6/18/2018 Disclosures None Thyroid Cases Case Based Discussion 69 yo healthy active man with abnormal thyroid tests • PMH – BPH, anxiety, mild hypertension, GERD • FH – Sister in her 60s being monitored for slightly elevated TSH • MED – Omeprazole • ROS CASE 1 – Nails a bit more brittle, a bit colder last year, BP perhaps slightly higher, constipation all his life • PE 148/92, pulse 80 – Lean, healthy – Thyroid exam: firm, not enlarged, no nodules 1
6/18/2018 Spontaneous Normalization of TSH Is Common 69 yo healthy active man with Repeat TSH! abnormal thyroid tests N=422,242 patients 2002-2006 If TSH normal on 1 st test • TSH 7.30 HI (0.45-4.12 mIU/L) 98% stayed normal • Free T4 10 (10-18 pmol/L), If TSH > 10 on 1 st test • Free T3 3.7 (2.6-5.7 pmol/L) 28% had nl TSH on repeat • Diagnosis: SUBCLINICAL HYPOTHYROIDISM If TSH 5.5 – 10 on 1 st test 62% had nl TSH on repeat Patient - “Should I be treated?” 35% stayed the same Should He? Meyerovitch Arch Intern Med 2007 TSH Free T4 Free T3 69 yo with subclinical hypothyroidism, asymptomatic (0.45-4.12 mIU/L) (10-18 pmol/L) (2.6-5.7 pmol/L) 1/4/2018 6.89 (H) 11 12/28/06 1/21/11 6/3/14 3/3/17 9/7/2017 7.30(H) 10 3.7 3/29/2016 6.17(H) 10 Cholesterol, Total 204 (H) 155 180 173 6/3/2014 6.72(H) 9 (L) 4.0 <200 mg/dL Triglycerides 134 69 74 98 4/24/2013 5.45(H) 10 4.4 <200 mg/dL 7/23/2012 7.76(H) 10 TPO > 830 HDL 65 55 74 60 9/21/2011 7.73(H) 10 >39 mg/dL LDL 112 86 91 93 5/11/2010 7.81(H) 10 <130 mg/dL 2/23/2010 8.52(H) 9 Treat ? Chol HDL Ratio 3.1 2.8 2.4 2.9 <6.0 2/9/2010 9.21(H) Any Additional Tests? Non HDL 139 100 106 113 4/15/2002 3.36 13 <160 mg/dL 11/9/2000 2.70 Treat? 2
6/18/2018 Subclinical Hypothyroidism Should this 69 yo man with subclinical hypothyroidism be treated with levothyroxine? • Definition: TSH > the upper limit of normal with 68% normal T4 A. Yes • Most common cause: autoimmune thyroiditis B. No 28% C. Undecided • Prevalence: 4 -10%* – Increases with age 5% – More common in women and in iodine sufficiency s o d e Y N e d i c e d n U *Hollowell JCEM 2002 *Biondi and Cooper Endo Rev 2008 Subclinical Hypothyroidism Subclinical Hypothyroidism • Risk of progression to overt hypothyroidism – TSH level, thyroid AB status • Not all elevated TSH (with normal T4) Whickham Survey * represent mild thyroid failure Women: annual progression – Assay interferences – 2.6% with elevated TSH • Heterophile AB – 2% if only anti-thyroid AB + – Obesity – 4.3% with both elevated TSH /+AB – Recovery from thyroiditis or nonthyroidal illness Diez JCEM 2004 (older than 55 yo)** – Elevated TSH > 10mIU/L – Medications: amiodarone/Lithium • 10mIU/L( Hazard Ratio 10) and 15mIU/L (HR 28) – Aging Samworu et JCEM 2012 (older than 65 yo)** ‒ Elevated TSH > 10 mIU/L *Vanderpump Clin Endocrinol 1995 ** JCEM 2004 & JCEM 2012 3
6/18/2018 TSH Range TSH - 97.5 centile by Age Group No known thyroid disease/goiter and Antibodies Negative NHANES III Distribution by Age NHANES III TSH 0.45 – 4.12 mIU/L = 2.5 to 97.5 percentile Hollowel J Clin Endocrinol Metab 2002 Surks J Clin Endocrinol Metab 2007 Surks J Clin Endocrinol Metab 2007 Back to the Patient More Questions… • What difference would I feel if I take the pill? • Could something bad happen to me if I don’t take the pill? 4
6/18/2018 Randomized Controlled Trial in Older Patients Randomized Controlled Trial in Older Patients • Primary outcomes • Inclusion – Hypothyroid symptoms (ThyPro) – Tiredness score – Population: 65 yo or older – Persistent subclinical hypothyroidism. TSH 4.60-19.99 • Secondary outcomes mIU/L, 3 months to 3 years apart. Free T4 normal. – Health related quality of life (EQ-5D) Did not look at TPO status – Hand grip • Exclusion – Executive function – Weight, BMI, weight circumference – Thyroid medications, lithium, amiodarone – Blood pressure – Thyroid surgery, RAI in the previous 12 months – Activities of daily living – Hospitalization, surgery, acute coronary artery events in the previous 4 weeks • Lack of power – Dementia – CV events – Terminal illnesses Characteristics Placebo (n=369) LT4 Group (n=368) 5.48±2.48 Age 74.8 ±6.8 yo 74 ± 5.8 yo Age range (65.1 ‒ 93.4) (65.2 ‒ 93) TSH 6.38 ± 2.01 mIU/L 6.41 ± 2.01 mIU/L Median 5.76 (5.10 ‒ 6.94) 5.73 (5.12 ‒ 6.83) Range 4.60 ‒ 17.60 4.60 ‒ 17.60 3.63±2.11 Outcome measures Hypothyroid 16.9 ± 17.9 17.5 ± 18.8 Symptoms Tiredness score 25.5 ± 20.3 25.9 ± 20.6 5
