Transcript Thyroid Physiology and Thyroiditis

Thyroid Physiology and
Thyroiditis
Heidi Chamberlain Shea, MD
Endocrine Associates of Dallas
Case Presentation
23 year old female
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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
Case Presentation
What is her diagnosis?
Tests that should be done?
Pathophysiology of her disease process?
Thyroid Trivia
“Bronchocele”
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Greek for tracheal
outpouch
1500 AD described by
Leonardo da Vinci
1656 AD “thyroid”
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Thomas Wharton
Shield shaped cartilage
Thyroid Trivia
Largest endocrine
gland
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20 grams in adult
Each lobe
2-2.5cm in width and
thickness
4cm in height
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Isthmus
0.5cm thick
2cm height and width
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
Thyroid
Largest of the endocrine glands
Blood flow 5x the weight of the gland/minute
Hormones produced
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93% thyroxine (T4)
7% triiodothyronine (T3)
4x the potency of thyroxine
Responsible for the basal metabolic rate
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Deficiency = 40-50% fall in metabolic rate
Excess = 60-100% increase in metabolic rate
Thyroid Histology
Multiple closed follicles
(100-300 micrometers)
Cuboidal epithelial cells
secrete colloid into the
follicles
Colloid = thyroglobulin
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Large glycoprotein with 70
tyrosine amino acids
Endoplasmic reticulum
and Golgi apparatus
synthesize and secrete
HYPOTHALAMUS
(-)
HYPOTHALAMICPITUITARY
PORTAL SYSTEM
(-)
TRH
(+)
ANTERIOR
PITUITARY
POSTERIOR
PITUITARY
TSH
THYROID GLAND
T4, T3 (T4 --> T3)
TRH
Produced by Hypothalamus
Release is pulsatile, circadian
Downregulated by T4, T3
Travels through portal venous system to
adenohypophysis
Stimulates TSH formation
TSH
Produced by Adenohypophysis Thyrotrophs
Upregulated by TRH
Downregulated by T4, T3
Travels through portal venous system to
cavernous sinus, body.
Stimulates several processes
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Iodine uptake
Colloid endocytosis
Growth of thyroid gland
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
Thyroid and Iodine
50 mg of iodides are needed per year
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1 mg/week
Iodized salt
1 part Na iodide to 100,000 parts NaCl
Iodides are ingested and oxidized to iodine in
the thyroid
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Nascent iodine(Io) or I3Peroxidase enzyme (hydrogen peroxide)
1/5 of ingested iodine utilized for hormone
synthesis
Iodide Circulation
Iodine uptake
Na+/I- symport protein
controls serum Iuptake
Based on Na+/K+
antiport potential
Stimulated by TSH
Inhibited by
Perchlorate
Iodide Pump
Thyroid gland actively pumps iodide into
the cell via the basal membrane
(iodide trapping)
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Iodide 30x the concentration of blood
Able to concentrate to 250x the concentration
in blood
Rate of iodide trapping
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TSH dependent
Thyroid Hormone Synthesis
Tyrosine backbone
Iodine
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Iodinase enzyme (enzyme I) attaches iodine
to thyroglobulin
Number of iodines determine activity of
thyroid hormone
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Thyroxine (4 iodines)
Triiodothyronine (3 iodines)
MIT / DIT Formation
Thyroid Peroxidase (TPO)
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Apical membrane protein
Catalyzes iodide oxidation to reactive iodine
Binds to Tyrosine residues of Thyroglobulin
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Antagonized by thionamides
Coupling enzyme
MIT with DIT= T3
Two DIT’s= T4
Pre-hormones secreted into follicular space
Transport of T3 and T4
When in circulation
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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
Secretion of Thyroid Hormone
Stimulated by TSH
Endocytosis of colloid on apical membrane
Coupling of MIT & DIT residues
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Catalyzed by TPO
MIT + DIT = T3
DIT + DIT = T4
Hydrolysis of Thyroglobulin
Release of T3, T4
Release inhibited by Lithium
Thyroid Hormones
Thyroglobulin Storage
Thyroglobulin molecule
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30 thyroxine molecules
Few triiodothyronine
Sufficient supply for 2-3
months
Deiodinase enzyme
recycles iodine when
thyroglobulin utilized
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
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Check T4 vs. TSH in the short term
assessment
Thyroid Hormone
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Majority of circulating hormone is T4
98.5% T4
1.5% T3
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Total Hormone load is influenced by serum
binding proteins
Thyroid Binding Globulin 70%
Albumin 15%
Transthyretin 10%
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Regulation is based on the free component of
thyroid hormone
Hormone Binding Factors
Increased TBG
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High estrogen states (pregnancy, OCP, HRT, Tamoxifen)
Liver disease (early)
Decreased TBG
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Androgens or anabolic steroids
Liver disease (late)
Binding Site Competition
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NSAID’s
Furosemide IV
Anticonvulsants (Phenytoin, Carbamazepine)
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
Hypothyroidism
Symptoms
Nervous system
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Forgetfulness and
mental slowing
Paresthesias
Carpal tunnel
Ataxia and decreased
hearing
Tendon jerk slowed
with prolonged
relaxation phase
Cardiovascular
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Bradycardia
Decreased cardiac
output
Pericardial effusion
Reduced voltage on
EKG and flat T waves
Dependent edema
Hypothyroidism
Symptoms
Gastrointestinal
