Thyroid Basics Deric Morrison August 1, 2012. Objectives At the end of this session you will: At the...

Thyroid Basics

Deric Morrison

August 1, 2012

Objectives At the end of this session you will:

Know the normal dimensions and weight of the thyroid

Know the main elements of thyroid/neck anatomy Be able to explain the differential diagnosis of the

potential patterns of thyroid function tests Be able to work through cases illustrating scenarios of

subclinical and true hyper/hypothyroidism Discuss the effects exccess iodine can have on the

thyroid

Thyroid Anatomy

Netter FH, The Ciba Collection of Medical Illustrations, vol. 4, Endocrine system and selected metabolic diseases, Ciba, 1965

Thyroid Anatomy

Weight: ~15-20g in North America

Right and Left Lobe Dimensions:~4 cm Superior to Inferior ~2 cm Lateral to Medial~2-3 cm Anterior to Posterior (deep)

Isthmus: ~5 mm Anterior to Posterior (deep)

Thyroid Physiology

bestpractice.bmj.com

Thyroid Function Tests

TSH ↔ or ↑

FT4/FT3 ↑

?????

TSH ↓

FT4/FT3 ↑

?????

TSH ↑

FT4/FT3 ↓

TSH ↔ or ↓

FT4/FT3 ↓

?????

TSH ↓

FT4/FT3 ↔

?????

TSH ↑

FT4/FT3 ↔

?????

TSH ↔

FT4/FT3 ↔

Thyroid Function Tests

TSH ↔ or ↑

FT4/FT3 ↑

Hyperthyroid

TSH ↓

FT4/FT3 ↑

Hypothyroid

TSH ↑

FT4/FT3 ↓

TSH ↔ or ↓

FT4/FT3 ↓

Subclinical Hyperthyroidism

TSH ↓

FT4/FT3 ↔

Subclinical Hypothyroidism

TSH ↑

FT4/FT3 ↔

Normal

TSH ↔

FT4/FT3 ↔

• Subclinical Hypothyroidism• Poor Adherence/Absorption

T4• Assay interference• NTI Recovery• TSH Resistance• Central Hypothyroidism

• Assay Interference• Poor L-T4 Adherence• Drugs (Amio,

heparin)• TSHoma• RTH

• Non Thyroidal Illness• Central Hypothyroidism

• Subclinical Hyperthyroidism

• Recent ↑T4 Treatment• Drugs (Steroids)• NTI

TSH ↔ or ↑

FT4/FT3 ↑

Hyperthyroid

TSH ↓

FT4/FT3 ↑

Hypothyroid

TSH ↑

FT4/FT3 ↓

TSH ↔ or ↓

FT4/FT3 ↓

TSH ↓

FT4/FT3 ↔

TSH ↑

FT4/FT3 ↔

Normal

TSH ↔

FT4/FT3 ↔

It’s not your thyroid! Or is it?

51F real estate agentRFR: TSH 7.6PMHx: Iron deficiency anemiaNo prescription meds, takes Fe, Ca, Vit DNon-Smoker, no EtOHFamHx: Aunt, Grandmother Hypothyroid

Hypothyroid History

HPI over last 2 years: 15lbs. Wt. gain despite diet + exerciseCold intoleranceMild difficulty with concentration and memorySlightly decreased energy and dry skinNormal menses and bowel movements

Physical Exam

Weight - 65.8 kg, BMI of 24.5 kg/m2. BP 97/59 mmHg, HR 60 bpm (reg)Skin dry, but warmDTRs 2/5 symmetricThyroid 2x ULN (39.7 g), no nodularity,

normal to firm texture, no lymph nodesResp, CVS, Abdo - Normal

Investigations

Repeat TSH 8.1, FT4 = 15, FT3 = 4.0CBC, B12, Ferritin - NormalLytes, Cr, Ca, Albumin, LFTs – NormalLDL 2.9, HDL 1.3

Assessment?Plan?

