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Vahab Fatourechi MD Professor of Medicine Mayo Clinic Rochester MN, USA

Vahab Fatourechi MD Professor of Medicine Mayo Clinic Rochester MN, USA. Subclinical Hypothyroidism: An Update Isfahan 2012. Subclinical Hypothyroidism (SCH) An Update. Elevated TSH above normal Normal serum T4 and T3. How Common is Subclinical Hypothyroidism?.

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Vahab Fatourechi MD Professor of Medicine Mayo Clinic Rochester MN, USA

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  1. Vahab Fatourechi MD Professor of Medicine Mayo Clinic Rochester MN, USA Subclinical Hypothyroidism: An Update Isfahan 2012

  2. Subclinical Hypothyroidism(SCH) An Update • Elevated TSH above normal • Normal serum T4 and T3

  3. How Common is Subclinical Hypothyroidism? Elevated TSH is very common (3-10% of population)

  4. Elevated TSH in US PopulationNHAINES III % of population TSH>4.5 mIU/L 2 3 4 5 6 7 8 9 Decades of life

  5. Serum TSH in 123958 Patients Age > 50Yrs( 1995-1997 ) TSH Fatourechi et al, 2002

  6. Normal Serum TSH Controversy

  7. TSH Normal Range Histograms NHANES III (1988-1994) 13,344 with No Thyroid Disease 95% had TSH <2.5 uU/mL Frequency 0.3 1.0 2.0 3.0 4.0 TSH (mIU/L) CP1232194-14

  8. TSH Population Reference Ranges 1990-2002 • Reasons for skew of TSH upper limit include • Euthyroid outliers – inherent TSH lability • Measurement of bioinactive isoforms • Occult thyroid dysfunction 95%limits ~0.45 1-1.5 ~2.5 ~4.0 10 *Canaris: Arch Intern Med 160:526, 2000 ** Hollowell: JCEM 87:489, 2000 CP1232194-7

  9. 5.7 5.5 5.8 8.3 13.5 14.4 18.1 30.6 28.0 30.9 54.6 85.2 96.5 NHANES – TPOAb Frequency Across0.5 mlu/L TSH Intervals SubclinicalHyperthyroidism Subclinical/OvertHypothyroidism Typical TSH Reference Range TPOAb (±TgAb) (%) 0.1 0.4 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5 10 >20 TSH (mIU/L) CP1232194-11

  10. Circadian Rhythm ofTSH in Normal Subjects Samplingtimes TSH(mU/L) Mantzoros: JCEM 86:3284, 2001 0800 1400 2200 0200 0800 Time of day CP1232194-8

  11. Variation of Serum TSH • Mean in white (NHANES) 1.4 mIU/L • Mean in Blacks (NHANES) 1.14 • Diurnal variation • Pregnancy first trimester 0.02-2.5 • Infancy <15 • Normal outliers • Slightly higher in teenagers and older individuals • Increased BMI, higher TSH-normalizes after WT loss • Bio-inactive TSH isoforms • Inactivating polymorphysim of TSH receptor

  12. Effects of Lowering the Upper Limit of the TSH Reference Range to 3.0 mIU/L Effect on 75,882 patients with no thyroid disease(x= fold increase) Fatourecbi et al JAMA, Dec 2003

  13. Normal TSH values (Mayo Study) • 139 healthy volunteers, Ages 21-67 Ys., 99 F, 40 M • Positive TPO antibodies excluded (n=10) • Nodules larger than 1cm on US excluded (n=10) • FH of thyroid disease included (F 38%, M,18%) • Remaining n=119 Normal range of TSH 0.7-4.5 mIU/L for Roche assay • Beckman assay 0.7-3.6 mIU/L • FH of thyroid disease excluded TSH Values 0.8-3.7 mIU/L To be published: Overson et al 2012

  14. Why Not to Lower Upper Limit of Normal TSH • Variation in one individual, time of day, day to day variation • No data for adverse effects at upper normal TSH • No data for benefits of therapy • Potential for widespread T4 therapy with potential risks Surks et al JCEM:90, 2005

  15. Common Sense Conclusion • Levels 3.0-5.0: higher risk of progression to significant dysfunction and may need follow up, TPO measurement may be helpful • Higher TSH acceptable for very old (age>80) • Propose any level between 3.6-5 mIU/L depending on assay system

  16. AACE/ATA Guidelines Proposed Upper limit of normal TSH 4.2 mIU/L for non-pregnant adults in iodine sufficient areas in the absence of age related adjusted values Sept 2012 . Endocrine Practice

  17. Subclinical Hypothyroidism

  18. Non thyroidal illness Nocturnal surge in TSH secretion Assay variability Heterophile antibodies Metoclopramide, domperidone TSH -secreting pituitary adenoma Thyroid hormone resistance Renal failure, adrenal failure Central hypothyroidism (biologically inactive TSH ) Elevated TSH not Associated with Subclinical Hypothyroidism

