Download Document

CORE TOPIC: Hashimoto’s Thyroiditis &
GRAVES DISEASE
Megha Poddar
PGY 5
Objectives
• Review basic Thyroid Physiology and function
• Review thyroid autoimmunity and thyroid
antibodies
• Review the clinical presentation, diagnosis,
management of Hashimoto’s thyroiditis using the
ATA Guidelines
• Review the clinical presentation, diagnosis,
management of Graves Disease using the ATA
Guidelines and CMAJ reviews
Thyroid Physiology
• Thyroid gland secretes mainly T4
• 20% of hormone secreted is T3
• Remainder of T3 converted in the
peripheral tissue from T4
• T3 is more biologically active in tissue
• Free hormones bind to TH receptors and
initiate various physiological and
biochemical responses
Thyroid Hormone
• T4 and T3 are poorly water soluble
• 99% of circulating T4 and T3 is bound to:
• Thyroid binding globulin
• Transthyretin
• Albumin
• TBG has a higher affinity for T4 and T3
• 10-20% of circulating T3 comes from direct
secretion by the thyroid gland
• 80-90% is produced by peripheral conversion
of T4  T3
• 5’-deiodination of T4 occurs in the liver, kidney and skeletal
muscle
• D1 is the most abundant deiodinase and is the major converter of
T4 to T3
Thyroid Hormone Function

•
•
•
•
Cardiovascular:
↓ peripheral vascular resistance (PVR) and ↑ intravascular volume
 ↑ cardiac output
↑ rate of myocardial diastolic relaxation
↑ rate of depolarization and repolarization of the SA node (↑ heart
rate)
Heightened adrenergic response (↑ alpha receptors)
Thyroid Hormone Function
• Pulmonary
• Thyroid hormone maintains ventilatory response to hypoxia and
hypocapnia in the brain stem respiratory centre
• Gastrointestinal
• ↑ gut motility
• ↑ protein turnover
• Bone
• ↑ bone turnover (resorption > formation)
• Cholesterol
• ↑ cholesterol synthesis and degradation
Thyroid Autoimmunity
• Macrophages ingest foreign material and present peptide
fragments to the cell surface
• This complex is recognized by T cell receptors on CD4
helper cells with stimulate the release of IL2 and
cytokines and stimulates B-cells to make antibodies.
• The CD8 suppressor is the regulator of this activity
• The thyroid cells have the ability to ingest antigens and
when stimulated by cytokines express cell surface
molecules to present to T lymphocytes
Thyroid Auto-antigens
• Thyroglobulin
• Thyroid Peroxidase
• TSH receptor
Autoimmune Hypothesis
• Stimulated by external antigens that leads to antibody and
immune cross reactivity
• Genetics clearly predispose to autoimmunity (HLA
subtypes)
• ex in Caucasians goitrous Hashimotos is associated with HLA DR5
• Genetically induced issue antigen specific defect in
suppressor T lymphocytes
• Particularly susceptible to:
• excessive iodine - kelp, amiodarone, seaweed, contrast
• meds that alter immunity: interferon alpha
• inability to escape from the Wolff-Chaikoff effect
Autoimmunity
Hypothyroidism - Epidemiology
• Common!
• Subclinical or Overt – TSH >10 with a subnormal T4
• Framingham data:
• 5.9% of women, 2.3% of men over the age of 60 had TSH >10
• 39% of them had subnormal T4 levels
Etiology of Hypothyroidism
• Most common cause in iodine sufficient areas: Autoimmune
thyroiditis
• Removal of gland
• Surgical
• RAI ablation
• Medications
• Lithium
• Amiodarone
• Anticonvulsants
• Iodine deprived areas (most common cause wordwide)
• Secondary/Central Hypothyroidism (5%)
• Hypopituitarism
• Hypothalamic disorders
Epidemiology: Hashimoto’s Thyroiditis
• 5-10 times more common in women than in men
• Increases in frequency with age
• More common with if have other autoimmune disease
• More common in those with a family history
• Goitre may or may not be present
• Can be associated with thyroid lymphoma
Associations
• Other autoimmune diseases:
• Type 1 DM, Addisons, Celiacs disease, pernicious anemia
• But don’t forget!: myasthenia gravis, SLE, RA
• Rare: Thyroid Lymphoma
• Genetic syndromes:
• Multiple autoimmune endocrinopathies
• Type 1 (AIRE – autoimmune regulator gene):
Hypoparathyroidism, Addisons, mucocutaneous candidiases.
10-15% have hypothyroidism.
