Can We Manage Thyroid Function TestsIn a Rational Way ?

Geoff BeckettEdinburgh

UK -10 Million Requests : £30 million

What Controls Our Workload?What Controls Our Workload?• ScreeningScreening• Expectations of the PatientExpectations of the Patient• Requesting StrategiesRequesting Strategies• Treatment of Sub-Clinical DiseaseTreatment of Sub-Clinical Disease• Treatment/follow-up regimens Treatment/follow-up regimens • Unnecessary testsUnnecessary tests

Managing Thyroid Function Tests

Guidelines !Guidelines !

Managing Thyroid Function Tests

1998200020022003

None tend to meet requirement ofpatients , physicians and laboratories

UK Guidelines For The Use of Thyroid Function Tests

Published on WebJuly 2006

Draft Consultation Document October 200533 responses

Group comprised of representatives from

•Association for Clinical Biochemistry

•British Thyroid Association •British Thyroid Foundation

Chaired by Dr Graham Beastall

 

 

Graham H Beastall BSc, PhD, FRCPath Secretary, Guidelines Development GroupConsultant Clinical Scientist, Glasgow Geoffrey J Beckett BSc, PhD, FRCPath Association for Clinical BiochemistryReader in Clinical Biochemistry, Edinburgh Jayne Franklyn MD, PhD, FRCP, FMedSci British Thyroid AssociationProfessor of Medicine, Birmingham William D Fraser MD, MRCP, FRCPath Association for Clinical BiochemistryProfessor of Clinical Biochemistry, Liverpool Janis Hickey British Thyroid FoundationFounder and Director Rhys John BSc, PhD, FRCPath Association for Clinical BiochemistryConsultant Clinical Scientist, Cardiff Pat Kendall-Taylor MD DCH FRCP British Thyroid AssociationProfessor of Endocrinology, Newcastle Upon Tyne Betty Nevens British Thyroid FoundationOffice Manager Mark Vanderpump MD, FRCP British Thyroid AssociationConsultant Physician, London

Introduction

Indications for thyroid function testing

Hypothyroidism

Hyperthyroidism

Thyroid function in pregnancy

Thyroid function testing in thyroid cancer

Laboratory aspects of thyroid function testing

UK Thyroid Guidelines - Chapters

Should Laboratories Make Local BiasAdjustments to the TSH Action Limits?

At several points in the text numerical results are represented (eg TSH > 10 mU/L)

WhickhamBias unknown Functional Sensitivity likely to be in the order of 1-2 mU/LIn-house RIA – Calibrated to 1st IRP

Colorado study London Diagnostics – Nichols Institute DiagnosticsBias ?

Rotterdam StudyBrahms LumitestBias?

Evidence Base

Introduction Chapter

At several points in the text numerical results are represented (eg TSH > 10 mU/L)These should be regarded as typical target figures rather than as absolute cut-offsThe historical nature of some of the evidence base together with uncertainty of the bias of the assays used in older studies means that absolute cut-offs cannot be presented.

Laboratories should use EQA and other data to determine if bias–related cut-offs are appropriate for the methods they use.

“In most cases it is unlikely that laboratories will have sufficient data to achieve an accurate adjustment of the TSH cut-offs quoted in these guidelines.”

Screening in the healthy population is not warranted

Screening

Women at the menopause or if visiting a GP with non-specific symptoms, may be justified to have TFTs in view of the high prevalence of thyroid failure

Hospitalised Patients

Routine testing of thyroid function in patientsadmitted acutely to hospital is not warranted

unless there are specific clinical indications exist.

Which Thyroid Function Test?

TSH alone as first line test ? Cascade to T4 / T3 if TSH abnormal

TSH with Free T4 as first-line tests ?Cascade with T3 if TSH is low

Digivote response from RCPath meeting in London• TSH alone

• TSH and T4 (free or total)

• TSH, T4, T3 (free or total)

• TSH and T3 (free or total)

• T4 (free or total) alone

Given no financial or other restrictions:- What would be your preferred TFT strategy?