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Constipation
Achlorhydria with
pernicious anemia
Ascitic fluid with high
protein
Renal
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Reduced excretion of
water load
Decreased renal blood
flow and glomerular
filtration
Responses to hypoxia and
hypercapnia are decreased
Pleural effusions high
protein
Musculoskeletal
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Hyponatremia
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Pulmonary
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Arthralgia
Joint effusions
Muscle cramps
CK can be elevated
Anemia
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Normochromic normocytic
Megaloblastic
Pernicious anemia
Hypothyroidism
Symptoms
Skin and hair
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Loss of lateral eye brows
Dry, cool skin
Facial features
Coarse and puffy
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Metabolism
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Orange skin
Carotene
Decreased lipoprotein
receptors
Reproductive system
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Menorrhagia from
anovulatory cycles
Hyperprolactinemia
No inhibition of thyroid
hormone
Hypothermia
Intolerance to cold
Increased cholesterol
and triglyceride
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Weight gain
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
Hypothyroidism
Etiologies
Thyroiditis
Thyroid ablation
External radiotherapy
Pharmacologic agents
Infiltrative disorders
Embryologic variants
Thyroiditis
Decreased uptake on
uptake scan
Transient
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Euthyroidism returns with
time
Lead to chronic thyroid
dysfunction
Etiology
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Infectious
Post-partum
Auto-immune
Transient
Chronic
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Drug
Thyroiditis
Thyrotoxic phase
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Short phase
Increased T3 and T4
Symptoms of
hyperthyroidism
Thionamides not
effective
Thyroid synthesis low
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Can use beta-blockers
Hypothyroid phase
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Transient or permanent
Symptomatic patients
need replacement
Can check for recovery
with stopping after 3-6
months
Thyroiditis
Time Course
Williams Text of Endocrinology, Fig 11.50
Infectious Thyroiditis
Etiology
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Bacterial 90%
Fungal
Mycobacterial
Parasitic
Syphilitic
Symptoms
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Thyroid pain and
tenderness
Fever
Dysphagia
Dysphonia
Treatment
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Treat the infection
Autoimmune Thyroiditis
Chronic Lymphocytic
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Silent Thyroiditis
Hashimoto’s
Women 3.5/1000
Men 0.8/1000
Frequency increases with
age
Familial history
Associated with
autoimmune diseases
Antibodies
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Thyroid peroxidase
More specific
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Thyroglobulin
Elevated in many types of
thyroid inflammation
Thyroiditis
Postpartum thyroiditis
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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
Transient/Destructive Thyroiditis
Subacute
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20% of thyrotoxic cases
De Quervain’s thyroiditis
Giant cell thyroiditis
Pseudogranulomatous
thyroiditis
Subacute painful thyroiditis
Symptoms
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Pain
Fever
Increased ESR
Hoarseness or dysphagia
Treatment
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ASA, NSAID
Steroid rarely
Comparison of Thyroiditis
Characteristic
Silent thyroiditis
Subacute thyroiditis
Age of onset (yr)
5-93
20-60
Sex ratio (F:M)
2:1
5:1
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
<5%
<5%
Relapse
Common
Rare
Permanent
hypothyroidism
Common
Infrequent
Drug Induced Thyroid Dysfunction
Lithium
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Inhibits thyroid hormone
secretion
Hypothyroidism
3.4% prevalence
Interferon-α
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Hyper/Hypothyroidism
Transient thyroiditis
TPO AB increases risk of
thyroid dysfunction
Interleukin-2
Aminoglutethimide
Ethionamide
Sulfonamides
Drug Induced Thyroid Dysfunction
Amiodarone
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75 mg iodine/200 mg
Hypothyroidism
Thyrotoxicosis
Type I and Type II
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Increased blood flow vs.
decreased blood flow
Not responsive to thionamides
Hypothyroidism
Infiltrative Disorders
Amyloidosis
Sarcoidosis
Hemochromatosis
Cystinosis
Pneumocystis carinii
Lymphoma
Riedel’s thyroiditis
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Invasive Fibrous Thyroiditis
Thyroid tissue replaced by
fibrous tissue
Rapidly enlarging neck
mass
Compressive symptoms
Surgical removal
Steroids and tamoxifen
Thyroid Hormone Replacement
1.3 ug/kg/day
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75-100 ug per day
Elderly or patients with
angina
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12.5-25 ug/day
Carefully increase every
month
IV dosing
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Use 60% of oral dose
Levothyroxine
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Synthroid
Levoxyl
Unithroid
Armour Thyroid
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T3/T4 preparation
Dessicated pig thyroid
Not a consistent amount of
T3/T4
Most T3 preparations give
higher than 1:11 ratio of
T3:T4
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
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?
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Transient
Treatment
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Levothyroxine therapy
Recheck every 6-8 months
After 3-6 months may be able to wean replacement
Post Partum Thyroiditis
Time Course
Changes in free T4
Williams Text of Endocrinology, Fig 11.51
Williams Text of Endocrinology, Fig 12.6