6/18/2018 Back to the Patient More Questions… • What difference would I feel if I take the pill? No Differences Probably Not Much Hypothyroid symptoms score Tiredness score • Could something bad happen to me if I don’t Secondary outcomes ( including BP) take the pill? Controversies of Treating Controversies of Treating Subclinical Hypothyroidism Subclinical Hypothyroidism • Literature massive, studies heterogeneous Hypothyroid symptoms – Age, degree of subclinical hypothyroidism, • Symptoms are nonspecific, also present in parameters studies, methods used euthyroid patients • Treatment has not always shown to • Outcome data mixed, some with uncertain reverse/improve symptoms clinical significance – most studies showed no differences in mild subclinical hypothyroidism • In the older population, mildly elevated TSH above the usual normal reference range of 4-5mIU/L may be normal • Many negative studies in this population Villar Cochrane Database 2007 Rugge Ann Intern Med 2015 6
6/18/2018 Controversies of Treating Subclinical Hypothyroidism Subclinical Hypothyroidism • TSH ≥ 10mIU/L Treat Cardiovascular system – More likely to develop hypothyroidism and more • Impaired cardiac functions have been observed symptomatic (but not all) – Large prospective epidemiologic cohort studies – Carotid intima media thickness, diastolic function, (Thyroid Studies Collaboration) smooth muscle relaxation, endothelial function, Associated with: arterial stiffness, etc • Increased heart failure (except for ≥ 80 yo) • Dyslipidemia has been observed but not all • Increased CHD events and mortality (except for ≥80 yo) – Treatment did not always reverse lipid abnormalities • Probably also increased stroke risk and mortality in younger patients (< 65 yo) • Conflicting observational studies • Evidence of treatment to lower CV events/mortality is lacking Pearce JCEM 2012 Gancer et al Circulation 2012 Rodondi JAMA 2010 • 25390 participants, median f/u 10.4 years, with a total f/u of • 55287 pts in 11 prospective cohorts, median f/u ranged 216248 person-years from 2.5 to 20 years, total f/u of 542494 person-years • Increased HF for TSH ≥ 10 but not in patients > 80 yo TSH 0.5-4.49 4.5-6.9 7-9.9 >10 7
6/18/2018 Subclinical Hypothyroidism • TSH ≥ 10mIU/L Treat Chaker et al JCEM 2015 • TSH < 10mIU/L Uncertainties (mixed results) • 47573 participants (17 cohorts), f/u from 1972 to 2014, a median f/u from 1.5 and 20 years and a total follow-up of 489192 person-years • No overall effects of subclinical hypothyroidism on stroke • Subgroup and post-hoc analyses → – Increased risk of stroke events in younger patients (younger than 65 yo) – Higher risk for fatal stroke for higher TSH 7-9.9 • TSH 10-19.9 – no association, probably lack of power Subclinical Hypothyroidism Treatment Effects on CV Events & Mortality • TSH < 10mIU/L Uncertainties (mixed results) Studies TSH N of patients Mean Age Outcomes – TSH 7 - 9.9 mIU/L levels (mIu/L) • may be associated with adverse CV outcomes ( Thyroid Studies Collaboration) – Increased CHD in younger patients (< 65yo) Razvi 2012 5-10 40-70 yo 40-70 yo Decrease in • Retrospective 1634 Tx (F/U: 7.6 yr) - Fatal and nonfatal CV • Ravzi JCEM 2008 • 1459 No Tx events UK – Protective effects observed - Death due to circulatory • Decreased mortality - Prospective study of > 85 yo from the >70 yo >70 yo disease • 819 Tx (F/U: 5.2 yr) - Cancer mortality Netherlands (Gussekloo JAMA 2004 ) • 932 No Tx Only in 40-70 yo • Decreased risk of all cause mortality - Retrospective study of 563700 individuals mean age 48.6 (SD±18.2) from Denmark (TSH 5-10mIU/L) (Selmer JCEM 2014) Andersen 2016 > 5 136 Tx 70 yo No differences in all cause – No adverse outcomes from studies in more recent years at Retrospective mortality in patients 18 yo or various TSH levels 1056 No Tx 74 yo older with the diagnosis of Denmark • Cardiovascular Health Study ( >65 yo, 10 yr f/u) (JCEM 2013) heart disease • WHI (Thyroid 2013 and JCEM 2014) No RCT – RCT: no clear benefits of treatment on non CV outcomes – No RCT on CV outcomes Razvi Arch Intern Med 2012 Andersen JCEM 2016 8
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