Subclinical Hypothyroidism Something or Nothing? E. Chester Ridgway University of Colorado SOM August 1-2, 2008

Transcription

1 Subclinical Hypothyroidism Something or Nothing? E. Chester Ridgway University of Colorado SOM August 1-2, 2008

2 Case: A 78 y/o female who is cold with fatigue, dry skin, and poor memory. Free T4 = 1.2 ng/dl TSH = 7 uu/ml Anti TPO = 72 U/L Chol = 242 mg/dl LDL = 138 mg/dl

3 Subclinical Hypothyroidism Biochemical Definition Normal FT4 and FT3 High Serum TSH

4 Is It Important?? 2001 Evidence-Based Consensus Guidelines Diagnosis and Management of SCH TSH = uu/ml SCH vs Controls Benefits of Rxment Symptoms None Insufficient Lipids Insufficient Insufficient Cardiac Dysfunction Insufficient Insufficient Adverse Outcomes Insufficient None TSH = > 10 uu/ml SCH vs Controls Benefits of Rxment Symptoms Insufficient Insufficient Lipids Fair Insufficient Cardiac Dysfunction Insufficient Insufficient Adverse Outcomes Insufficient None Surks et al JAMA, 2004

5 Is Mild Thyroid Failure Important.???? Prevalence: A Moving Target Cognition Lipids Cardiac Dysfunction Adverse Outcomes

6 PREVALENCE HIGH TSH THE COLORADO STUDY 25,862 SUBJECTS TSH > 5.1 = 9.5% Subclinical Hypothyroidism = 95% NHANES III STUDY 17,353 SUBJECTS TSH > 4.5 = 4.7% Subclinical Hypothyroidism = 94% Canaris et al Archives Int Med 160:526, 2000 Hollowell et al JCEM 87:489, 2002

7 Number of Undiagnosed Individuals in USA If High TSH = Men Women >74 Total Men = 4.5 Million Total Women = 9.5 Million

8 14 Million High TSH Patients IF High TSH > uu/ml What if the upper limit of TSH is not ?

9 TSH Normal Range Variance TSH miu/l n = 4212 African American n = 4689 US Caucasians n = 250 French Caucasians n = 150 Italian Caucasians n = 363 German Caucasians n = 4298 German Caucasians NHANES III JCEM 87:489, 2002 d'herbomez et al Clin Chem Lab Med 43:102, 2005 Volzke (SHIP study) Thyroid 15:279, 2005

10 NHANES III National Health and Nutrition Examination Survey People surveyed between Younger (>12 yr) Older African Americans Mexican Americans Testing TT4 TSH Thyroid Antibodies Oversampled

11 NHANES III National Health and Nutrition Examination Survey Median TSH 95% Confidence All (17353) to 5.8 Disease Free (16533) to 5.5 Reference (13344) to 4.12 Disease Free (16533) = Minus those with known thyroid disease Reference (13344) = Minus E2, T, Lithium, Positive Antibodies, Pregnancy Hollowell et al JCEM 87:489, 2002

12 Normal Reference Range 2.5% 2.5% -2 sd (2.5%) -1 sd mean +1 sd +2 sd (97.5%)

13 TSH Reference Range TSH (uu/ml)

14 If the TSH Distribution were Gaussian NACB = National Association for Clinical Biochemistry AACE = American Association Clinical Endocrinology TSH Normal Range Would Be Changed from 0.5 to 4.5 uu/ml To 0.5 to 2.5 uu/ml Number SCH 14 Million To 51 Million

15 WHY? 1. Histograms and Frequency Analysis 2. The Whickham, England Follow-up Survey

16 TSH mu/l 5.6 TSH Levels in Normals Nl = 0.3 to 5.0 uu/ml Different Immunometric Assays 20 Normal Subjects From: Nicoloff & Spencer JCEM 71:553, 1990

