Hypothyroidism

Ally P. H. PrebtaniProfessor of Medicine

Internal Medicine, Endocrinology & MetabolismMcMaster University

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2

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

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

Thyroid Axis

UpToDate 2006

T3 > potency vs T4

•80% from gland

•20% from 5’ DI enzyme conversion

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

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

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

Prevalence

J Clin Endocrinol Metab 2001 Oct;86(10):4585-90

Delayed DTRs

Zimmermann et al. Lancet Vol 372 Oct 4, 2008

Zimmermann et al. Lancet Vol 372 Oct 4, 2008

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

Garber et al. Endocrine Practice Vol 18 No. 6

TPO Ab

• Subclinical hypothyroidism

• Nodular thyroid disease

• Recurrent miscarriage/infertility

Screening

N Engl J Med 2001 Jul 26;345(4):260-5

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…

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

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

Symptoms

J Clin Endocrinol Metab 2001 Oct;86(10):4585-90

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

• 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!!!

Allergic/Intolerant to l-T4

• Decrease dose

• Change product

• Change to compounded preparation

– No evidence improves bioavailablity

– Only if allergic to excipient

• Gelatin capsules

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

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

Refractory Hypothyroidismesp if > 2.5mcg/kg/d l-thyroxine

Ramadhan et al. CMAJ, February 7, 2012, 184(2)

Garber et al. Endocrine Practice Vol 18 No. 6

Interfering Substances

Ramadhan et al. CMAJ, February 7, 2012, 184(2)

• sertraline

Approach to Tx Resistant Hypothyroidism

Ramadhan et al. CMAJ, February 7, 2012, 184(2)

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

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

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

What if Subclinical untreated?

• Controversial– Cardiac

– Lipids

– Symptoms

– Neuropsych

– Overt Hypothyroidism

• > if higher TSH

• But does Tx make a difference ??

Subclinical Evaluation

• Repeat in 3 months

• Assess Risk factors

– For overt hypothyroidism

• TPO Antibody testing

• Monitor q6-12 months

Pros of TreatmentSubclinical

1. May relieve symptoms

2. May decrease cardiac disease, lipids

3. May decrease neuro-psych Sx

4. Prevent overt hypothyroidism

Cons of TreatmentSubclinical

Thyrotoxicosis

– 14-21% subclinical

• A. Fib

• Osteoporosis

• Neuro-psych Sx

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

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

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

Question # 2

What is not a cause of a persistently elevated TSH?

1.Non adherence

2.Inadequate dosing

3.1º hyperthyroidism

4.Central hyperthyroidism

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

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

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