• Type 2 (Schmidts Syndrome): Addisions, type 1 DM,
autoimmune thyroiditis
Signs of Hypothyroidism
Findings
Hypothyroidism
General
Vitals
Lethargic and slow
HR: bradycardia
BP: narrow pulse pressure (↑ DSP)
Temp: hypothermic
Hands
Cool, rough skin, yellow discolouration (carotene)
H&N
Hair: coarse, thick
Eyes:
Periorbital edema
Loss of lateral 1/3 eyebrows (Queen Anne’s sign)
Mouth
Macroglossia
Skin
CVS
Vitiligo, non-pitting edema
Pericardial effusion, diastolic hypertension
Resp
CNS
Pleural effusions
Proximal muscle weakness, Reflexes = delayed relaxation, carpal
tunnel syndrome
Histology
• Extensive lymphocytic infiltration with T cells and plasma
•
•
•
•
cells
Atrophic follicles with Hürthle cells
Fibrosis but does not extend beyond capsule
Epithelium may have enlarged or overlapping nuclei with
partial nuclear clearing
Initial lesion is focal, then oxyphilic metaplasia of follicular
cells and nodularity; later little thyroid parenchyma is
present
Diagnosis of Hashimotos
• TSH is the primary screening modality
• Elevated antibody titres
• Anti TG antibodies
• Anti microsomal/anti-thyroid peroxidase ab, TPOAb
• TSH recepter ab
• Once present, ab rarely disappear spontaneously
• Many patients are biochemically euthyroid
• The presence of TPOab in subclinical hypothyroidism
predicts progression to overt hypothyrodism
• 4.3% with positive antibodies
• 2.6% with negative antibodies
When should you order antibodies?
• Subclinical hypothyroidism – predicts future risk
• Any patient with a goitre
• Other autoimmune diseases, chromosomal abnormalities
(Down’s), lithium, interferon alpha, amiodarone – helps
determine prognosis
• In pregnant women who are hypothyroid with a history of
Graves’ – determines risk of neonatal thyrotoxicosis
(TSHrab)
Pitfalls with using TSH as screening
• May be some diurnal variation – lowest in the late
afternoon and highest in the first hour of sleep
• NHANES III reference population was further analyzed
(97.5th percentile)
• TSH values as low as 3.24 for African Americans
between the ages of 30 and 39 years
• 7.84 for Mexican Americans ≥80 years of age.
• For every 10-year age increase after 30-39 years,
serum TSH increases by 0.3 mIU/L.
Pitfalls with using TSH as screening
• TSH may be abnormal in hospitalized patients or recovering
•
•
•
•
patients, pregnancy, those on steroids or others interfering
medications
Patients with central hypothyroidism can still have mildly
elevated TSH levels if they have bioinactive forms of TSH
TSH may be elevated in patients with thyroid hormone
resistance
Assay interference: heterophile/interfering antibody
Adrenal insufficiency will have elevated TSH which normalize
follow glucocorticoid treatment
ALWAYS DRAW FREE HORMONE LEVELS BEFORE
STARTING TREATMENT!
Treatment
• Levothyroxine
• Dose: based on age, sex, weight
• Approximately 1.6mcg/kg
• Post Op/RAI ablation/subclinical hypothyroid or Graves’ patients
will likely require less
• If patients has CAD – the dose is started at 12.5-25mcg less then
the usual starting dose
• 50-60 years old – start at 50mcg
• Synthroid vs Eltroxin – doesn’t matter!
• Various tablets have different formulations and bioequivalence
• ATA suggests: encourage the use of a consistent L-thyroxine
replacement
• Ideally take 4 hours after last meal or 60min before breakfast
• Should not be taken with other medications that interfere with
absorption
Whats the deal with triiodothyronine/T3?
• Randomized, double-blind crossover intervention study done
•
•
•
•
comparing T3 monotherapy with T4,14 patients for 6 weeks
Comparable TSH levels were achieved.
Mild weight loss and decreases in total cholesterol, LDL cholesterol,
and apolipoprotein levels were seen without differences in
cardiovascular function, insulin sensitivity, or quality of life with T3
compared with T4
Dose: used TID dosing for both groups
ATA - not enough evidence to support its use
Dose Adjustments
• Repeat TSH q4-8weeks with initiation and dose
adjustment
• Once stable can check 6 to 12 months
• Check TSH for dose adjustments if:
• Pregnant
• With change in medications that effect binding proteins absorption
• With significant weight changes
• With elderly patients
GRAVES’ THYROTOXICOSIS
Definition&Epidemiology
• “thyrotoxicosis” refers to a clinical state that results from
inappropriately high thyroid hormone action in tissues
generally due to inappropriately high tissue thyroid
hormone levels. (ATA Guidelines, 2011)
• Graves Disease: autoimmune disorder TRAb (thyrotropin
receptor antibodies) stimulate the TSH receptor to
produce thyroid hormone
• Remission occurs in approx 30% of those who are not
treated
Symptoms
• Elderly patients
may present
with atypical
symptoms
Findings associated with Graves’
• Diffuse goitre
• Thyroid bruit
• Thyroid acropachy (clubbing)
• Lymphodenopathy (rare)
• Localized dermopathy (rare)
• Opthalmopathy
Pathogenesis of Opthalmopathy
• It initiates cytokine which activates glycosaminoglycans
• Increases osmotic pressure
• Extraocular muscle volume
• Fluid accumulation
• Clinical opthalmopathy
• 50% do not have clinically evident eye findings at
diagnosis
• Rare (<10%) can have eye disease with normal TFT’s,
however, patients will likely become hyperthyroid within
18 months
• Rendering patients euthyroid often improves
opthalmopathy
Complications
• Inability to close the eye =
corneal ulceration/visual
loss
• Proptosis/EOM = diplopia
• Optic nerve compression =
colour vision
disruption/visual loss
Dermopathy (Pretibial myxedema)
Nonpitting edema with occasional raised, hyperpigmented,
violaceous papules.
