Thyroid Cases Case Based Discussion Chienying Liu: no disclosures - PDF document

4/13/2018 Thyroid Cases Case Based Discussion • Chienying Liu: no disclosures • Jennifer Park-Sigal: no disclosures 1

4/13/2018 CASE 1 69 yo healthy active man with abnormal thyroid tests • PMH – BPH, anxiety, mild hypertension, GERD – “Type A” personality • FH – Sister in her 60s being monitored for slightly elevated TSH • MED – Omeprazole • ROS – Nails a bit more brittle, a bit colder last year, BP perhaps slightly higher, constipation all his life – baseline anxiety undergoing therapy • PE 148/92, pulse 80 – Lean, healthy – Thyroid exam firm, not enlarged, no nodules 2

4/13/2018 69 yo healthy active man with abnormal thyroid tests • TSH 7.30 HI (0.45-4.12 mIU/L) • Free T4 10 (10-18 pmol/L), • Free T3 3.7 (2.6-5.7 pmol/L) • Diagnosis: SUBCLINICAL HYPOTHYROIDISM Patient - “Should I be treated?” Should He? Endocrine Pearl If TSH Abnormal - Repeat! N=422,242 patients 2002-2006 If TSH normal on 1 st test 98% stayed normal If TSH > 10 on 1 st test 28% had nl TSH on repeat If TSH 5.5 – 10 on 1 st test 62% had nl TSH on repeat 35% stayed the same Meyerovitch Arch Intern Med 2007 3

4/13/2018 TSH Free T4 Free T3 (0.45-4.12 mIU/L) (10-18 pmol/L) (2.6-5.7 pmol/L) 1/4/2018 6.89 (H) 11 9/7/2017 7.30(H) 10 3.7 3/29/2016 6.17(H) 10 6/3/2014 6.72(H) 9 (L) 4.0 4/24/2013 5.45(H) 10 4.4 7/23/2012 7.76(H) 10 9/21/2011 7.73(H) 10 5/11/2010 7.81(H) 10 2/23/2010 8.52(H) 9 2/9/2010 9.21(H) 4/15/2002 3.36 13 11/9/2000 2.70 Treat ? Any Additional Lab Tests? 69 yo with subclinical hypothyroidism, asymptomatic 12/28/06 1/21/11 6/3/14 3/3/17 Cholesterol, Total 204 (H) 155 180 173 <200 mg/dL Triglycerides 134 69 74 98 TPO > 830 <200 mg/dL HDL 65 55 74 60 >39 mg/dL LDL 112 86 91 93 <130 mg/dL Chol HDL Ratio 3.1 2.8 2.4 2.9 <6.0 Non HDL 139 100 106 113 <160 mg/dL Treat? 4

4/13/2018 Subclinical Hypothyroidism • Definition: TSH > the upper limit of normal with normal T4/T3 • Most common cause: autoimmune thyroiditis • Prevalence: 4 -10%* – Increases with age – More common in women and in iodine sufficiency • Rate of progression to overt hypothyroidism Whickham Survey ** – 2.6% per year with elevated TSH – 2% if only TPO AB + – 4.3% with both elevated TSH and TPO *Hollowell JCEM 2002 Diez JCEM 2004 (older than 55 yo) *Biondi and Cooper Endo Rev 2008 **Vanderpump Clin Endocrinol 1995 – Elevated TSH > 10mIU/L • 10mIU/L( Hazard Ratio 10) and 15mIU/L (HR 28) Subclinical Hypothyroidism • Not all elevated TSH (with normal T4/T3) represent mild thyroid failure – Heterophile AB – Obesity – Recovery from thyroiditis or nonthyroidal illness – Medications: amiodarone/Lithium – Aging 5

4/13/2018 TSH Range No known thyroid disease/goiter and Antibodies Negative NHANES III NHANES III Distribution by Age 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 TSH - 97.5 centile by Age Group Surks J Clin Endocrinol Metab 2007 6

4/13/2018 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? 7

4/13/2018 Randomized Controlled Trial in Older Patients • Inclusion – Population: 65 yo or older – Persistent subclinical hypothyroidism. TSH 4.60-19.99 mIU/L, 3 months to 3 years apart. Free T4 normal. Did not look at TPO • Exclusion – Thyroid medications, lithium, amiodarone – Thyroid surgery, RAI in the previous 12 months – Hospitalization, surgery, acute coronary artery events in the previous 4 weeks – Dementia – Terminal illnesses Randomized Controlled Trial in Older Patients • Primary outcomes – Hypothyroid symptoms (ThyPro) – Tiredness score • Secondary outcomes – Health related quality of life (EQ-5D) – Hand grip – Executive function – Weight, BMI, weight circumference – Blood pressure – Activities of daily living • Lack of power – CV events 8

