Case. Nothing to disclose. Pesky Thyroid Problems

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1 Pesky Thyrid Prblems Nthing t disclse UCSF Cntrversies in Wmen s Health December 13, 2013 Elizabeth J. Murphy, MD, DPhil Prfessr f Clinical Medicine University f Califrnia, San Francisc Chief, Divisin f Endcrinlgy San Francisc General Hspital Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin Wuld yu screen fr thyrid disease? A) Yes B) N Cper and Bindi, Lancet, 379:1142;

2 Case fr Rutine Screening 65 yw fllwed in endcrine fr primary hyperparathryidism and DM2. Date TSH 6/ / / / / / / / / / / Screening fr Thyrid Disease If yu d check a TSH and it s cmpletely nrmal, there is n need t recheck fr 5 years unless there is a clinical change Screening is recmmended fr Newbrns DM1, Dwn Syndrme, Turner s Syndrme, Addisin s disease Amidarne, lithium New nset a.fib. Histry f neck irradiatin Cnsider screening prir t pregnancy 5 6 Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin TSH 8.9 H ( ) What nw? a) Treat with levthyrxine b) Order thyrid perxidase antibdy (TPO) c) Recheck a TSH d) Recheck a TSH and Free T4 Factrs Altering TSH Diurnal variatin (ncturnal surge resulting in highest values in the mrning and lwer values in the afternn) Nn-thyridal illness Assay Issues Heterphile antibdies HAMA antibdies Assay variability 7 8

3 Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin TSH 8.9 H ( ) TSH 12 H ( ) FT L ( ) Hypthyrid - Treat Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin Thyrid: firm, nrmal size TSH 8.9 H ( ) TSH 9.2 H ( ) FT4 1.1 ( ) Subclinical Hypthyridism 9 10 Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin Thyrid: firm, nrmal size TSH 8.9 H ( ) TSH 9.2 H ( ) FT4 1.1 ( ) Nrmal fr the ppulatin Relatinship f TSH t Free T4 A given individual will have a narrwer nrmal range. 11 Quest Diagnstics, D. Fisher, J. Nelsn 12

4 Case 45 yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Exam: 80 kg, BMI 32, dry skin Thyrid: firm, nrmal size TSH 8.9 H ( ) TSH 9.2 H ( ) FT4 1.1 ( ) What nw? a) Treat with levthyrxine b) Order thyrid perxidase antibdy (TPO), treat if psitive c) Recheck a TSH in 6 mnths d) Recheck a TSH and Free T4 in 6 mnths Subclinical Hypthyridism Prevalence in US 4.3% NHANES III 9.5% Clrad Mall Study Prevalence Increased in idine sufficient areas Increases with age Increased in wmen Decreased in African Americans Only 25% f peple with subclinical hypthryidism have TSH > Race and Ethnicity Specific TSH Distributins NHANES III Subclinical Hypthyridism Deciding When t Treat There is n clear right r wrng answer Cnsensus Statement Rutine treatment fr TSH miu/l is nt warranted as there is n evidence f benefit. Treat fr TSH > 10 miu/l. Subsequently scieties tk issue with this recmmendatin as lack f evidence is nt the same as evidence against There is n clear right r wrng answer Hllwell J G et al. JCEM 2002;87: JAMA 2004; 291:

5 Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Prgressin t Hypthyridism Increased likelihd fr the develpment f vert hypthyridism : Female, lder, TPO antibdy psitive, higher TSH Apprximately 2.5% f antibdy negative individuals per year prgress t vert hypthryidism and 4.5% f TPO antibdy psitive individuals Wmen with +TPO antibdies have a 38 fld increased risk f develping hypthyridism TSH nrmalizes in abut 5% f individuals at ne year Almst half f patients with subclinical hypthyridism (43%) will have prgressed in 10 years 17 Tunbridge et al., Clinical Endcrinlgy 7:481, 1977; Vanderpump et al., Clinical Endcrinlgy 43:55, 1995; Walsh et al., JCEM 95:1095, Prgressin t Hypthyridism Increased likelihd fr the develpment f vert hypthyridism : Female, lder, TPO antibdy psitive, higher TSH Apprximately 2.5% f antibdy negative individuals per year prgress t vert hypthryidism and 4.5% f TPO antibdy psitive individuals Wmen with +TPO antibdies have a 38 fld increased risk f develping hypthyridism TSH nrmalizes in abut 5% f individuals at ne year The majrity f patients with subclinical hypthyridism (57%) will nt have prgressed in 10 years Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Tunbridge et al., Clinical Endcrinlgy 7:481, 1977; Vanderpump et al., Clinical Endcrinlgy 43:55, 1995; Walsh et al., JCEM 95:1095,