• Patients often have high titres of TSH receptor antibodies
• Trauma may initiate or exacerbate
• 10% will have a increased
free T3 with a normal free
T4
• Confirmation is with RAIU
• If a cold nodule is present it
should be confirmed with an
ultrasound +/- biopsy
Treatment
Treatment Modalities - ATD
Why Pick ATD
•
High likelihood of remission
• Limited life expectancy/High surgical risk
• Moderate to severe active GO
• Previous irradiated /operated neck
Contraindications
•Adverse reactions to previous ATD
•Baseline low neutrophil count (<0.5), transaminase >5x ULN
Impact on Patient Preference
If remits – eliminates need for lifelong thyroid hormone replacement
• Avoid surgery/exposure to radiation
• Continued monitoring for side effects and disease reoccurrence
•
Treatment Modalities – I131
Why Pick I131
• Females planning pregnancy after 6-12 months
• Comorbidities that increase surgical risk
• Contraindication to ATD use/no surgeon available in area
Contraindications
•
•
•
•
Pregnancy/Lactation
Thyroid Cancer/Suspicion for Cancer
Unable to comply with radiation safety guidelines
Planning pregnancy in next 4-6 months
Patient Preference
•
•
•
•
Higher chance of definitive control
Avoids surgery
Rapid resolution
Can worsen GO
Treatment Modalities - Surgery
Why Pick Surgery
•
•
•
•
•
Symptomatic compression (>80g)
Low uptake of iodine
Suspicion for malignancy
Moderate-severe active GO
Females planning pregnancy in less than 4-6 months (esp if TRab
high)
• Co –existing hyperparathyroidism requiring surgery
Contraindications
•
•
Substantial comorbidities
Pregnancy *relative – late-second trimester
Patient Preference Impact
•
•
•
•
Rapid and definitive control
Avoidance of radiation exposure
Need lifelong thyroid replacement
Invasive treatment modality
ATD
• Methimazole has better side effects profile
• Use PTU in first trimester of pregnancy, if do not have private drug
coverage
• Inform patients of Side Effects
• Rash
• Agranulocytosis: fever, pharyngitis
• Hepatic Injury: Jaundice, pale stools/dark urine, arthralgia,
abdominal pain
• Need baseline: CBC, LFT’s, Bilirubin
• Aplasia Cutis in babies
• PTU: ANCA small vessel vasculitis
• CBC if fever/pharyngitis – not routinely
• Taper after 12-18 months if TSH is normal, recheck TRab
I131
• Complications
• GO
• Thyroid Storm
• Rare
• Pretreat 1) elderly 2) comorbidities intolerable to hyperthyroid symptoms
3) Free T4 2-3x Normal or highly symptomatic
• Pretreat with Bblocker +/- ATD
• Pregnancy test for all females of childbearing age 48
hours before
• Most patients respond within 4-8 weeks – required 4-6
repeat monitoring
• If still hyperthyroid after 6 months – need retreatment with
radiation
38.7 vs 21.3%
J Clin Endocrinol Metab. 2009 Oct;94(10):3700-7. doi: 10.1210/jc.2009-0747. Epub 2009 Sep 1.
Steroids for GO
• Prednisone, 0.5 mg/kg, start day after radioiodine for 1
month then taper over the next 3 months could prevent
radioiodine-induced worsening of ophthalmopathy.
• Suggested: reserve steroids only for patients with
significant diplopia or proptosis, active eye disease
• Reduce the risk:
• ensuring stability of ophthalmopathy for 6 months before
radioiodine
• pretreatment with antithyroid drugs
• smoking cessation
• Use ablative doses of radioiodine
• ? Starting L-thyroxine when patient is euthyroid
References
1.
2.
3.
4.
5.
6.
7.
CMAJ March 4, 2003 vol. 168 no. 5 Review, Diagnosis and management of Graves' disease, Jody
Ginsberg
ATA/AACE Guidelines HYPERTHYROIDISM AND OTHER CAUSES OF THYROTOXICOSIS:
MANAGEMENT GUIDELINES OF THE AMERICAN THYROID ASSOCIATION AND AMERICAN
ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS Rebecca S. Bahn
ATA/AACE Guidelines CLINICAL PRACTICE GUIDELINES FOR HYPOTHYROIDISM IN
ADULTS: COSPONSORED BY THE AMERICAN ASSOCIATION OF CLINICAL
ENDOCRINOLOGISTS AND THE AMERICAN THYROID ASSOCIATION Jeffrey R. Garber
UptoDate
Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind,
Crossover Trial of Liothyronine Versus Levothyroxine Francesco S. Celi
http://www.pathpedia.com/education/eatlas/histopathology/thyroid_gland/hashimoto_thyroiditis.as
px
Thyroid-Associated Ophthalmopathy after Treatment for Graves’ Hyperthyroidism with Antithyroid
Drugs or Iodine-131Frank Träisk,