17 Frequency Frequency TSH Normal Range Histograms Behring Corning D P C Ortho TSH mu/l

18 WHICKHAM SURVEY PREDICTION 4 Vanderpump et al Clin Endocrinol43:55,1995 Logit Probability of Developing Hypothyroidism within 20 years Antibody positive (fitted model) Antibody negative (fitted model) Observed data (smoothed) Serum TSH mu/l

19 TSH Normal Range NHANES III Median Total Population Autoimmune Thyroid Disease Lower 2.5% Upper 2.5% TSH (uu/ml) Hollowell et al JCEM 87:489, 2002

20 100 NHANES III (n = 4519) (Hollowell JCEM 87:489,2002) Frequency of TPOAb * Danish Study (n = 4649) Vejbjerg Eur J Endocrinol 155:547, 2006 Frequency of Ultrasound Hypoechogenicity * % * 60 % 40 * * * * * * * < >20 < >5 * p < 0.05 vs. TSH miu/l TSH miu/l

21 TSH Normal Range Median NHANES III Total Population Disease-Free Reference Population Antibody-Negative Autoimmune Thyroiditis Apparent on Ultrasound Lower 2.5% Upper 2.5% TSH (uu/ml) Hollowell et al JCEM 87:489, 2002

22 Hanford Thyroid Disease Study Data 1861 randomly selected subjects (subset of HTDS) Ages years (median 51) Three reference ranges: TOTAL GROUP: 1861 NRG 1: No hx thyroid disease or thyroid hormone use, normal thyroid exam (n=1448) NRG 2: NRG 1 + no anti-thyroid Abs (n=1186) NRG 3: NRG 2 + normal thyroid US (n=766) Hamilton et al JCEM 93:1224, 2008

23 TSH Upper Limit of Normal 97.5 Percentile Hanford Thyroid Disease Study 6 TSH uu/ml Total NRG1 NRG2 NRG3 1 0 Total NRG1 NRG2 NRG3 Hamilton et al JCEM 93:1224, 2008

24 TSH Normal Range Hanford Thyroid Disease Study NDF3 NDF3 TSH Upper Limit = 3.4 uu/ml Log Transformation TSH (uu/ml) TSH (uu/ml) Hamilton et al JCEM 93:1224, 2008

25 OK Should the Upper Limit be Higher?

26 THE COLORADO STUDY 25 PREVALENCE OF HIGH TSH LEVELS 20 Percent Femal Male >74 Age Canaris et al Archives Int Med 160:526, 2000

27 18 The Nhanes III Study Prevalence of High TSH Values Subjects Percent >80 AGE Hollowell et al JCEM 2002 Male Female

28 The Nhanes III Study Prevalence of Positive Anti-TPO Antibodies Subjects Percent >80 AGE Male Female Hollowell et al JCEM 87:489, 2002

29 The Nhanes III Study High TSH Values Percent Male Female 0 Total Reference Hollowell et al JCEM 87:489, 2002

30 16 High Serum TSH Percent of Population % < >80 Age Total Disease-Free Reference Hollowell et al JCEM 87:489, 2002

31 TSH Upper Limit of Normal Range Reference Population by Age 4 TSH < >80 Hollowell et al JCEM 87:489, 2002

32 TSH Levels and Age Mean Median 97.50% 12 to >80 Surks et al JCEM 92:4575, 2007

33 Percent of Reference Population At Different TSH Levels to >80 < >4.5 Surks et al JCEM 92:4575, 2007

34 Is Mild Thyroid Failure Important.???? Prevalence: A Moving Target Cognition Lipids Cardiac Dysfunction Adverse Outcomes

35 What is Cognition? Cognition Perception Language Memory Attention/ Executive Psychomotor Concentration function function Mood (affect) impacts all of these functions

36 Declarative memory: Hippocampus / Medial Temporal lobe Working memory: Prefrontal cortex Motor learning: Basal ganglia/ cerebellum adapted from LONI