6 Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Recmmendatins Fr Thyrid Screening in Pregnancy The Endcrine Sciety 2012 End Sciety High Risk Universal screening f healthy wmen befre pregnancy is nt recmmended (USPSTF I, evidence pr ) Screen high risk wmen (I, evidence pr) JCEM 97:2543,

7 Recmmendatins Fr Thyrid Screening in Pregnancy The Endcrine Sciety 2012 Universal screening f healthy wmen befre pregnancy is nt recmmended (USPSTF I, evidence pr ) Screen high risk wmen (I, evidence pr) Newly pregnant wmen Screen all pregnant wmen by week 9 r at time f first visit (C, evidence fair) Dn t knw, s nly d high risk unless that s t hard and then d everyne (I, evidence pr) Maternal Thyrid and Kid IQ Studied children f wmen with undiagnsed hypthryidism (TSH 13) 1 Offspring IQ Age 7 JCEM 97:2543, Haddw et al, NEJM, 341:549; Maternal Thyrid and Kid IQ Antenatal screening at 12w3d gestatin 21,800 wmen screened (390 rx, 404 cntrl) TSH 3-4 Treatment fr hypthryidism didn t imprve cgnitive functin at age 3 1 Study Flaws Fetal thyrid develps at wk 12 Median TSH 3.8/3.1 Half f thse enrlled were enrlled fr a lw FT4 alne Age 3 might be t early t study Desn t prvide useful data fr prepregnancy screening SHEP Study Subclinical Hypthryid and Idine Deficiency in Early Pregnancy and Wmen Planning fr Pregnancy: Screening and Interventin Trial Screening 21,5000 wmen and treat 4,800 Treat pre-pregnancy 1 Lazarus et al, NEJM, 366:493;

8 Cst f Universal versus High Risk Screening in Pregnancy Recmmendatins Fr Thyrid Screening in Pregnancy The Endcrine Sciety 2012 Universal screening f healthy wmen befre pregnancy is nt recmmended (USPSTF I, evidence pr ) Screen high risk wmen (I, evidence pr) Newly pregnant wmen Screen all pregnant wmen by week 9 r at time f first visit (C, evidence fair) Dn t knw, s nly d high risk unless that s t hard and then d everyne (I, evidence pr) Dsiu et al, JCEM 97:1536, JCEM 97:2543, Guideline Recmmendatins In Pregnancy Endcrine Sciety 2012 Guideline 1 Treat all wmen with subclinical hypthyridism American Thyrid Assciatin Guideline Treat if TSH > 10 Treat if TPO-Ab+ American Cllege f Obstetricians and Gyneclgists 2007/reaffirmed 2012 Withut evidence that identificatin and treatment f pregnant wmen and subclinical hyp imprves.. utcmes, rutine screening fr subclinical hypthrydiism is nt currently recmmended. Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm 31 32

9 Subclinical Hypthyridism Lng Term Effects CVD CHD Gd prspective studies give discrdant results fr CHD Meta-analysis suggests significant increased CHD risk 1 - Age < 65 OR 1.51 ( ); age > 65 OR 1.05 NS - TSH > 10 OR 1.69 ( ); TSH > 4.5 OR 1.06 NS CV Dysfunctin Diastlic and systlic dysfunctin Small trials shw imprvement when made euthyrid CHF Events Health ABC 2 increased events if TSH > 7 CV Health Study 3 RR fr events 1.9 if TSH > 10 1 Osch Ann Intern Med, 2008; 2 Rndndi Arch Int Med 2005; 3 Rndndi JACC Subclinical Hypthyridism and the Risk f Crnary Heart Disease and Mrtality By Degree f TSH Elevatin! Patient level metananalysis f individual patient data frm 11 prspective chrt studies Bdndi et al., JAMA. 2010;304: " Subclinical Hypthyridism and the Risk f Crnary Heart Disease and Mrtality By Age! Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Bdndi et al., JAMA. 2010;304: " 36