  19. What about central Subclinical Hypothyroidism? • Central hypothyroidism is 1000 times less common than primary hypothyroidism • Subclinical central hypothyroidism can not be directly diagnosed • Inappropriately low T4 with low normal TSH in clinical setting may be suggestive • In autoimmune hypophysitis or drug induced hypophysitis TSH may be the first hormone to be disturbed. Persani L, JCEM ,Sept 2012

  20. Progression to clinical hypothyroidism Systemic symptoms of hypothyroidism Lipid abnormalities Adverse cardiac end points Cardiac and endothelial dysfunction Adverse fetal effects Adverse pregnancy outcomes Neuro-muscular dysfunction Cognitive dysfunction Hypercoagulability Metabolic syndrome Proposed Consequences of SCH

  21. Surks et al JAMA,291:228,2004

  22. Surks et al JAMA,291:228,2004

  23. Whickham Study: Risk of progression of subclinical hypothyroidism to clinical hypothyroidism Annual risk 20-yr cumulative Positive test (%) incidence (%) TSH N, Ab+ 2.1 27 TSH , Ab– 2.6 33 TSH , Ab+ 4.3 55 Vanderpump M: Clin Endocrinol 43:55, 1995 CP1232194-3

  24. Spontaneous Normalization of Elevated TSH • N=175, age >55 33.2 months F/U • Normalized TSH 37% • For TSH 5-10 , Normalization 52% • For TSH 10-15, normalization 13% • Predictor of Progression to overt hypo: Multivariate: TSH level Univariate : Symptoms, TSH, antibodies Diez JJ, et al JCEM 2004

  25. Progression of SCH to Overt Hypothyroidismin Elderly Japanese Population • N=71 atomic bomb survivors, 4.2 year F/U • 50% normalized TSH • Lower TSH, normal US of thyroid was predictive of normalization • TSH > 8 was predictive of overt hypothyroidism Imaizumi M et al. Thyroid: Nov 2011

  26. Progression of SCH in Children • n=382, mean age 10.5, 3 Yr F/U • elevated TSH--TSH normalized in 39% • 39 % stable TSH • Remainder progressed to overt hypothyroidism Radetti G et. Al. Endocrinol (Oxf) OCT 2011

  27. SCH During Pregnancy • Adverse pregnancy outcome • Offspring of mothers with SCH at second trimester 7 point reduced IQ at 7-9 years Haddow et.al NEJM 1999

  28. Intellectual Development of Offsprings of Mothers with SCH • n=44 , ages 4-15 • Mothers on T4 pre gestation, during pregnancy 19 Normal TSH, 25 increased TSH, 19 SCH 6 overt • Mean TSH 11.3 in cases 1.4 in controls • Results : IQ levels and cognitive performance of offsprings of T4 treated mothers Same in in SCH and normal TSH Behrooz HG , Tohidi, Mehrabi, behrooz Eg, Tehrandoust and Azizi : Thyroid, OCT 2011

  29. High serum TSH in First Trimester and Outcome of Pregnancy • First trimester pregnancy n=2801 • Higher TSH levels associated with: • Small for gestational age • Miscarriage • But predictive accuracy was poor • Conclusion: TSH Screening not recommended Francisco J: JCEM Sept 2012

  30. Guidelines of ATA for SCH in Pregnancy • AB+ with SCH should be treated with thyroxine • Goal of therapy: First trimester TSH O.1 -2.5 mIU/L second 0.2-3.0-, third 0.3 -3.0 • If on T4 therapy before pregnancy, take 2 extra TAB/WK on missed period • Can not advise Rx for AB+ normal TSH , but frequent monitoring recommended Thyroid Volume 21, page 1081 , 2011

  31. Endocrine Society Practice GuidelinesIn Pregnancy for SCH ( frequency 2-4%) • TSH >2.5 in first trimester, >3.0 in second trimester = Thyroxine therapy • TSH 2.5-10 = Thyroxine 50 mcg or more • Universal screening not recommended • Screen before pregnancy if known thyroid disease • Agree with adding 2 extra TAB/per/week as soon as pregnant Degroot et al. JCEM 2012

  32. Colorado Study TSH and Cholesterol All TC values sig different from euthyroid TC values (P<0.003) LDL increased P<0.001 Total cholesterol (mg/dL) TSH (mIU16/L) Canaris: Arch Int Med 160:526, 2000 CP1232194-16

  33. Subclinical Hypothyroidismand Lipid alteration: Update • Apo B may be increased • Clinical trials : No consistent benefit from T4 therapy on lipid levels in SCH Pearce E, JCEM Feb 2012