37 Subclinical Hypothyroidism Neuropsychological Function and Symptoms 89 Pts with SCH vs 154 Controls 14 Cognitive Function Tests General Health Questionaire Hypothyroid Symptom Questionaire 69 Pts with SCH enrolled in RCT SCH : TSH = uu/ml FT4 and FT3 = Normal Jorde et al JCEM Nov, 2005

38 Subclinical Hypothyroidism Neuropsychological Function and Symptoms Cross Sectional 14 Cognitive Function Tests: No Differences SCH vs Controls General Health Questionaire: : No Differences SCH vs Controls Hypothyroid Symptom Questionaire: : No Differences SCH vs Controls RCT LT4 vs Placebo: No Significant Difference Patients could not distinquish LT4 from Placebo Jorde et al JCEM Nov, 2005

39 Subclinical Hypothyroidism Study - Experimental Design - 19 healthy adults with primary hypothyroidism, on stable doses of L-T4 with normal TSH levels Randomized to usual dose L-T4 (EU) vs. lower dose L-T4 (SCHypo) for 12 weeks in doubleblinded, cross-over fashion Target TSH levels mu/l on SCHypo arm SF-36, POMS, Cognitive Tests Samuels MH et al JCEM 92:

40 Subclinical Hypothyroid Study - Experimental Design - Week 0: Baseline Week 12: Cross-over Week 6 Week 18 Week 24: End of Study TSH, ft4, ft3 SF-36 POMS Cognitive tests TSH, ft4, ft3 SF-36 POMS Cognitive tests TSH, ft4, ft3 SF-36 POMS Cognitive tests Weeks 6 and 18: L-T4 dose adjustment as needed

41 N-Back Task 1-Back Time r Q A a P X Target

42 N-Back Task 3-Back Time r Q A j P a Target

43 Subject Ordered Pointing Task (6 pictures) TRIAL 1 TRIAL 2 TRIAL 3

44 Subject Ordered Pointing Task (10 Pictures)

45 Working Memory N-Back Subject Order Pointing Euthyroid SCH Euthyroid SCH P< P<0.02 P< Back 3-Back SOP-6 SOP-8 SOP-10 SOP-12 Samuels MH et al JCEM 92:

46 Declarative memory: Hippocampus / Medial Temporal lobe Paragraph recall, Complex figure Working memory: Prefrontal cortex N-back, SOP, Digit Span Motor learning: Basal ganglia/cerebellum Pursuit rotor adapted from LONI

47 Is Mild Thyroid Failure Important.???? Prevalence: A Moving Target Cognition Lipids Cardiac Dysfunction Adverse Outcomes

48 THE COLORADO STUDY MEAN CHOLESTEROL LEVELS 250 P < LOW NORMAL >80 TSH LEVEL Canaris et al Archives Int Med 160:526, 2000

49 LT4 Treatment in Mild Hypothyroidism Impact on Total Cholesterol A Metanalysis RCTs Danese, et al. JCEM 2000;85:2993

50 Author Pts > Controls? Decrease With Rx? LT4<Placebo Tzotzas 2000 No No N/A Efstathiadou 2001 Meier 2001,2003 Caraccio 2002 Kong 2002 Milionis 2003 Yes No Yes N/A Yes Yes, if chol>240 or TSH >10 Yes, esp chol>240, TSH>12 Yes N/A No 4/6 6/8 2/5 Yes No No No N/A Monzani 2004 Yes Yes Yes Razvi 2007 N/A Yes Yes

51 Effect of LT4 on Lipids in SCH 45 Subclinical Hypo Patients TSH = 6.3 uu/ml 32 matched controls TSH = 1.2 (gender, age, BMI) * p<0.05 * Control SC Hypo 100 No obesity, smokers, DM. Blinded RCT 50 0 Chol LDL Monzani F et al. JCEM 89(5):

52 SCH and LT4 Therapy * p<0.05 Pre LT4 150 Post LT4 * Pre Placebo 100 Post Placebo 50 0 TSH stable for 6 mos, Median RX 10.5 mos Monzani F et al. JCEM 89(5):

