Disclosures. Clinical Dilemmas in Thyroid Disease 10/11/ yo healthy active man with abnormal thyroid tests CASE 1. None. Case Based Discussion

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1 Disclosures None Clinical Dilemmas in Thyroid Disease Case Based Discussion Chienying Liu MD CASE 1 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 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

2 69 yo healthy active man with abnormal thyroid tests TSH 7.30 HI ( miu/l) Free T4 10 (10-18 pmol/l), Free T3 3.7 ( pmol/l) Diagnosis: SUBCLINICAL HYPOTHYROIDISM Spontaneous Normalization of TSH Is Common Repeat TSH! If TSH normal on 1 st test 98% stayed normal If TSH > 10 on 1 st test 28% had nl TSH on repeat 35% remained elevated N=422,242 patients Patient - Should I be treated? If TSH on 1 st test 62% had nl TSH on repeat 35% stayed the same Meyerovitch Arch Intern Med 2007 TSH ( miu/l) 1/4/ (H) 11 Free T4 (10-18 pmol/l) 9/7/ (H) /29/ (H) 10 6/3/ (H) 9 (L) 4.0 4/24/ (H) /23/ (H) 10 9/21/ (H) 10 5/11/ (H) 10 2/23/ (H) 9 2/9/ (H) 4/15/ /9/ Free T3 ( pmol/l) Treat? Any Additional Tests? 69 yo with subclinical hypothyroidism, asymptomatic Cholesterol, Total <200 mg/dl Triglycerides <200 mg/dl HDL >39 mg/dl LDL <130 mg/dl Chol HDL Ratio <6.0 Non HDL <160 mg/dl 12/28/06 1/21/11 6/3/14 3/3/ (H) Treat? TPO > 830 2

3 Should this 69 yo man with asymptomatic subclinical hypothyroidism be treated with levothyroxine? 1. Yes 2. No 3. Undecided Subclinical Hypothyroidism Definition: TSH > the upper limit of normal with normal T4/T3 The most common cause: autoimmune thyroiditis Prevalence: 4-10%* Increases with age More common in women and in iodine sufficiency *Hollowell JCEM 2002 *Biondi and Cooper Endo Rev 2008 Subclinical Hypothyroidism Risk of progression to overt hypothyroidism TSH level, thyroid AB status Whickham Survey -Clinic Endo 1995 * Women: annual progression 2.6% if TSH, 2% if anti-thyroid AB +, 4.3% if both factors Men: higher risk for progression OR 44 (vs 8 for women) if TSH, OR 25 (vs 8) if AB+, 173 (vs 38) if both Diez JCEM 2004 (older than 55 yo)** Elevated TSH > 10mIU/L 10mIU/L( Hazard Ratio 10) and 15mIU/L (HR 28) For TSH < 10, 52% had normal TSH during follow up Samworu et JCEM 2012 (older than 65 yo)** Elevated TSH > 10 miu/l *Vanderpump Clin Endocrinol 1995 ** JCEM 2004 & JCEM 2012 Differentials of Elevated TSH Not all elevated TSH (with normal T4) represent mild thyroid failure Assay interferences Heterophile AB Obesity (functional alterations) Recovery from thyroiditis or nonthyroidal illness Medications: amiodarone/lithium Aging 3

4 TSH Range No known thyroid disease/goiter and Antibodies Negative TSH centile by Age Group NHANES III NHANES III Distribution by Age TSH 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

5 Randomized Controlled Trial in Older Patients Inclusion Population: 65 yo or older Persistent subclinical hypothyroidism. TSH miu/l, 3 months to 3 years apart. Free T4 normal. Did not look at TPO status 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 Characteristics Placebo (n=369) LT4 Group (n=368) Age 74.8 ±6.8 yo 74 ± 5.8 yo Age range ( ) ( ) TSH 6.38 ± 2.01 miu/l 6.41 ± 2.01 miu/l Median 5.76 ( ) 5.73 ( ) Range Outcome measures Hypothyroid Symptoms 16.9 ± ± 18.8 Tiredness score 25.5 ± ± ± ±2.11 5

6 Back to the Patient More Questions No Differences Hypothyroid symptoms score Tiredness score Secondary outcomes ( including BP) 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? 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 in mild subclinical hypothyroidism Villar Cochrane Database 2007 Rugge Ann Intern Med

7 Controversies of Treating Subclinical Hypothyroidism Cardiovascular system Impaired cardiac functions have been observed (but not all) Parameter studies: 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 Results from observational studies - conflicting 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) Associated with: Increased heart failure (except for 80 yo) Increased CHD events and mortality (except for 80 yo) Probably also increased stroke risk and mortality in younger patients (< 65 yo) Gancer et al Circulation participants, median f/u 10.4 years, with a total f/u of person-years Increased HF for TSH 10 but not in patients > 80 yo Rodondi JAMA pts in 11 prospective cohorts, median f/u ranged from 2.5 to 20 years, total f/u of person-years TSH >10 7