Differential Diagnosis

TSH ↑

FT4/FT3 ↔


• Subclinical Hypothyroidism• Poor L-T4 Adherence• Malabsorption of L-T4• Assay interference• NTI Recovery• TSH Resistance• Central Hypothyroidism

TSH ↑

FT4/FT3 ↔

Subclinical Hypothyroidism Progression to hypothyroidism

33-55% over 10-20 years Normalization of TSH is more likely (~60%) if:

Negative antithyroid antibodies TSH <10

Cardiovascular Conflicting data re: association of increased CV

mortality Association of increased LDL, TC

Pregnancy Risk factor for miscarriage, low birth weight and

decreased IQ in the offspring

Age Specific Normal TSH908 patients with no thyroid disease or

autoimmunity.


L-Thyroxine Treatment?TSH > 10?? non-elderly patients TSH 4.5 to 10 ??:

Symptoms suggestive of hypothyroidism High titers of Anti-TPOGoiter/nodules Dyslipidemia

Pathophysiology of Hashimoto’s

AntibodiesAnti – TPOAnti – thyroglobulin

Lymphocytic infiltration of thyroid tissueFollicular destruction

Nature Reviews Immunology. March 2002

Remember Her Iron Deficiency?

Mean hemoglobin levels increased by 0.4 g/dl in the iron group [0.2– 0.7, P 0.001],

Increased by a mean of 1.9 g/dl in the iron/levothyroxine group (1.5–2.3, P 0.0001).


TSH ↓

FT4/FT3 ↔




Recent meta-analysis shows an increased risk of total mortality, CHD mortality, and incident AF, with higher risks of CHD mortality and AF with TSH below 0.10

Hypothyroidism Diagnosis

Mrs. ADPresented with fatigue.

TSH 32Started LT4 50 mcg daily

Repeat TSHs remain high, still TSH of 45 ~ 6 months later, now on LT4 300 mcg daily

What next?

Hypothyroidism Diagnosis

ClinicalAnxious, tremulous, heat intolerant,

palpitationsLaboratory

TSH 40, FT4 42, FT3 11

Plan?

Hypothyroidism? Diagnosis

LT4 stopped:TSH 32, FT4 = 12, FT3 = 4

Differential Diagnosis

Patterns of TFTs

TSH ↑

FT4/FT3 ↔



Methodological Interference

TSH MeasurementNon-competitive two antibody system

Negative interference (falsely low TSH) Patient antibody binds assay capture antibody

Positive interference (falsely high TSH) Patient antibody links assay capture and detection

antibodies (without needing TSH)

Non linear levels in dilution series indicate interference

Assay Interference

Assay Interference

Heterophile (Anti-Animal) antibodiesRheumatoid FactorMacro TSH

Investigations

Roche: TSH=25, FT4=13, FT3= 4.7Evidence of some interference by Non

specific antibodies (TSH=18.4)No change when treated for heterophile Abs

ADVIA Centaur: TSH - 4.55, FT4 – 14, FT3 - 4.5

RF = 21 (Not elevated)

Methodological Interference

Free T4 (and free T3) measurementCompetitive assays (labelled T4 competes

with serum T4 for binding sites)Antibodies binding tracer or serum T4 can

confoundWash step reduces interference

Gold standard is equilibrium dialysis

Hashimoto’s

Goiter palpated incidentally on physical exam

U/S – Bulky, enlarged thyroid, very heterogeneous, small nodules vs. pseudonodules

TSH = 164, FT4 = 6, FT3 = 1.8Anti-TPO = 12400

Hypothyroid

Started on levothyroxine ~0.1mg/dayHeadaches, stopped treatment

Tried 0.025 mg/day + gradual increaseHeadaches, stopped treatment

Tried liothyronine (T3) and at time of referral on liothyronine 0.050 mg/day

TSH = 73, FT4 < 6, FT3 = 4.5

Hypothyroid

Assessment?

Plan?

Patient intelligent, informed and reasonable, wants to simplify treatment and monitoring, wants to be able to take levothyroxine, willing to try again.