53 Subclinical Hypothyroidism and CV Risk Effect of L-T4 Therapy 100 Patients in UK, Mean Age 54 Community Dwelling, 27 General Practices RCT + Crossover Design TSH = 6.6 uu/ml LT4 = 100 ug/d vs Placebo Treatment Periods = 12 weeks Primary Outcomes: Cholesterol Endothelial Function Razvi S et al JCEM 92:1715, 2007

54 Subclinical Hypothyroidism and CV Risk Effect of L-T4 Therapy % P < % Placebo LT4 3 2 Cholesterol LDL FMD Razvi S et al JCEM 92:1715, 2007

55 SCH and LT4 Therapy in Brazil TC and LDL 38 SCH Patients TSH = 7.6 uu/ml RCT TC LDL Better Effect 5 TSH > 8 TPO AB Placebo LT4 BMI > Menopause P < 0.01 P < 0.02 Telixeira PFS et al Horm Metab Res 40:50, 2008

56 Is Mild Thyroid Failure Important.???? Prevalence: A Moving Target Cognition Lipids Cardiac Dysfunction Adverse Outcomes

57 Mild Thyroid Failure Diastolic and Systolic Function P < P < 0.03 P < 0.01 IVRT PEP/ET Peak A Controls MTF Monzani et al JCEM 86:1110,2001

58 Mild Thyroid Failure Doppler Echocardiography Diastolic Function IRT = Isovolumic Relaxation Time 45 Pts vs 23 Controls Blinded RCT TSH = 8.4 uu/ml Mean LT4 = 64 ug/d msec P < P < P < 0.05 Controls Controls 6 mo Pre LT4 Post LT4 6 mo Post LT4 12 mo Pre Plac Post Plac 6 mo 75 IRT Yazici et al Internat J. Card 95:135, 2004

59 SCH and Coronary Flow Reserve 50 pts (TSH=9.3) vs 30 controls (TSH 1.2) CFR = Peak-Resting Coronary Flow by TT Doppler Controls SCH 3 P < CFR Baycan et al Clin Card 30:562, 2007

60 SCH Treatment and Coronary Flow Reserve 10 pts (TSH=7.6) vs 10 controls (TSH 1.7) Effect of LT4 for 6 months in SCH P < Baseline 6 Month Controls SCH Oflaz et al Endocrine 32:264, 2007

61 Thyroid Hormone Deficiency Altered Cardiac Gene Expression Systolic Diastolic Dec Alpha Myosin Inc Beta Myosin Dec Beta Adren Rec Dec SERCA Inc Phospholambin Systolic and Diastolic Dysfunction Diastolic > Systolic CHF Is There Any?? Morbidity And Mortality

62 Is Mild Thyroid Failure Important.???? Prevalence: A Moving Target Cognition Lipids Cardiac Dysfunction Adverse Outcomes

63 Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study Random sample = 1149 females Age = 69 +/- 7.5 yrs TSH Elevated = 10.8% (>4 uu/ml) End Points = Aortic Atherosclerosis (Aortic Calcification) Myocardial Infarction ( EKG) Methods = Cross-sectional + Short Longitudinal Hak AE et al Annals Int Med 132:270, 2000

64 Subclinical Hypothyroidism and Atherosclerosis The Rotterdam Study MI High TSH + TAB High TSH Euthyroid Aortic Ca++ Short Longitudinal = NS Odds Ratio *Adjusted for age, BP, BMI, smoking, lipids Hak AE et al Annals Int Med 132:270, 2000

65 CV Disease Mortality Minimally Elevated TSH Imaizumi et al. JCEM subjects 10.2% TSH > 5 240/257 (96%) TSH 5-10 Males p<0.05 In patients with TSH 5-10: Overall OR 2.7 for Ischemic heart disease. Men OR 4.5 Women OR 1.7 INDEPENDENT OF CVD RF Females NS

