Case 45 yow comes to see you complaining of fatigue, depressive symptoms and weight gain over the past year. Case for Routine Screening

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1 N 6/25/ yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. Pesky Thyrid Prblems Exam: 80 kg, BMI 32, dry skin Wuld yu screen fr thyrid disease? 93% UCSF Internal Medicine Updates June 24, 2013 A. Yes B. N 7% Y e s fr Rutine Screening 65 yw fllwed in endcrine fr primary hyperparathryidism and DM2. Date TSH 6/ / / / / / / / / / Cper and Bindi, Lancet, 379:1142; /

2 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 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 T r e a t w i t h l e v... 31% O r d e r t h y r i d... 12% R e c h e c k a T S H 8% 50% R e c h e c k a T S H 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 Assay variability 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 7 8 2

3 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 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 A given individual will have a narrwer nrmal range Relatinship f TSH t Free T4 Quest Diagnstics, D. Fisher, J. Nelsn 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 ( ) T r e a t w i t h l e v... 52% What nw? 1. Treat with levthyrxine 2. Order thyrid perxidase antibdy (TPO), treat if psitive 3. Recheck a TSH in 6 mnths 4. Recheck a TSH and Free T4 in 6 mnths O r d e r t h y r i d... 3% R e c h e c k a T S H... 3% 42% R e c h e c k a T S H

4 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 > 10 Race and Ethnicity Specific TSH Distributins NHANES III 13 Hllwell J G et al. JCEM 2002;87: 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 Newest data is causing a push fr mre treatment There is n clear right r wrng answer 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 1 JAMA 2004; 291:

5 Prgressin t Hypthyridism Increased likelihd fr the develpment f vert hypthyridism : Female, lder, 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 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 Prgressin t Hypthyridism Increased likelihd fr the develpment f vert hypthyridism : Female, lder, 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 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 Tunbridge et al., Clinical Endcrinlgy 7:481, 1977; Vanderpump et al., Clinical Endcrinlgy 43:55, 1995; Walsh et al., JCEM 95:1095, Tunbridge et al., Clinical Endcrinlgy 7:481, 1977; Vanderpump et al., Clinical Endcrinlgy 43:55, 1995; Walsh et al., JCEM 95:1095, 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

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 Maternal Thyrid and Kid IQ Studied children f wmen with undiagnsed hypthryidism (TSH 13) 1 21 Haddw et al, NEJM, 341:549; Offspring IQ Age 7 22 Maternal Thyrid and Kid IQ Antenatal screening at 12w3d gestatin, 21,800 wmen, 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 had a lw FT4 Age 3 might be t early t study Guidelines dn t recmmend antenatal screening hwever, prenatal screening is likely mre beneficial 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 1 Lazarus et al, NEJM, 366:493;

7 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 shws 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:

8 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 29 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:

9 Mrtality in 85 Year Olds Based n TSH H i g h T S H 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

10 D N Harm Cardivascular Health Study > 65 y Cnclusins Subclinical Hypthyridism There is increased CHD events and 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 Treat generally 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/CVD Smwaru, L. L. et al. J Clin Endcrinl Metab 2009;94: yw cmes t see yu cmplaining f fatigue, depressive symptms and weight gain ver the past year. 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? Have yu changed what yu wuld d? (ptins were treat, fllw, get mre infrmatin) 33% A. Yes B. N Y e s 67% N 39 Exam: 80 kg, BMI 32, dry skin Thyrid: firm, nrmal size TSH 8.9 H ( ) TSH 9.2 H ( ) FT4 1.1 ( ) What nw? 1. Treat with levthyrxine 2. Order thyrid perxidase antibdy (TPO), treat if psitive 3. Recheck a TSH in 6 mnths 4. Recheck a TSH and Free T4 in 6 mnths T r e a t w i t h l e v... 12% O r d e r t h y r i d... 4% R e c h e c k a T S H... 4% 80% R e c h e c k a T S H

11 35 yw cmplains f fatigue, dcumented weight gain, cld intlerance and amenrrhea. TSH 1 ( ) FT4 0.3 L ( ) What nw? O r d e r i m a g i n g... 24% 1. Order imaging and get an endcrine cnsult 2. Treat with levthyrxine T r e a t w i t h l e v... 8% 8% 4% T r e a t w i t h l e v... R e c h e c k l a b s i... 56% 3. Treat with levthyrxine and get an endcrine cnsult 4. Recheck labs in 6 mnths 5. Get an endcrine cnsult G e t a n e n d c r i yw cmplains f fatigue, dcumented weight gain, cld intlerance and amenrrhea. TSH 1 ( ) FT4 0.3 L ( ) Treat with 50 mcg daily f l-thyrxine (70 kg x 1.4 mcg/kg/d = 98 mcg) Get a call frm ED that yur patient came in with nausea, vmiting and hyptensin MRI Pituitary Tumr 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

12 Labs n HD #2 Subsequent Curse 6/15/07 TSH ( ) 1.12 FT4 ( ) 0.46 L What culd be ging n? 1. Euthyrid sick 2. Lab errr 3. Pituitary tumr 4. Other 5. All f the abve 28% 3% E u t h y r i d s i c k L a b e r r r P i t u i t a r y t u m... 7% 62% 0% O t h e r A l l f t h e a b... 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 n teststerne Labs Further Histry End visit 6/07 8/07 10/08 1/09 TSH ( ) FT4 ( ) 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 Exam: tremr, lid lag, stare

13 Labs Subclinical Hypthyridism 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. 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 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 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. 1/24/ N meds 51 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,

14 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) 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

15 57 58 PRINT THIS OUT AND TAKE TO YOUR DOCTOR Thyrid Disrders Endcrinlgists Dn t Knw abut r Underdiagnse Euthyrid Hypthyridism Wilsn s 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 Natinal Academy f Hypthryidism, Dr. Kent Hltrf

16 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 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 Saravanan Clin End 57:577, Saravanan JCEM 90:805, Weber J Endcrinl Invest 25:106, Jnklaas JAMA 229:769,

17 Cnclusins T3 r nt T3 Sme patients may feel better n T3 There may be a bilgic basis fr this in a small subset f patients. Ppulatins studied are very prne t placeb effect N validated metric fr dsing Chances f hyperthyridism withut a lng acting T3 preparatin are significant Wuld avid suppressing TSH If yur patient is put n T3 fr depressin, it is up t yu t assess fr hyperthryidism 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 If yu have a patient n a T3 preparatin, ensure they are nt hyperthryid and avid initiating T San Francisc General Hspital and Trauma Center 17