Hypothyroid

Started levothyroxineHow much? (N.B. on liothyronine 0.05mg)

Hypothyroid

T4 : T3 serum molar ratios in humansBioavailable ~14:1, Secreted ~11:1

T4 vs. T3 equivalent dosagesLevothyroxine dose ~ Liothyronine x 4

But variable, re: conversion

Hypothyroid

Started on levothyroxine 0.125mg/day and stopped liothyronine

2 weeks later, stopped levothyroxine re: headaches,later found out also fatigue and dizziness

Instructed to resume liothyronine at 0.03mg BID

6 weeks later patient tells me has not resumed any thyroid replacement yet

Hypothyroidism

Re-assessment – headaches, fatigue and dizziness on thyroid replacement, since stopping feels great, working at high pressure job, busy family life, camping…

Assessment?

Plan?

Hypothyroidism

TSH = 239, FT4 = 4, FT3 = 1.7Cortisol = 398 (8:40), ACTH = 2.4 (2-12)

Plan?

T4 vs T3 vs T4/T3

Inconsistent poor quality evidence ? Some benefit T3 for weight and CV risk

parameters

Persistent symptoms, variable deiodinase activity etc. ? Possible benefits

No good formulations to mimic physiologic T4 + T3 easily re: short half life and minimal dose strengths of T3

Future Studies?

Hyperthyroidism

Mrs. DH, 50 F presents with ~ 15 lb. weight loss periorbital edema, blurry vision and

diplopia at ends of her field of viewBrittle nails Infrequent heart palpitations.She does not note any heat or cold

intolerance, or tremor

Hyperthyroidism

Hyperthyroidism

Physical ExamVitalsGeneral appearanceHandsSkinEyesHead/Neck/ThyroidCardiovascular/Respiratory

Hyperthyroidism

How many ophthalmic signs (with eponyms) do you know for hyperthyroidism?

What signs (with eponyms) are specific for Graves’

Ophthalmic phenomena reflecting thyrotoxicosis per se and apparently resulting from sympathetic overactivity (9):

Wide palpebral aperture (stare) Dalrymple sign Lid lag von Graefe sign Lower lid lag on upward gaze Griffith sign Infrequent blinking Stellwag sign Absence of forehead wrinkling on upward gaze Joffroy sign Tremor of closed eyelids Rosenbach sign Spasmodic lid retraction during fixation Kocher sign Nystagmoid jerks during abduction to adduction Wilder sign

Ophthalmic phenomena unique for Graves' disease caused by specific pathologic changes in the orbit and its contents (4):

Inability to keep the eyeballs converged Mobius sign Extrinsic muscle palsies Ballet sign Increased pigmentation Jellinek sign Edema of lower lid Enroth sign

Hyperthyroid - Investigations

TSH < 0.01, FT4 = 38, FT3 = 19

Differential

High Uptake Hyperthyroidism Treatment Options

Radioactive Iodine Ablation favoured High surgical risk Previous neck surgery or radiation Contraindication to Antithyroid drugs (ATDs)

RAI contraindicated/discouraged Planning pregnancy in < 6 months Currently pregnant, lactating Thyroid cancer, suspicion for thyroid cancer Moderate/severe active Graves’ orbitopathy Thyroid storm/need for immediate resolution Can’t follow radiation safety instructions


ATDs RecommendedHigh likelihood of remission

Female, mildly hyper, minimal/no goiter, low/neg TBII

High surgical riskCan’t follow radiation safety protocolHopes to avoid long term therapy

ATDs discouragedPrior adverse reaction to ATDs


Surgery recommendedSymptomatic or very large goitersSuspected thyroid cancer/ worrisome nodulesModerate to severe active Graves’ orbitopathy

Surgery discouragedHigh risk for surgeryPregnancy

If responsive to ATDs, but if necessary surgery in 2nd trimester is best time.

