hypothyroidism · hypothyroidism ally p. h. prebtani professor of medicine internal medicine,...
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Hypothyroidism
Ally P. H. PrebtaniProfessor of Medicine
Internal Medicine, Endocrinology & MetabolismMcMaster University
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Case
• 55yo woman
• Feeling well, otherwise healthy
• Mother with Grave’s disease
• No meds
• Exam normal except irregular thyroid gland
• TSH 11, Free T4 normal
• 6 months later TSH 20, Free T4 8
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One year later
• More tired, cold, constipated, weight gain
• On l-thyroxine 250mcg daily
• On exam
– Looks tired, BP 140/92 P 62
– Thyroid irregular
– Periorbital puffiness
– DTR delayed
• TSH 35, Free T4 6
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Thyroid Axis
UpToDate 2006
T3 > potency vs T4
•80% from gland
•20% from 5’ DI enzyme conversion
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Definition
• Subclinical– TSH above the upper limit normal
– Normal T4
– 0.45-4.12mIU/L• ? 0.5-2.5mIU/L
– Few or no Sx
• Overt– High TSH
– Low T4
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DDx High TSH
• Recovery from illness– Sick Euthyroid
• Central Hyperthyroidism– Free T4 high
• Thyroiditis recovery– Transient
• rhTSH (Thyrogen)• Assay variability• 10 Adrenal Insufficiency
– Untreated• Heterophilic/interfering antibodies
– Murine, RF, anti-TSH • Thyroid hormone resistance
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Epidemiology
• 4.0-8.5% U.S.A. Subclinical• 0.3% Overt• Higher Risk
– Age– Women 60yo– Thyroid disease Hx– DM-1/Other Autoimmune– Turner’s/Kleinfelter’s Syndromes– Family History– XRT H&N– On l-thyroxine– + TPO Ab
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Prevalence
J Clin Endocrinol Metab 2001 Oct;86(10):4585-90
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Delayed DTRs
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Zimmermann et al. Lancet Vol 372 Oct 4, 2008
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Zimmermann et al. Lancet Vol 372 Oct 4, 2008
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Dx & Screening• TSH is best screening test for primary
– Outpatient, stable
– Not central, NO recent hyperT4 Tx
– Use uln of reference laboratory
• Free T4
– if abnormal TSH
– Suspect central hypothyroidism (TSH useless!!)• 99.97% protein bound
• Esp TBG
– Affected by drugs, diseases, pregnancy
• Free T4 inaccurate in pregnancy
– Low
– Thus use Total T4
• Collect T4 before l-T4 dosing
• T3 quite useless in hypothyroid assessment
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Garber et al. Endocrine Practice Vol 18 No. 6
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TPO Ab
• Subclinical hypothyroidism
• Nodular thyroid disease
• Recurrent miscarriage/infertility
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Screening
N Engl J Med 2001 Jul 26;345(4):260-5
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Screening
• Controversial– High risk
• Symptoms
• ? > 60yo
• Goitre/nodules
• ? All pregnant
• Hx thyroid disease
• DM-1/Autoimmune Disease
• FH 1st degree relative
• XRT H&N, surgery
• On l-thyroxine, amio, Li, others…
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Treatment
• TSH > 10• TSH 4.5-10 more controversial
– Trial for Sx if • ? Placebo effect
– Pregnant or planning (? TSH > 2.5)• Fetus needs in T-1• Neurocognitive effects
– Infertility– Goitre/nodules– ? TPO Ab
• Overt Hypothyroidism– Aim TSH low-normal
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Goals of Tx• Improve Sx
– Not all Sx improvement with normal TSH
• ? Genetics dec T4 -> T3
• ? T4 transporter defect
– Acknowledge
– r/o other causes
– ? Psych
• Minimize complications– Lipids, CVD…
• Normalize TSH
– Consider Sx, comorbidities
– Higher targets for elderly
• Avoid over Tx (esp older, post-menopause, TSH < 0.1)– A.fib, osteoporosis
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Symptoms
J Clin Endocrinol Metab 2001 Oct;86(10):4585-90
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How to Tx
• L-thyroxine (Synthroid/Eltroxin)
– Standard, efficacy, safety, long term experience, cheap
– Once daily po
• Once weekly if adherance issue (since t ½ 7 days)
– 1.6mcg/kg od if young, healthy
– No dose issues with CKD or CLD
– higher doses Nephrotic syndrome
– 25-50mcg od to start– Older/CVD
– Subclinical
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• Same preparation/brand if possible on repeats
• Empty stomach
– 60min ac breakfast or 4hrs pc
– 70-80% bioavailability on fasting
• Consistent timing, avoid drug interactions
• Adjust q4-6weeks & aim normal TSH
– Dose/brand change, drug interaction, pregnant, wt change…
– then q6-12mos
• NOT Dessicated, Extracts, T3/Cytomel, Nutracetical, Diet supps
• If suspect Adrenal Insufficiency (AI)– r/o 1st and treat 1st before l-thyroxine!!!
