion
• Reduced voltage on EKG and flat T waves
• Dependent edema

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HypothyroidismSymptoms

• Gastrointestinal
• Constipation
• Achlorhydria with pernicious anemia
• Ascitic fluid with high protein
• Renal
• Reduced excretion of water load
• Hyponatremia
• Decreased renal blood flow and glomerular
  filtration

• Pulmonary
• Responses to hypoxia and hypercapnia are
  decreased
• Pleural effusions high protein
• Musculoskeletal
• Arthralgia
• Joint effusions
• Muscle cramps
• CK can be elevated
• Anemia
• Normochromic normocytic
• Megaloblastic
• Pernicious anemia

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HypothyroidismSymptoms

• Skin and hair
• Loss of lateral eye brows
• Dry, cool skin
• Facial features
• Coarse and puffy
• Orange skin
• Carotene
• Reproductive system
• Menorrhagia from anovulatory cycles
• Hyperprolactinemia
• No inhibition of thyroid hormone

• Metabolism
• Hypothermia
• Intolerance to cold
• Increased cholesterol and triglyceride
• Decreased lipoprotein receptors
• Weight gain

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Thyroid Hormone

• Metabolic effect of thyroxine noticed 2-3 days
  after release
• Steady state of thyroid hormone 10-12 days after
  ingestion
• Half life of 15 days
• Due to steady state, thyroid hormone is typically
  adjusted every 4-6 weeks
• Check T4 vs TSH in the short term assessment

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HypothyroidismEtiologies

• Thyroiditis
• Thyroid ablation
• External radiotherapy
• Pharmacologic agents
• Infiltrative disorders
• Embryologic variants

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Thyroiditis

• Decreased uptake on uptake scan
• Transient
• Euthyroidism returns with time
• Lead to chronic thyroid dysfunction
• Etiology
• Infectious
• Post-partum
• Auto-immune
• Transient
• Chronic
• Drug

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Thyroiditis

• Thyrotoxic phase
• Short phase
• Increased T3 and T4
• Symptoms of hyperthyroidism
• Thionamides not effective
• Thyroid synthesis low
• Can use beta-blockers

• Hypothyroid phase
• Transient or permanent
• Symptomatic patients need replacement
• Can check for recovery with stopping after 3-6
  months

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ThyroiditisTime Course
Williams Text of Endocrinology, Fig 11.50
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Infectious Thyroiditis

• Symptoms
• Thyroid pain and tenderness
• Fever
• Dysphagia
• Dysphonia
• Treatment
• Treat the infection

• Etiology
• Bacterial 90
• Fungal
• Mycobacterial
• Parasitic
• Syphilitic

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Autoimmune Thyroiditis

• Chronic Lymphocytic
• Silent Thyroiditis
• Hashimotos
• Women 3.5/1000
• Men 0.8/1000
• Frequency increases with age
• Familial history
• Associated with autoimmune diseases
• Antibodies
• Thyroid peroxidase
• More specific
• Thyroglobulin
• Elevated in many types of thyroid inflammation

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Thyroiditis

• Postpartum thyroiditis
• 2-21 of pregnancies
• Can occur up to one year post partum
• Usually transient and returns to euthyroid state
• Treat
• Hypothyroidism
• Symptoms with hyperthyroidism

• Presence of TPO AB increases risk of long term
  hypothyroidism

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Transient/Destructive Thyroiditis

• Subacute
• 20 of thyrotoxic cases
• De Quervains thyroiditis
• Giant cell thyroiditis
• Pseudogranulomatous thyroiditis
• Subacute painful thyroiditis
• Symptoms
• Pain
• Fever
• Increased ESR
• Hoarseness or dysphagia
• Treatment
• ASA, NSAID
• Steroid rarely

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Comparison of Thyroiditis
Characteristic Silent thyroiditis Subacute thyroiditis
Age of onset (yr) 5-93 20-60
Sex ratio (FM) 21 51
Etiology Autoimmune Viral
Pathology Lymphocytic infiltration Giant cells, granulomas
Prodrome Pregnancy Viral illness
Goiter Non-painful Painful
Fever/malaise No Yes
TPO/thyroglobulin AB High and rising Low, absent or transient
ESR Normal High
RAIU lt5 lt5
Relapse Common Rare
Permanent hypothyroidism Common Infrequent
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Drug Induced Thyroid Dysfunction

• Lithium
• Inhibits thyroid hormone secretion
• Hypothyroidism
• 3.4 prevalence
• Interferon-a
• Hyper/Hypothyroidism
• Transient thyroiditis
• TPO AB increases risk of thyroid dysfunction

• Interleukin-2
• Aminoglutethimide
• Ethionamide
• Sulfonamides

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Drug Induced Thyroid Dysfunction

• Amiodarone
• 75 mg iodine/200 mg
• Hypothyroidism
• Thyrotoxicosis
• Type I and Type II
• Increased blood flow vs. decreased blood flow
• Not responsive to thionamides

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HypothyroidismInfiltrative Disorders

• Riedels thyroiditis
• Invasive Fibrous Thyroiditis
• Thyroid tissue replaced by fibrous tissue
• Rapidly enlarging neck mass
• Compressive symptoms
• Surgical removal
• Steroids and tamoxifen

• Amyloidosis
• Sarcoidosis
• Hemochromatosis
• Cystinosis
• Pneumocystis carinii
• Lymphoma

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Thyroid Hormone Replacement

• 1.3 ug/kg/day
• 75-100 ug per day
• Elderly or patients with angina
• 12.5-25 ug/day
• Carefully increase every month
• IV dosing
• Use 60 of oral dose

• Levothyroxine
• Synthroid
• Levoxyl
• Unithroid
• Armour Thyroid
• T3/T4 preparation
• Dessicated pig thyroid
• Not a consistent amount of T3/T4
• Most T3 preparations give higher than 111 ratio
  of T3T4

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Case Presentation

• 23 year old female
• G1P1
• 6 months post partum
• Palpitations that were intermittent for a couple
  of weeks and now resolved
• Now with 1 month of increased fatigue, hair loss
  and 10 pound weight gain

45
Case Presentation

• What is her diagnosis?
• Post partum thyroiditis
• Tests that should be done?
• TSH 15 uIU/ml, Free T4 1.2 ng/dl
• TPO AB negative
• Pathophysiology of her disease process?
• Transient
• Treatment
• Levothyroxine therapy
• Recheck every 6-8 months
• After 3-6 months may be able to wean replacement

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Post Partum ThyroiditisTime Course
Changes in free T4
Williams Text of Endocrinology, Fig 11.51
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Williams Text of Endocrinology, Fig 12.6