66 Coronary Heart Disease and SCHypo Western Australia 20 years Community Health Study (Busselton) 2108 Subjects, Archived Serum ( ) Mean Age = 50 yrs (17-89) SCHypo = 5.6% (TSH>4.0, NL FT4) Cross-sectional Study-Coronary Heart Disease Longitudinal Study Coronary Heart Disease Events Cardiovascular Mortality Walsh et al, Arch Inter Med 165:2467, 2005

67 Coronary Heart Disease and SCHypo Cross-sectional Analysis TSH > 4 P = 0.01 Adjustments: Age, Sex, BMI, DM, Smoking, Lipids, BP, Thyroid Disease, TSH > 10 TSH 4-10 P = 0.03 P = SCH Euthyroid Mortality = 1.5 P = 0.1 Walsh et al, Arch Inter Med 165:2467, 2005

68 Congestive Heart Failure and SCHypo Memphis and Pittsburg 4 years Medicare Eligible Caucasions and African Americans 2730 Subjects (1997) Mean Age = 75 yrs (70-79) SCHypo = 12.4% (TSH>4.5, NL FT4) Cross-sectional Study-Cardiovascular Disease Longitudinal Study Cardiovascular Disease Events Cardiovascular Mortality Rodondi et al, Arch Inter Med 165:2460, 2005

69 Congestive Heart Failure and SCHypo Longitudinal Analysis 4 years TSH > 4.5 TSH > 10 TSH 7-10 * * P < 0.05 * SCH Euthyroid TSH Increment 4 uu/ml 30% Inc CHF Adjustments: Age, Sex, BMI, DM, Smoking, Lipids, BP, Thyroid Disease, TSH P = NS No Increase Other ASD Or Death Rodondi et al, Arch Inter Med 165:2460, 2005

70 Congestive Heart Failure and SCHypo Longitudinal Analysis 4 years Rodondi et al, Arch Inter Med 165:2460, 2005

71 Subclinical and Overt Hypothyroidism Survival in the Oldest of Old Low TSH Normal TSH SCH Overt Hypo Gussekloo et al JAMA 292:2591, 2004

72 Subclinical Hypothyroidism and CAD Meta-Analysis Fourteen Observational Studies 10,540 Subjects with 1362 CAD Events Sensitivity and Subgroup Analysis OR = 1.6 (95% CI = ).01.1 Pooled Fixed Effects Pooled Random Effects Rodondi et al. AJM 119: , 2006

73 Subclinical Hypothyroidism and Adverse Outcomes Longitudinal Studies 2008 CVD CVD Mortality Total Mortality Haentjens (EJE) 1.22 ( ) Community 1.03 ( ) Co-morbidities 1.76 ( ) Razvi (JCEM) 1.27 ( ) 1.09 ( ) < 65 yrs 1.68 ( ) 1.37 ( ) >65 yrs 1.02 ( ) 0.85 ( ) Ochs (AIM) 1.20 ( ) 1.18 ( ) 1.12 ( ) < 65 yrs 1.51 ( ) 1.50 ( ) 1.20 ( ) >65 yrs 1.05 ( ) 1.12 ( ) 1.10 ( )

74 Subclinical Hypothyroidism Cardiovascular Risk is Age Dependent Biondi and Cooper Endo Reviews, Dec 2008

75 The Lessons.. 1. Subclinical Hypothyroidism is common (5-10%) Or is it 35% or 2-3% 2. Most is Mild 3. Women > Men 4. Age in Both Sexes is Critical 5. Ethnicity is Important 6. Cognitive Defects (Memory) may exist 7. TC and LDL may be higher and respond to LT4 8. Diastolic > Systolic Cardiac Dysfunction Smoke but No Fire 9. More Morbidity than Mortality: 10. Lack of Prospective RCTs (But Improving)

76 The Patient She was treated with LT-4 88 ug/d. Her TSH=1.0