72%

9 %

17%

2%

0%

TSH and FT4 needed in:-

•Symptomatic Patients being tested for the first time

•Screening/monitoring pregnancy

•Pituitary axis is not intact or unstable•Hyperthyroidism- Early months of anti-thyroid therapy•Hypothyroidism -Optimising T4 therapy (new patients) •Central hypothyroidism•TSHoma•End organ resistance

UK Guidelines

TSH alone 

•Stable - on T4•Follow-up of “at risk” patients•AF •Dyslipidaemia•Osteoporosis•Subfertility

Cascade to FT4/FT3 if TSH is abnormal

Surveillance of “At Risk Patients”Using TSH

Diabetes

•Type 1 – Annual TFT check

•Type 2 – Check TFT at diagnosis – Routine annual testing is not recommended

Down and Turner’s syndromeAnnual check

Amiodarone Check before treatmentMonitor every 6 months; continue to 12 months after cessation

LithiumCheck before treatmentMonitor every 6 – 12 months

Post – neck irradiation Annual check

Radioiodine / Thyroid surgery

Needs T4 not TSH for first 6-12 months

4-8 weeks – post treatment3 monthly for first yearAnnually thereafter with TSH

It is the responsibility of the requesting physician to provide clinical information to guide the laboratory in the selection of the most appropriate TFT.

 

If labs are unable to identify those specimens that requireTSH and FT4, it may be prudent to measure TSH+FT4rather than embark on first-line TSH. 

UK Guidelines

Sub-clinical HypothyroidismHigh TSH with normal FT4

Exclude transient and drug causes of elevated TSH,exclude recovery from NTI.

•Repeat to confirm at 3-6 months

No Change in recommendations:-

TSH > 10 mU/L – Treat with T4

Treating Sub-Clinical Hypothyroidism

S t a r t O n T 4W h e n T S H i s > 1 0 m U / L

A n n u a l T S HC h e c k E a r l i e r I f

S y m p t o m s D e v e l o p

T P O A bP o s i t i v e

M o n i t o r A p p r o xE v e r y 3 y e a r s

T P O A bN e g a t i v e

M e a s u r e T P O A b

T S H R a i s e d b u t < 1 0 m U / LD o N o t S t a r t O n T 4

Treating Sub-Clinical Hypothyroidism?

Many patients with raised TSH that is < 10 mU/L will normalise TSH with time

Spontaneous Normalization of Thyrotropin Concentrations in Patients with Subclinical Hypothyroidism Juan J. Díez, Pedro Iglesias and Kenneth D. Burman

40/107 patients normalised TSH on follow-up12 (18) 72 months

TSH raised but < 10 mU/L

•There is no clear evidence to support the benefit of routine early treatment with T4 in non-pregnantpatients.

A high percentage (~ 10%) of patients treated with T4will have a TSH < 0.1 mU/L (Harmful? to bone and heart)

Treating Sub-Clinical Hypothyroidism?

Physicians may wish to consider the suitability of a therapeutic trial of T4 on an individual patient basis eg goitre or seeking pregnancy 

The primary target of T4 replacement therapy is:-

•Make the patient feel well

•Achieve a TSH that is within the reference range

(FT4 may have to be slightly above reference range to achieve this)

Thyroxine Replacement Therapy

There is no compelling evidence or need tolower the upper reference limit or treatment target to 2.5 mU/L in non-pregnant patients

NHANES study (USA)17,353 subjects 13,344 – Reference population

TPO Ab negativeReference Range was 0.45 – 4.2

Denmark1512 subjects 3 – Reference population

TPO Ab negative Reference Range 0.58 – 4.1

Studies Using Ultrasound Exclusion with TPOAb

SHIP study Germany1488 subjects (previous iodine deficiency)Ref range 0.25 – 2.12

Germany 453 blood donorsRef Range 0.4 – 3.77

Denmark3174 participantsRef Range 0.4 – 3.6

Published Reference Ranges

Monitoring T4 Therapy•TSH and T4 is required for initial optimisation of T4 therapy