8 Subclinical Hypothyroidism Chaker et al JCEM 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 person-years TSH 10mIU/L Treat No overall effects of subclinical hypothyroidism on stroke TSH < 10mIU/L Uncertainties (mixed results) 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 TSH no association, probably lack of power Subclinical Hypothyroidism- TSH< 10 The Bad May be associated with CV mortality & fatal strokes for TSH miu/l (Thyroid Studies Collaboration) Increased CHD in younger patients (< 65yo) (Ravzi JCEM 2008) The Good protective effects Decreased mortality Prospective study of > 85 yo from the Netherlands (Gussekloo JAMA 2004 ) Decreased risk of all cause mortality Retrospective study of individuals mean age 48.6 (SD±18.2) from Denmark (TSH 5-10mIU/L) (Selmer JCEM 2014) The Neutral No adverse outcomes from studies in more recent years at various TSH levels <10 Cardiovascular Health Study ( >65 yo, 10 yr f/u) (JCEM 2013) WHI (Thyroid 2013 and JCEM 2014) The Unknown RCT: no clear benefits of treatment on non CV outcomes No RCT on CV outcomes Studies Treatment Effects on CV Events & Mortality Razvi 2012 Retrospective UK Andersen 2016 Retrospective Denmark TSH levels (miu/l) N of patients Mean Age Outcomes yo 1634 Tx 1459 No Tx > Tx >70 yo 819 Tx 932 No Tx 1056 No Tx yo (F/U: 7.6 yr) >70 yo (F/U: 5.2 yr) 70 yo 74 yo No RCT Decrease in - Fatal and nonfatal CV events - Death due to circulatory disease - Cancer mortality Only in yo No differences in all cause mortality in patients 18 yo or older with the diagnosis of heart disease Razvi Arch Intern Med 2012 Andersen JCEM

9 Back to the Patient 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? TSH ( miu/l) 1/4/ (H) 11 Free T4 (10-18 pmol/l) 9/7/ (H) /29/ (H) 10 6/3/ (H) 9 (L) 4.0 4/24/ (H) /23/ (H) 10 9/21/ (H) 10 5/11/ (H) 10 2/23/ (H) 9 2/9/ (H) 4/15/ /9/ Free T3 ( pmol/l) Should this 69 yo man with asymptomatic subclinical hypothyroidism be treated with levothyroxine? 1. Yes 2. No 3. Undecided RCT of SubHypo on Non-CV Outcomes (Younger Patients) Smaller RCT studies No differences in most Age 32 yo to 70 yo outcomes TSH 4.1 to 11.0 (most Exceptions: studies < 10) Higher TSH levels (> 10) Sample size patients Fatigue improved In one study (TSH was treated Duration 3-12 months to 0.5 miu/l) Various outcomes being measured BP Cholesterol BMI, weight In one study of TPO positive population Lipids Mixed results on Total cholesterol and LDL Lower Triglyceride observed in Quality of life many studies, but p value not significant (sample size and Cognition clinical significance?) Rugge et al Ann Intern Med

