Can We Manage Thyroid Function Tests In a Rational Way ? Geoff Beckett Edinburgh

1. Can We Manage Thyroid Function TestsIn a Rational Way ?Geoff BeckettEdinburgh UK -10 Million Requests : £30 million

2. Managing Thyroid Function Tests What Controls Our Workload? • Screening • Expectations of the Patient • Requesting Strategies • Treatment of Sub-Clinical Disease • Treatment/follow-up regimens • Unnecessary tests

3. Managing Thyroid Function Tests Guidelines ! 2000 2002 1998 2003 None tend to meet requirement of patients , physicians and laboratories

4. UK Guidelines For The Use of Thyroid Function Tests • Group comprised of representatives from • Association for Clinical Biochemistry • British Thyroid Association • British Thyroid Foundation • Chaired by Dr Graham Beastall Published on Web July 2006 Draft Consultation Document October 2005 33 responses

5. Graham H Beastall BSc, PhD, FRCPath Secretary, Guidelines Development Group Consultant Clinical Scientist, Glasgow Geoffrey J Beckett BSc, PhD, FRCPath Association for Clinical Biochemistry Reader in Clinical Biochemistry, Edinburgh Jayne Franklyn MD, PhD, FRCP, FMedSci British Thyroid Association Professor of Medicine, Birmingham William D Fraser MD, MRCP, FRCPath Association for Clinical Biochemistry Professor of Clinical Biochemistry, Liverpool Janis Hickey British Thyroid Foundation Founder and Director Rhys John BSc, PhD, FRCPath Association for Clinical Biochemistry Consultant Clinical Scientist, Cardiff Pat Kendall-Taylor MD DCH FRCP British Thyroid Association Professor of Endocrinology, Newcastle Upon Tyne Betty Nevens British Thyroid Foundation Office Manager Mark Vanderpump MD, FRCP British Thyroid Association Consultant Physician, London

6. UK Thyroid Guidelines - Chapters Introduction Indications for thyroid function testing Hypothyroidism Hyperthyroidism Thyroid function in pregnancy Thyroid function testing in thyroid cancer Laboratory aspects of thyroid function testing

7. At several points in the text numerical results are represented (eg TSH > 10 mU/L) Should Laboratories Make Local Bias Adjustments to the TSH Action Limits?

8. Evidence Base Whickham Bias unknown Functional Sensitivity likely to be in the order of 1-2 mU/L In-house RIA – Calibrated to 1st IRP Colorado study London Diagnostics – Nichols Institute Diagnostics Bias ? Rotterdam Study Brahms Lumitest Bias?

9. 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-offs The 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.”

10. Screening Screening in the healthy population is not warranted 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

11. Hospitalised Patients Routine testing of thyroid function in patients admitted acutely to hospital is not warranted unless there are specific clinical indications exist.

12. 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

13. Given no financial or other restrictions:- What would be your preferred TFT strategy? • 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 9 % 72% 17% 2% 0%

14. UK Guidelines • 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

15. TSH alone • Stable - on T4 • Follow-up of “at risk” patients • AF • Dyslipidaemia • Osteoporosis • Subfertility Cascade to FT4/FT3 if TSH is abnormal

16. Surveillance of “At Risk Patients” Using TSH

17. Diabetes • Type 1 – Annual TFT check • Type 2 – Check TFT at diagnosis – • Routine annual testing is not recommended

18. Down and Turner’s syndrome Annual check Post – neck irradiation Annual check Amiodarone Check before treatment Monitor every 6 months; continue to 12 months after cessation Lithium Check before treatment Monitor every 6 – 12 months

19. Radioiodine / Thyroid surgery Needs T4 not TSH for first 6-12 months 4-8 weeks – post treatment 3 monthly for first year Annually thereafter with TSH

20. UK Guidelines 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 require TSH and FT4, it may be prudent to measure TSH+FT4 rather than embark on first-line TSH.

21. Sub-clinical Hypothyroidism • High TSH with normal FT4 • Exclude transient and drug causes of elevated TSH, • exclude recovery from NTI. • Repeat to confirm at 3-6 months

22. Treating Sub-Clinical Hypothyroidism No Change in recommendations:- TSH > 10 mU/L – Treat with T4

23. Treating Sub-Clinical Hypothyroidism? Many patients with raised TSH that is < 10 mU/L will normalise TSH with time

24. 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-up 12 (18) 72 months

25. Treating Sub-Clinical Hypothyroidism? • TSH raised but < 10 mU/L • There is no clear evidence to support the benefit of • routine early treatment with T4 in non-pregnant • patients. • A high percentage (~ 10%) of patients treated with T4 • will have a TSH < 0.1 mU/L(Harmful? to bone and heart) • Physicians may wish to consider the suitability of a • therapeutic trial of T4 on an individual patient basis • eg goitre or seeking pregnancy

26. Thyroxine Replacement Therapy • 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) There is no compelling evidence or need to lower the upper reference limit or treatment target to 2.5 mU/L in non-pregnant patients

27. Published Reference Ranges • Denmark • 1512 subjects • – Reference population • TPO Ab negative • Reference Range 0.58 – 4.1 NHANES study (USA) 17,353 subjects 13,344 – Reference population TPO Ab negative Reference Range was 0.45 – 4.2 Studies Using Ultrasound Exclusion with TPOAb SHIP study Germany 1488 subjects (previous iodine deficiency) Ref range 0.25 – 2.12 Germany 453 blood donors Ref Range 0.4 – 3.77 Denmark 3174 participants Ref Range 0.4 – 3.6

28. 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 Increased metabolism Phenytoin Carbamazepine Barbiturates Rifampicin Altered TBG Oestrogens, Tamoxifen Heroin, Methadone Androgens, Anabolic steroids Glucocorticoids Impaired Absorption of T4  PPIs / H2 antagonists Calcium carbonate Soy protein Aluminium hydroxide Ferrous sulphate Cholestyramine Cholestapol Sucralfate

29. Sub-Clinical Hyperthyroidism Low 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)

30. Pregnancy Use bothTSH and FreeT4(Free T3 if TSH is low) to asses thyroid status and monitor T4 therapy

31. Use Trimester-Related Ref Ranges For All Tests 5.0 TSH mU/L 0.1

32. 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 thyroiditis • and foetal impairment

33. 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

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

35. 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

36. 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)

37. Thyroid Cancer Thyroglobulin 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

38. Thyroid Cancer Thyroglobulin and TgAb • Identify possible assay interference by • RIA/IMA discordance • TgAb positive samples • Recovery alone is not recommended

39. Discordant RIA / IMA Tg results at Edinburgh Royal Infirmary over a 17 month period. 14% of total results

40. RIA/IMA concordance in Tg Ab Negative Samples Data from Edinburgh Royal Infirmary IMA

41. RIA/IMA concordance in TgAb positive samples Data from Edinburgh Royal Infirmary Radioimmunoassay Sanofi IRMA

42. There is a UK NEQAS scheme for thyroglobulin. Data from scheme illustrates the poor performance of Tg assays

43. How Should We Inform GPs ?

44. Guideline Group Plan to Produce a Version for GPs • But • Perhaps 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 issues • After Consultation with the Local Endocrinologists • And Obstetricians!