4/13/2018 Characteristics Placebo LT4 Group 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 Outcome measures Hypothyroid 16.9 ± 17.9 17.5 ± 18.8 Symptoms Tiredness score 25.5 ± 20.3 25.9 ± 20.6 5.48±2.48 3.63±2.11 9

4/13/2018 No Differences Hypothyroid symptoms score Tiredness score Secondary outcomes ( including BP) Back to the Patient More Questions … • What difference would I feel if I take the pill? Probably Not Much • Could something bad happen to me if I don’t take the pill? 10

4/13/2018 Controversies of Treating Subclinical Hypothyroidism • Literature massive, studies heterogeneous – Age, degree of subclinical hypothyroidism, parameters studies, methods used • Outcome data mixed, some with uncertain clinical significance • 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 Controversies of Treating Subclinical Hypothyroidism Hypothyroid symptoms • Symptoms are nonspecific, also present in euthyroid patients • Treatment has not always shown to reverse/improve symptoms – most studies showed no differences Villar Cochrane Database 2007 Rugge Ann Intern Med 2015 11

4/13/2018 Controversies of Treating Subclinical Hypothyroidism Cardiovascular system • Impaired cardiac functions have been observed (but not all) – Carotid intima media thickness, diastolic function, smooth muscle relaxation, endothelial function, arterial stiffness, etc • Dyslipidemia has been observed but not all – Treatment did not always reverse lipid abnormalities • Conflicting observational studies • Evidence of treatment to lower CV events/mortality is lacking Pearce JCEM 2012 Subclinical Hypothyroidism • TSH ≥ 10mIU/L Treat – More likely to develop hypothyroidism and more symptomatic – Large prospective epidemiologic cohort studies (Thyroid Studies Collaboration) • Increased heart f ailure (except for ≥ 80 yo) • Increased CHD events and mortality (except for ≥80 yo) • Probably also increased strokes and mortality in younger patients (< 65 yo) 12

4/13/2018 Gancer et al Circulation 2012 • 25390 participants, median f/u 10.4 years, with a total f/u of 216248 person-years • Increased HF for TSH ≥ 10 but not in patients > 80 yo Rodondi JAMA 2010 • 55287 pts in 11 prospective cohorts, median f/u ranged from 2.5 to 20 years, total f/u of 542 494 person-years 0.5-4.49 4.5-6.9 7-9.9 >10 13

4/13/2018 Chaker et al JCEM 2015 • 47 573 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 489 192 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) – Increased risk for higher TSH 7-9.9 • TSH 10-19.9 – no association, probably lack of power Subclinical Hypothyroidism • TSH ≥ 10mIU/L Treat • TSH < 10mIU/L Uncertainties (mixed results) – TSH 7 - 9.9 mIU/L • may be associated with adverse CV outcomes – Protective effects observed • Decreased mortality - Prospective study of > 85 yo from the Netherlands (Gussekloo JAMA 2004 ) • 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) – No adverse outcomes from studies in more recent years at various TSH levels • Cardiovascular Health Study ( >65 yo, 10 yr f/u, in 2013) (Hyland JCEM 2013) • WHI (Thyroid 2013 and JCEM 2014) – No clear benefits of treatment on non CV outcomes 14

4/13/2018 Treatment Effects on CV Events & Mortality Studies TSH N of patients Mean Age Outcomes levels (mIu/L) Razvi 2012 5-10 40-70 yo 40-70 yo Decrease in • 1634 Tx (F/U: 7.6 yr) - Fatal and nonfatal CV Retrospective • 1459 No Tx events (UK) - Death due to circulatory >70 yo >70 yo disease • 819 Tx (F/U: 5.2 yr) - Cancer mortality • 932 No Tx (only in 40-70 yo) Andersen 2016 > 5 136 Tx 70 yo No differences in all cause Retrospective mortality in patients 18 yo or 1056 No Tx 74 yo older with the diagnosis of Denmark heart disease No RCT Razvi Arch Intern Med 2012 Andersen JCEM 2016 TSH Free T4 Free T3 (0.45-4.12 (10-18 pmol/L) (2.6-5.7 pmol/L) mIU/L) 1/4/2018 6.89 (H) 11 9/7/2017 7.30(H) 10 3.7 3/29/2016 6.17(H) 10 6/3/2014 6.72(H) 9 (L) 4.0 4/24/2013 5.45(H) 10 4.4 7/23/2012 7.76(H) 10 9/21/2011 7.73(H) 10 5/11/2010 7.81(H) 10 2/23/2010 8.52(H) 9 2/9/2010 9.21(H) 4/15/2002 3.36 13 11/9/2000 2.70 15