10 Treatment Effects on BP Studies Age TSH baseline (after Tx) N Outcomes P Monzani 2004 RCT 6 months Razvi 2007 RCT (crossover) 2.8 months Nagasaki 2009 RCT 5 months 37 Tx 37 No Tx 53 Tx 54 No Tx 64 Tx 66 No Tx 6.03 Tx ( 1.32) 5.68 No Tx BP 110s/60s-70s 5.4 Tx 100mcg ( 0.5) SBP: 133 +/- 23 DBP: 79 +/ No Tx SBP:135 +/- 23 DBP: 80 +/ Tx ( 2.7) 7.3 no tx BP /73 22 Tx Tx Tx 47 SBP: -2 mmhg DBP: -3 mmhg SBP: -2 mmhg DBP: -1 mmhg (Sig outcomes) LDL: -12 mg/dl Hip/W ratio FMD SBP: -3 mmhg DBP: 0 mmhg Studies Age TSH -> TSH after Tx N Outcomes P Meier Kong 2002 RCT 6 months Jorde 2006 RCT 12 months Razvi 2007 (crossover ) 2.8 months Parle 2010 RCT 12 months Abu-Helalah 2010(crossover) 2 months Winther 2016 Prospective TPO/TSH> 4 Treatment Effects on Quality of Life Tx No Tx Tx ( dec by 4.6) 7.3 No Tx ( dec by 1.7) 5.8 Tx 109.7mcg No Tx 5.4 Tx 100mcg NoTx 6.6 Tx 50mcg 6.6 No Tx Tx 72mcg (considered poor quality) Tx TSH weeks TSH months 33 Tx Tx Tx Tx 42 Billewicz & Zulewski scores HADS anxiety/depression GHQ-30 Beck Depression GHS-30 Tiredness SF36, ThyTSQ,ThyDQoL HADS depression for TSH > 12 < /31 QOL Odds of feeling better higher with higher pretreatment TSH ThyPro, SF Better Studies Age TSH TSH after Tx N Outcomes P Jaeschke 1996 RCT 6 months Jorde 2006 RCT 12 months Parle 2010 RCT 12 months Treatment Effects on Cognition Tx (68mcg) No Tx 10.6 Many with hypothyroid symptoms 5.8 Tx (109.7mcg) No Tx 6.6 Tx 50mcg 6.6 No Tx 18 Tx Tx Tx 42 Memory composite score (small improvement only) Cognition, mood, energy, activity Cognitive functional score Trail making test MEAMS, MMSE, SCOLP, Trail making test 0.01 Studies Age TSH TSH after Tx N Outcomes P Kong 2002 RCT 6 months Monzani 2004 RCT 6 months Iqbal 2006 RCT 12 months Razvi 2007 (crossover ) 2.8 months Duman 2007 RCT 8 months Nagasaki 2009 RCT 5 months Treatment Effects on BMI & WT Tx ( dec by 4.6) 23 Tx BMI change No Tx ( dec by 1.7) Tx Tx BMI 24.7 to 23.7 Tx No Tx to Tx (96mcg) 1 32 Tx BMI No Tx Tx (100mcg) Tx Wt 75.9 to 75.8 kg Tx No tx to 76.5 kg Tx (100mg ) Tx BMI 25 to 24.8 Tx No Tx to Tx (25.8mcg) Tx BMI 22 to 21.8 Tx No Tx to

11 Recommendations from Consensus Groups TSH ATA/AACE ETA 10 (ETA) > 10 Yes (should be considered) Younger pts ( 70, <65-70) - Yes even without symptoms Older patients (>70, 65-70) - Yes - if clear symptoms - If risks of vascular events high TSH Goal on Treatment in Older Patients TSH for the 97.5 th percentile of the population increases with increasing age groups 97.5% confidence interval for healthy 80 yo or older persons 7.5mIU/L < 10 (ETA) 10 Consider factors - Symptoms - TPO status - CVD or HF status - Risk factors for above Younger pts ( 70, <65-70) - Consider a trial (if symptoms) Older patients (>70, esp 80-85) - Observe & monitor Target for TSH on treatment ATA - 4-6mIU/L as a reasonable target for yo European Society 1-5mIU/L for > yo Peeters N Engl J Med 2017, Pearce et al Eur Thyroid J 2013, Jonklaas et al Thyroid 2014 Pearce et al Eur Thyroid J 2013 Jonklaas et al Thyroid 2014 WOMEN DESIRE PREGNANCY Data and consensus recommendations on subclinical hypothyroidism do not apply Pregnancy specific TSH range Internal established population/trimester specific reference range is recommended Upper limit: 4mIU/L or 0.5mIU/L less than the normal reference Subclinical hypothyroidism Tx: if attempting IVF or ICSI (goal < 2.5mIU/L) if pregnant/+ TPO positive if pregnant / TPO but TSH > 10mIU/L Consider Tx: If attempting natural conception If pregnant /+ TPO and TSH > 2.5mIU/L If pregnant / TPO and TSH < 10mIU/L CASE 2 Guidelines: Alexander et al Thyroid

12 76 yo Man with a 1.4 cm Papillary Thyroid Carcinoma 76 yo man with rising TSH after lobectomy for 1.4 cm PTC Found to have a right thyroid nodule during evaluation for parotid swelling Evaluation: US and US guided FNA PMH Mild HTN, PVC, RBBB Meds Amlodipine and MVI FH One brother with FTC Lobectomy or total? Potential benefits of lobectomy Decreased complications Not needing life long T4 replacement? After lobectomy What is his risk of subclinical/hypothyroidism? What is his risk of needing T4 to keep TSH < 2 76 yo Man s/p Lobectomy for a low risk 1.4 cm PTC 76 yo man with rising TSH after lobectomy Feb 2017: TSH 1.43 miu/l March 2017: Lobectomy Path: 1.9 cm PTC. No adverse features. One lymph node negative for metastasis. No evidence of thyroiditis. May 2017: TSH months postop June 2017: Not feeling himself, more fatigued TSH 4.99 / free T4 1.0 Subclinical Hypothyroidism Treat? 25 mcg started 50mcg alternating 75mcg 12