A Heart Pounding Case

73 M with history of CVD, MI, A. Fib and an implanted ICD presents due to uncontrolled A. Fib.

TSH <0.01, FT4 = 37, FT3 = 9

Medications

Amiodarone 200 mg daily for 2 yearsStatin, ASA, ACEi

Digoxin and bisoprolol added – now rate controlled

Iodine and Thyroid

Autoregulation of follicular cells to compensate for excess iodine

Sudden exccess leads to inhibition of organification of iodide to prevent hyperthyroidism

Wolff-Chaikoff EffectNormal individual will reach new steady

state and escape

Iodine and Thyroid

Hyperthyroidism results when there are autonomous functioning areas of the thyroid are exposed to iodine

Haven’t had enough iodine to cause problems before

Underlying Graves’ or toxic adenoma(s)

Jod-Basedow Effect

Amiodarone and thyroid

HypothyroidInability to escape for Wolff-Chaikoff

Hyperthyroid1. Type 1 - Undiagnosed autonomous thyroid

tissue (Jod-Basedow)

2. Type 2 - Thyroiditis

Amiodarone + Hyperthyroid

Amiodarone

Radioactive Iodine Uptake = 2.2 %

N.B. Scan is unnecessary – why?

An Eye Popping Case

82FPMHx:

HypertensionDyslipidemiaHypothyroidism (Age 38)

Meds :Diovan/hydrochlorothiazide, ASA, Crestor, Calcium and vitamin D

FHx: Unknown

An Eye Popping Case

Started on thyroid hormone replacement ~ 50 years ago

Stable dose over last ~ 10 years

An Eye Popping Case

Presented with lid lag and dry itchy eyesReviewed by ophthalmology Inflammation to the lid margins Lid retraction Hertel measurements:

Right 19mm (<20mm=N)Left 18mm

Graves’?

Hypothyroid No More

Assessment?Further investigations?

TSH <0.05, FT4 – 32, FT3 – 8

Plan?

Hypothyroid No More

Off L-T4 for 6 monthsTSH 0.01, FT4 – 19, FT3 – 5.6

Further investigations?

Differential?

TSHR Antibodies

Not all TSHR-Abs are stimulatory. Some block the binding and action of TSH Some with Graves' disease have a mixture

of TSHR-AbsStimulating and blocking

Clinical presentation may depend upon the balance

Pathogenesis TSH-binding inhibitory

immunoglobulin (TBII) measure displacement of bovine TSH off solubilized

porcine TSH receptor measure displacement of bovine TSH off immobilized

solubilized human TSH receptor measures thyroid stimulating (TSAb) or blocking (TBAb)

Functional assay measure cAMP in chinese hamster ovary cells transfected

with the human TSH receptor can differentiate between thyroid stimulating (TSAb) or

blocking (TBAb)

TSHR Antibodies in Pregnancy

TSH receptor antibodies (TSHR-Ab)Fetal hyperthyroidism (2-10% of women with

Graves’)Should measure TBII in:

previous Graves’ Rx with Sx or I131

concurrent hyper and pregnancy (early 3rd trimester) previous neonatal hyperthyroidism (early in 1st trim)

Treatment?Monitoring?

Graves’ Orbitopathy

Prevention of GO with RAI

Mild Graves’ Orbitopathy Treatment

Selenium for GO

Selenium (100 μg BID), pentoxifylline (600 mg BID), or placebo (BID) orally for 6 months then followed for 6 months after.

Selenium in patients with mild Graves’ orbitopathyImproved quality of life, Reduced ocular involvement,Slowed progression of the disease

GO Treatment

Smoking cessation!

Consider antithyroid drugs or thyroidectomy to treat hyperthyroidism

Corticosteroids (PO vs IV)

Eye Surgery

Summary



• Assay Interference• Poor L-T4 Adherence• Drugs (Amio,

heparin)• TSHoma• RTH

• Non Thyroidal Illness• Central Hypothyroidism



TSH ↔ or ↑

FT4/FT3 ↑

Hyperthyroid

TSH ↓

FT4/FT3 ↑

Hypothyroid

TSH ↑

FT4/FT3 ↓

TSH ↔ or ↓

FT4/FT3 ↓

TSH ↓

FT4/FT3 ↔

TSH ↑

FT4/FT3 ↔

Normal

TSH ↔

FT4/FT3 ↔

Summary Hypothyroid

Subclinical = TSH > N, N FT3/4 Treat if

TSH>10, consider if TSH 5-10 + other reason Iron deficiency?

Hyperthyroid Thyroid Autoimmunity Iodine and Thyroid Graves’ Orbitopathy

Smoking, Steroids if using RAI, Selenium Discordant TFTs

Remember differentials, may need further investigation

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