  34. Other Proposed Emerging Risk Factors in Subclinical Hypothyroidism • Lipoprotein a (Lpa) Not proven to be high • Homocysteine Not elevated in subclinical • Elevated in clinical hypo • CRP may be a factor, More data needed • Endothelial factor, Very soft data. • Hypercoagulable state Mostly in overt disease

  35. Rotterdam Study (SCH) • Aortic Atherosclerosis Odds Ratio • SCH 1.7 • Myocardial Infarction Odds Ratio • SCH 2.3 Hak et al. Ann Int Med. 2000;132:132

  36. Adverse Cardiac Endpoints in Subclinical Hypothyroidism No association Wickham study (Vanderpump et al) 1995 English study (Parle et al) 2001 Coppola 2006 Association Rodondi metaanalysis 2006 Ochs metaanalysis 2008 Sing meta-analysis 2008 Hentjens meta-analysis 2008 Razvi meta-analysis 2008 Conclusion Risk for ages <65 No risk age 70-80 Possible survival benefit age >80

  37. Serum TSH in CHD Patients Age > 50Yrs and Controls (1995-1997) n= 123958 Fatourechi et al , ATA abstract, 2000

  38. SCH and Metabolic Syndrome in Older Adults (Health ABC study) • N=2119 • SCH with TSH >10 mIU/L significantly associated with prevalent metabolic Syndrome Waring AC et al: ClinEndocrinol Dec 2011

  39. Mortality and SCH in Very old (Mean age 85) • N= 1049 men and women • 4.8 Ys . Mean F/U • 10 % SCH • No association with TSH, TPO and mortality Waring et.al. Thyroid 21: 2012

  40. SCH and Myocardial Blood Flow • N=10 ,male and female, mean TSH 16 • Compared to 8 controls • Myocardial blood flow and flow reserve measured by PET • SCH had lower levels Coronary microcirculation improved with T4 therapy in SCH Traub – Weidiner et. al. Jan 2012

  41. Subclinical hypothyroidism and Heart Failure in High Risk Elderly • 199 patients on Pravastatin, male and female • Ages 70-82 • 3.2 Yrs.. F/U • Only TSH >10 associated with increased heart failure Nanchang et.al, JCEM 2012

  42. SCH and all Cause Mortality in Age>65 Men • 8 years F/U, n=1587 • Only 8 with TSH>10 • No increased risk of all cause mortality • No increased risk of CV mortality Waring et. al, JCEM, 2012

  43. SCH and Risk of CAD and Mortality • Meta-analysis • N=2597 and 7 cohorts • CAD events and mortality increased particularly for TSH>10 Rodandi JAMA: Sept , 2010

  44. SCH and Mortality in Men Age >65 • N=1587, Age >65 males , 8.3 yr F/U • SCH was not associated with all cause or CV mortality in older men Avantika C , et al, JCEM march 2012

  45. Mortality and SCH • All patients seen at Cleveland Clinic • TSH <6 not associated with mortality • TSH 6.1-10 associated with increased mortality if under age 65 • Increased mortality if TSH>10 Mcquade et al Thyroid: Aug 2011

  46. Age Influence on SCH and Ischemic Heart Disease • Meta-analysis 15 studies n=2531 SCH 26,491 controls • Age <65 ischemic heart disease higher, mortality CV also higher • Age >65 no difference with euthyroids Razvi et. Al. JCEM Aug 2008

  47. T4 therapy of SCH and Ischemic Heart Disease Events (IHD) • UK GP data base TSH 5.1-10 mIU/L, 9 yr period, F/U mean 7.6 Yrs. • Group 1: 40-70, n=3093, 53% Rx with T4 • Group2: >70 ys n= 1642 50% Rx with T4 • Group 1: IHD 4.2% with T4 therapy 6.6 % noT4 • Group2: IHD 12 % with T4 therapy 10.7% no T4 Conclusion ; T4 therapy in younger patients associated with fewer IHD , Not so for older individuals RazviS. et al Arch Int Med. April 2012

  48. Randomized Studies of Therapy for Subclinical Hypothyroidism: Symptoms • . Author #Pts TSH Results Cooper 33 3-35 Improved Nystrom 20 3-16 Improved Jaeschke 37 6-32 only memory Meier 55 5-50 Improved Kong 40 5-10 Not improved

  49. Summary of Studies for Benefits of Screening and Therapy of SCH • Evaluation of randomized studies • No benefit or harm noted • No benefit in quality of life, BP or weight • Possible 5% improvement in lipid profile • Large scale studies needed Rugge B et. al AHRQ comparative effectiveness reviews : Agency for health care research Oct 2011

  50. Consensus for Therapy of SCH • There is consensus for therapy of all with TSH above 10 mIU/L • For TSH 5-10 there is no consensus

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