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Allergic/Intolerant to l-T4
• Decrease dose
• Change product
• Change to compounded preparation
– No evidence improves bioavailablity
– Only if allergic to excipient
• Gelatin capsules
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Pregnancy• Risks
– Maternal
• Abruptio/PPH
• Miscarriage
• HTN/Preeclampsia
– Fetal
• Preterm delivery
• LBW
• No fetal production of T4 till 2nd trimester– IQ/Brain development
– Motor
– Neuro-psych
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Pregnancy
– > doses in pregnancy by 25-50% (increased TBG)
– 2 extra doses per week– At onset of pregnancy
– TSH– Check q4weeks 1st half of preg; then qtrimester
– T1 0.1-2.5
– T2 0.2-3.0
– T3 0.3-3.0
– 6 weeks after dose change
– Back to pre-pregnancy dose post-partum– TSH in 4-6 weeks
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Refractory Hypothyroidismesp if > 2.5mcg/kg/d l-thyroxine
Ramadhan et al. CMAJ, February 7, 2012, 184(2)
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Garber et al. Endocrine Practice Vol 18 No. 6
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Interfering Substances
Ramadhan et al. CMAJ, February 7, 2012, 184(2)
• sertraline
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Approach to Tx Resistant Hypothyroidism
Ramadhan et al. CMAJ, February 7, 2012, 184(2)
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Therapeutic Endpoints
• Clinical
• TSH most important– Target controversial
– 0.45-4.12 if no reference range for lab
– ? < 2.5
– Pregnancy trimester specific
– FT4– Central hypothyroidism
– Avoiding over-Tx
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Special Situations
• Infertility– Even normal TSH
– + TPO• L-T4 Tx
• Obese– No Tx if TSH normal
• Sx but n TSH (“Wilson’s Syndrome”)– No Tx
– Much overlap
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Natural History of Subclinical
• 2-5%/year progress to Overt Hypothyroidism (decreased Free T4)
• > if antibodies– TPO
– Thyroglobulin
• > if TSH higher– > 10mIU/L
• 5% return to normal in 1 year
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What if Subclinical untreated?
• Controversial– Cardiac
– Lipids
– Symptoms
– Neuropsych
– Overt Hypothyroidism
• > if higher TSH
• But does Tx make a difference ??
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Subclinical Evaluation
• Repeat in 3 months
• Assess Risk factors
– For overt hypothyroidism
• TPO Antibody testing
• Monitor q6-12 months
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Pros of TreatmentSubclinical
1. May relieve symptoms
2. May decrease cardiac disease, lipids
3. May decrease neuro-psych Sx
4. Prevent overt hypothyroidism
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Cons of TreatmentSubclinical
Thyrotoxicosis
– 14-21% subclinical
• A. Fib
• Osteoporosis
• Neuro-psych Sx
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ApproachSubclinical
Elevated TSH
Repeat TSH Elevated
n Free T4
Pregnant Goitre/Nodules
Symptoms Already on l-Thyroxine
Ovulatory Dysfunction
? Antibodies ? Lipids
Yes No
l-Thyroxine Monitor q6-12 months
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When to refer to Endo?
• Children & infants
• Refractory to Tx
• Woman planning conception
• Cardiac disease
• Abnormal thyroid gland
• Adrenal/pituitary disease
• Confusing thyroid tests
• Medications affecting thyroid status
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Question # 1
What are some indications to treat subclinical Hypothyroidism which is persistent?
1. All with TSH 5-10
2. If pregnant and TSH > 10
3. Especially in elderly with TSH 5-10
4. Dyslipidemia
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Question # 2
What is not a cause of a persistently elevated TSH?
1.Non adherence
2.Inadequate dosing
3.1º hyperthyroidism
4.Central hyperthyroidism
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Case
• 55yo woman
• Feeling well, otherwise healthy
• Mother with Grave’s disease
• No meds
• Physical Exam normal except irregular thyroid gland
• TSH 11, Free T4 normal
• 6 months later TSH 20, Free T4 8
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One year later
• More tired, cold, constipated, weight gain
• On l-thyroxine 250mcg daily
• On exam
– Looks tired, BP 140/92 P 62
– Thyroid irregular
– Periorbital puffiness
– DTR delayed
• TSH 35, Free T4 6
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Summary
• Common
• Screening controversial
• Risk factors
• TSH best screening test
• Evidence not great for subclinical state
• Treatment best with levothyroxine
• Target to reference range TSH
• For pregnancy trimester specific