10 Treatment in Subclinical Hypthyridism There are n prspective randmized cntrlled treatment trials pwered t address this issue Such a study wuld need rughly 2000 patients There is little interest in funding such a study (thugh they are trying t put tgether ne in Eurpe) The lack f evidence is nt the same as evidence against Razvi et al patients in the UK with new subclinical hypthyridism (TSH 5-10). Patients received usual care and were fllwed fr 7.6 years. Excluded: Histry f ischemic heart disease Histry f cerebrvascular disease Patients n lithium, amidarne, sterids in previus year 37 Ravzi et al Arch Intern Med 2012; 172: Multivariate-Adjusted Cumulative Fatal and Nn-Fatal Ischemic Heart Disease Events AGE patients 53% received treatment HR = 0.61 (CI ) AGE > patients 50% received treatment HR = 0.99 (CI ) Thyrid Functin in the Elderly Increased T 1/2 f T4 Reductin in the amunt f T4 replacement needed Mst studies shw with age Increased TSH independent f antibdy status Decreased free T3 Increased rt3 Decreased thyrid functin likely a nrmal part f aging Chrnic disease increases with age Ravzi et al Arch Intern Med 2012; 172:

11 Mrtality in 85 Year Olds Based n TSH High TSH Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm Gussekl, J. et al. JAMA 2004;292: Subclinical Hypthyridism Deciding When t Treat Reasns t treat Prevent prgressin t frank hypthyridism Imprve symptms Imprve lipids Pregnant/cnsidering pregnancy Assciated with increased mrtality and/r mrbidity Reasns nt t treat Treatment has nt yet been shwn t imprve mrtality in a prspective trial Expense Culd d harm D N Harm Thyrtxicssis During Hrmne Replacement Clrad Study 21% f patients with TSH < 0.3 1% with TSH <0.01 Whickham Study 36% f the patients n thyrxine therapy had TSH < 0.5 6% with TSH < 0.05 Framingham Heart Study 48% Cardivascular Health Study 41% TSH < % TSH <0.1 and high FT

12 D N Harm Cardivascular Health Study > 65 y Cnclusins Subclinical Hypthyridism There is increased CHD events and CHD mrtality with TSH > 10 and there is likely a cntinuum Relatinship between age and utcmes is unclear In the elderly, higher TSH is assciated with decreased mrtality and may be part f nrmal aging Treating Always recheck TSH with a Free T4 befre treating Generally treat fr TSH >10 TSH ULN 10 base n patient, prvider desire Treating yunger patients maybe justified Treating wmen interested in getting pregnant seems like a gd idea Always start with lw dse l-thyrxine and g up slwly (d n harm) Use cautin in patients with CAD Smwaru, L. L. et al. J Clin Endcrinl Metab 2009;94: Case 50 ym with hypertensin, HIV, depressin and besity was admitted with substernal chest pain. Hspital curse included a NSTEMI and hypertensive emergency with diastlic BPs in the 140s. Crnary lesin was nt amenable t stenting. He was discharged n medical therapy n HD Labs n HD #2 6/15/07 TSH ( ) 1.12 FT4 ( ) 0.46 L What culd be ging n? a) Euthyrid sick b) Lab errr c) Pituitary tumr d) Other e) All f the abve 48

13 Subsequent Curse Patient cntinued t have intermittent CP with visits t ED but n further admissins 1.5 yrs later referred t endcrine because f cncern fr hyperthyridism with suppressed TSH 0.02 Expedited int end clinic ver cncern fr a pituitary prcess given lw FT4 f 0.49 and presumed histry f hypgnadism as patient n teststerne. Labs 6/07 8/07 10/08 1/09 TSH ( ) FT4 ( ) Further Histry End visit In the setting f severe depressin 2 years prir (6 mths prir t MI) patient had been started n thyrid medicatin by his psychiatrist fr an elevated TSH. Had had a steady dse increase since then. Current meds: L-thyrxine 75 mcg am Lithyrnine 75 mcg bedtime (cytmel) Exam: tremr, lid lag, stare Labs 6/07 8/07 10/08 1/09 1/09 TSH ( ) FT4 ( ) FT3 ( ) 5.00 A TTE perfrmed earlier in the mnth shwed intermittent atrial fibrillatin