13 Risk of Elevated TSH after Lobectomy Meta-analysis of 32 studies Indeterminate nodules Non-toxic nodules MNG Most studies did not specify subclinical or overt Overall risk of hypothyroidism of both types 22% (CI 19-27) Based on 4 studies specifying subclinical vs overt 12% risk of subclinical hypothyroidism 4% risk of overt hypothyroidism Verloop et al. JCEM 2012 Risk of Elevated TSH after Lobectomy Risk factors Old age in 4 studies not replicated in 8 studies Higher preop TSH (still in normal range) in 12 studies TPO positivity in 6 studies (conflicting results for TgAB) Thyroiditis on pathology in 11 studies but not in 2 other studies Timing of hypothyroidism In some patients, hypothyroidism is transient Usually diagnosed first 6 months (in studies reporting time) There can be late occurrences Verloop et al. JCEM 2012 TSH Trend After Lobectomy in Euthyroidism Timing of Hypothyroidism In Long Term Follow up Retrospective study of PTMC patients (335 pts) from Korea (iodine sufficient ) with a median follow up of 56 months: TSH >1.7 risk factor < 12 months Patients who remained euthyroid 36% >12 months Risk Factor TSH 3.1 at 1 yr 29 % needing T4 or Persistent SH Tomoda et al (Kuma Hospital) 2010 Meantime to recover 12.2 months Park et al JCEM 2017 Risk Factors for persistent SH: Preop TSH > 1.7 Peak TSH >

14 Take Home Messages Overall risk of elevated TSH after lobectomy 22% Risk factors: higher preop TSH, older age, TPO positivity, or evidence of thyroiditis on surgical pathology About 2/3 of patients with mild asymptomatic subclinical hypothyroidism postop can recover to euthyroidism. Recovery can take 1 year CASE 3 Many patients with low risk thyroid cancer (1-4 cm) may still need to take levothyroxine after lobectomy to keep TSH 0.5-2mIU/L 63 yo Man with Weight Loss Suppressed TSH and Low normal T4 63 yo man previously healthy not feeling himself, with unintentional weight loss Exam Thyroid, not enlarged, somewhat firm, no nodules, no bruits Endocrine pearl: This is a case of T3 toxicosis that can be seen in the early phase of hyperthyroidism due to Graves disease or toxic nodules. Infrequently frankly low free T4 with elevated T3 can be observed. TSH < 0.01 Free T ( ) Free T (< 4.2) Differential Diagnoses Low TSH/ low or low normal T4 Lab error or assay interferences (biotin)? Central Hypothyroidism? Taking T3 or supplements with T3? Euthyroid sick? T3 toxicosis? Recovery phase of hyperthyroidism/thyoiditis? Thyroid Tasting Menu (Hyperthyroidism) qanti TPO AB qanti Thyroglobulin AB qtrab (TSI or TBII ) qthyroglobulin qultrasound qthyroid scan TSH < 0.01 Free T ( ) Free T (< 4.2) Physical Exam unrevealing 14

15 What test would you order for additional evaluation? 1. Anti TPO AB 2. Anti Thyroglobulin AB 3. Thyroglobulin 4. TSI or TBII 5. Thyroid uptake scan 6. Neck ultrasound 7. All of the above Thyroid Tasting Menu (Hyperthyroidism) q Anti TPO AB Autoimmune disease marker Present in 50% of patients with painless thyroiditis (autoimmune spectrum) Present in as high as % of patients with Graves disease Consider if TSH is elevated (AAE) q Anti Thyroglobulin AB Autoimmune disease marker Present in as high as 70 % of patients with Graves disease q TRAB (TSI or TBII ) Sensitivity and Specificity for GD > 90% q Thyroglobulin Not helpful in diagnosing cancer Not routinely recommended in the evaluation of thyroid nodule (ATA, ETA, AAE) Consider if exogenous thyroid hormone use is suspected q Ultrasound Evaluation of vascularity (ATA) (please do not order routinely) q Thyroid scan Differentiating various types of hyperthyroidism Thyroiditis Graves disease Toxic nodule Toxic MNG TSI Bioassay, measuring camp activity TBII Immunoassay (inhibitory immunoassay) Cooper et al Thyroid 2009 Gharib et al Endo Practice 2010 Pacini et al Euro J Endocrinol 2006 Paschke et al. Nat Rev Endocrinol 2011 *Borget JCEM yo Man with Hyperthyroidism Take Home Messages TSH < 0.01 Free T (<1.8) Free T (< 4.2) TPO antibody 101 (<34) Thyroglobulin antibody positive Iodine Uptake scan Diffuse uptake 4h 10% and 24 h 21% Diagnostic Test of Choice TSH receptor antibody testing TSI 433 (< 140 %) T3 toxicosis is common in Graves (as well as toxic nodules) Free T4 may be low normal or less likely low TSH receptor antibody testing should be considered as the first line of testing in the work up of hyperthyroidism, followed by iodine scan as appropriate Most common cause of hyperthyroidism in the US is Graves disease 15

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