•At least annual follow-up with TSH alone

•If T4 dose is changed allow 2-3 months before checking TFTs

•Be alert (inform patient) to concomitant drug treatment

Impaired Absorption of T4 PPIs / H2 antagonistsCalcium carbonateSoy proteinAluminium hydroxideFerrous sulphateCholestyramineCholestapolSucralfate

Increased metabolismPhenytoinCarbamazepineBarbituratesRifampicin

Altered TBGOestrogens, TamoxifenHeroin, MethadoneAndrogens, Anabolic steroidsGlucocorticoids

Sub-Clinical HyperthyroidismLow TSH normal T4 and T3

•Exclude NTI/drugs

•Repeat 1-2 months later

•Persistent sub-clinical hyperthyroidism should prompt a specialist referral.

•If treatment is not undertaken measure TSH every 6-12 months (with FT4 and FT3 if TSH is low)

Pregnancy

Use both TSH and FreeT4 (Free T3 if TSH is low) to asses thyroid status and monitor T4 therapy

Use Trimester-Related Ref Ranges For All Tests

0.1

5.0

TS

H m

U/L

Screening for Thyroid Disease in Pregnancy

•Type 1 diabetes•Previous history of thyroid disease•Current thyroid disease•Family history of thyroid disease•Goitre•Features of hypothyroidism

•Use TSH and Free T4 •Consider TPOAb as a predictor of post partum thyroiditisand foetal impairment

Hypothyroidism and Pregnancy

For patients with established hypothyroidism check TFTs•Before conception (if possible)•At diagnosis of pregnancy•At antenatal booking•At least one in each trimester and 2-4 weeks postpartum

Newly diagnosed patients •Should be checked ever 4-6 weeks until stabilised

T4 Therapy and Pregnancy

First trimester Adjust T4 dose such that Free T4 is at upper half of non-pregnant ref range and TSH is low normal 0.4 – 2.0 mU/L

Ideally monitor against trimester – related reference ranges

Patients who become pregnant usually need an extra 25-50 micrograms of T4. Reduce dose approx 4 weeks after delivery

TRAbs and Pregnancy

Patients with current or previous hyperthyroidism may benefit from a TRAbs at antenatal booking.

•If negative need not be measured again.•High titre can predict chance of intrauterine thyrotoxicosis

Post-partum Thyroiditis

Occurs in 5% of population within 2-6 months of delivery or miscarriage. (non-specific symptoms tiredness, anxiety, depression)

Post-partum patients should have TFTs at 6-8 weeks if they have:-•Goitre•Previous history of post-partum thyroiditis•Previous history of autoimmune thyroid disease•Positive TPOAb

•If thyrotoxic profile - differentiate from Graves’ disease (TRAbs)

•If hypothyroid and symptomatic start on T4 (for approx 6 months)

Thyroid CancerThyroglobulin and TgAb

TgAb are useful as :-

•A prognostic indicator •To validate the reliability of a Tg measurement

TgAb should be measured at diagnosis and simultaneously with Tg for follow-up

Thyroid CancerThyroglobulin and TgAb

Identify possible assay interference by

•RIA/IMA discordance •TgAb positive samples

•Recovery alone is not recommended

Discordant RIA / IMA Tg results at EdinburghRoyal Infirmary over a 17 month period.

14% of total results

RIA/IMA concordance in Tg Ab Negative Samples

IMA

Data from Edinburgh Royal Infirmary

RIA/IMA concordance in TgAb positive samples  

  Sanofi IRMA  

Rad

ioim

mun

oassay

Data from Edinburgh Royal Infirmary

There is a UK NEQAS scheme for thyroglobulin.

Data from scheme illustrates the poor performance of Tg assays

How Should We Inform GPs ?

Guideline Group Plan to Produce a Version for GPs

ButPerhaps Labs should give GPs a brief version of the relevant points that are applicable to local practice. eg•When to request TSH and TSH + FT4•Screening in menopause•When to repeat tests in SC thyroid disease•When to refer SC hyperthyroidism•Target for T4 therapy•Drugs and T4 therapy•Pregnancy issuesAfter Consultation with the Local Endocrinologists And Obstetricians!