14 Subclinical Hypthyridism 11/99 2/01 2/07 1/09 TSH ( ) FT4 ( ) N TPO/antimicrsmal antibdies. Had spntaneus nrmalizatin f subclinical hypthyridism in the past. Patient was made thyrxic cntributing t MI and a.fib. 54 ym severe depressin referred t endcrine fr thyrid ndules. At ne year fllw-up pt was nted t have anxiety, 10 lb weight lss. He had been given adjuvant treatment fr his depressin with T3. Meds: citalpram 40 daily, lithyrnine 100 mcg daily TSH FT4 FT3 7/15/ N meds 11/13/12 < L 8.62H T3 100 mcg daily 12/14/ L 2.26L N meds 1/24/ N meds T3 fr Depressin Used as augmentatin therapy in majr depressive disrder STAR*D Trial shwed equal t better remissin than lithium with fewer side effects 1 There was n placeb and n bld mnitring fr thse placed n T3 T3 als ffers the advantage f lack f need fr bld level mnitring Safety mnitring recmmended in 2011 clinical guidance piece 2 Textbks and 2010 APA guidelines suggest gd evidence fr the use f T3 in depressin but dn t mentin rutine mnitring f thyrid functin. Many psychiatrists are nevertheless uncmfrtable prescribing thyrid hrmnes t essentially euthyrid patients, and sme f ur clleagues in endcrinlgy may als find this practice cntrversial. T3 Metablism T3 is abut fur times as ptent as T4 Rati f T4:T3 in thyrid gland excretins in humans is rughly 14:1 In pigs this rati is clser t 4:1 T4:T3 In humans abut 80% f T3 is made via peripheral cnversin frm T4 T3 is very rapidly and effectively absrbed with a much shrter T 1/2 (2.5 d) than T4 (7 d) 1 Nierenberg, et al. A Cmparisn f Lithium and T3 Augmentatin Fllwing Tw Failed Medicatin Treatments fr Depressin, Am J Psychiatry 163:1519, Rsenthal et al, T3 Augmentatin in MDD: Safety Cnsideratins, Am J Psychiatry 168:1035,

15 T3 preparatins lithyrnine Cytmel (King Pharma (was Jnes)) T3 CONTAINING PREPARATION DESICATED PIG THYROID Westhrid (RLC labs) Nature-Thrid (RLC labs) T4:T3 in a rati f 4.22:1 1 grain = 65 mg, (38 mcg T4, 9 mcg T3) Armr Thyrid (Frest) T4:T3 in a rati f 4.22:1 1 grain (60 mg) TE Thyrid USP All generic frms have been discntinued by manufacturers (n FDA apprval), can get cmpunded frms SYNTHETIC litrix (Thyrlar) (Frest) T4:T3 in a rati f 4:1 1 tablet = 50 mcg T4, 12.5 mcg T

16 PRINT THIS OUT AND TAKE TO YOUR DOCTOR 61 Natinal Academy f Hypthryidism, Dr. Kent Hltrf 62 Thyrid Disrders Endcrinlgists Dn t Knw abut r Underdiagnse Euthyrid Hypthyridism Wilsns Syndrme T3 resistance Cmmn characteristics Nrmal TSH yet patient still hypthyrid Dn t have enugh T3 actin Often have t much rt3 Need t treat with T3 T3 r nt T3 Westn Area T4 T3 Study (WATTS) 2 Same grup had previusly shwn significantly impaired well-being in patients n T4 replacement with nrmal TSH hypthyrid patients in England Replaced 50 mcg f LT4 with 10 mcg T3 Randmized duble blind placeb trial Significant drp ut due t perceived SE in bth grups Bth grups had significant imprvement in psychlgical scres cmpared with baseline 39% relative imprvement in the placeb grup N difference between grups 63 1 Saravanan Clin End 57:577, Saravanan JCEM 90:805,

17 Summary Of T3 and Replacement Studies Ptential selectin bias f peple studied n thyrid hrmne Nt all studies determine if initial treatment was fr frank hypthyridism. Up t 5 % f adults in idine-sufficient cuntries have untreated subclinical hypthryidism Patients wh end up n treatment are the nes mre likely t have symptms that culd be attributable t the thyrid Large placeb effect (up t 40%) in these studies Several large studies suggest psychlgical mrbidity in patients n T4 alne Sme patients feel better hyperthyrid Sme patients feel better n T3 (nly hyperthyrid?) Patients n T4 have a higher serum T4:T3 rati 1,2 1 Weber J Endcrinl Invest 25:106, Jnklaas JAMA 229:769, Summary Lisa Murphy Opinin Given the lack f definitive data, use yur judgment and cnsult with the patient when cnsidering treatment fr subclinical hypthyridism. Never treat based n a single value Treat if TSH > 10 r patient interested in pregnancy Dn t treat if TSH < 10 and age > 65ish D n harm T3 Treatment If yu have a patient n a T3 preparatin, ensure they are nt hyperthyrid Until a lng acting T3 preparatin is available wuld avid initiating T

18 San Francisc General Hspital and Trauma Center