11 Murphy Thyroid - UCSF CME Murphy Thyroid.pdf4/10/14 5 Subclinical Hypothyroidism Deciding When to Treat • Reasons to treat o Prevent progression to frank hypothyroidism o Improve

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Pesky Thyroid Problems

UCSF Primary Care Updates April 6, 2014

Elizabeth J. Murphy, MD, DPhil Professor of Clinical Medicine

University of California, San Francisco Chief, Division of Endocrinology San Francisco General Hospital

Nothing to disclose

Case

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

Exam: 80 kg, BMI 32, dry skin

Would you screen for thyroid disease?

4 Cooper and Biondi, Lancet, 379:1142; 2012.

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Case for Routine Screening

Date TSH 6/2002 1.30 10/2004 1.37 11/2005 1.31 12/2006 1.63 5/2007 1.78 5/2008 1.65 2/2009 1.37 7/2009 1.16 5/2010 1.12 3/2011 1.55 9/2011 1.17

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65 yow followed in endocrine for primary hyperparathryoidism and DM2.

Screening for Thyroid Disease •  If you do check a TSH and it’s completely normal,

there is no need to recheck for 5 years unless there is a clinical change

•  “Screening” is recommended for •  Newborns •  DM1, Down Syndrome, Turner’s Syndrome,

Addision’s disease •  Amiodarone, lithium •  New onset a.fib. •  History of neck irradiation

• Consider screening prior to pregnancy 6

Case



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TSH 8.9 H (0.45-4.20)

What now? a) Treat with levothyroxine b) Order thyroid peroxidase antibody (TPO) c) Recheck a TSH d) Recheck a TSH and Free T4

Factors Altering TSH •  Diurnal variation (nocturnal surge resulting in

highest values in the morning and lower values in the afternoon)

•  Non-thyroidal illness •  Assay Issues

o  Heterophile antibodies o  HAMA antibodies o  Assay variability

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Case



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•  TSH 8.9 H (0.45-4.20) •  TSH 12 H (0.45-4.20)

FT4 0.63 L (0.65-1.78 ng/L) 7 L pmol/L

Hypothyroid - Treat

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

Exam: 80 kg, BMI 32, dry skin Thyroid: firm, normal size

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TSH 8.9 H (0.45-4.20) TSH 9.2 H (0.45-4.20) FT4 1.1 (0.65-1.78) 15 pmol/L

Subclinical Hypothyroidism



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TSH 8.9 H (0.45-4.20) TSH 9.2 H (0.45-4.20) FT4 1.1 (0.65-1.78) – Normal for the population

A given individual will have a narrower normal range.

Relationship of TSH to Free T4

12 Quest Diagnostics, D. Fisher, J. Nelson

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TSH 8.9 H (0.45-4.20) TSH 9.2 H (0.45-4.20) FT4 1.1 (0.65-1.78)

What now? a) Treat with levothyroxine b) Order thyroid peroxidase antibody (TPO), treat if

positive c) Recheck a TSH in 6 months d) Recheck a TSH and Free T4 in 6 months

Subclinical Hypothyroidism •  Prevalence in US

o  4.3% NHANES III o  9.5% Colorado Mall Study

•  Prevalence o  Increased in iodine sufficient areas o  Increases with age o  Increased in women o  Decreased in African Americans

• Only 25% of people with subclinical hypothryoidism have TSH > 10

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Race and Ethnicity Specific TSH Distributions – NHANES III

15 Hollowell J G et al. JCEM 2002;87:489-499

Subclinical Hypothyroidism Deciding When to Treat •  There is no clear right or wrong answer •  Consensus Statement 20041

Routine treatment for TSH 4.5-10 mIU/L is not warranted as there is no evidence of benefit. Treat for TSH > 10 mIU/L.

•  Subsequently societies took issue with this recommendation as lack of evidence is not the same as evidence against

•  There is no clear right or wrong answer

16 1JAMA 2004; 291:228-238

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Subclinical Hypothyroidism Deciding When to Treat •  Reasons to treat

o  Prevent progression to frank hypothyroidism o  Improve symptoms o  Improve lipids o  Pregnant/considering pregnancy o  Associated with increased mortality and/or morbidity

•  Reasons not to treat o  Treatment has not yet been shown to improve

mortality in a prospective trial o  Expense o  Could do harm

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Progression to Hypothyroidism

  Increased likelihood for the development of overt hypothyroidism :

o  Female, older, TPO antibody positive, higher TSH

  Approximately 2.5% of antibody negative individuals per year progress to overt hypothryoidism and 4.5% of TPO antibody positive individuals

  Women with +TPO antibodies have a 38 fold increased risk of developing hypothyroidism

  TSH normalizes in about 5% of individuals at one year   Almost half of patients with subclinical hypothyroidism

(43%) will have progressed in 10 years

18 Tunbridge et al., Clinical Endocrinology 7:481, 1977; Vanderpump et al., Clinical Endocrinology 43:55, 1995; Walsh et al., JCEM 95:1095, 2010

Progression to Hypothyroidism

  Increased likelihood for the development of overt hypothyroidism :

o  Female, older, TPO antibody positive, higher TSH

  Approximately 2.5% of antibody negative individuals per year progress to overt hypothryoidism and 4.5% of TPO antibody positive individuals

  Women with +TPO antibodies have a 38 fold increased risk of developing hypothyroidism

  TSH normalizes in about 5% of individuals at one year   The majority of patients with subclinical hypothyroidism

(57%) will not have progressed in 10 years

19 Tunbridge et al., Clinical Endocrinology 7:481, 1977; Vanderpump et al., Clinical Endocrinology 43:55, 1995; Walsh et al., JCEM 95:1095, 2010



•  Reasons not to treat o  Treatment has not yet been shown to improve mortality

in a prospective trial o  Expense o  Could do harm

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Recommendations For Thyroid Screening in Pregnancy

•  Universal screening of healthy women before pregnancy is not recommended (USPSTF I, evidence poor )

•  Screen high risk women (I, evidence poor)

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The Endocrine Society 2012

JCEM 97:2543, 2012

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Endo Society High Risk

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•  Universal screening of healthy women before pregnancy is not recommended (USPSTF I, evidence poor )

•  Screen high risk women (I, evidence poor) •  Newly pregnant women

o  Screen all pregnant women by week 9 or at time of first visit (C, evidence fair)

o  Don’t know, so only do high risk unless that’s too hard and then do everyone (I, evidence poor)

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The Endocrine Society 2012

JCEM 97:2543, 2012


•  Universal screening of healthy women before pregnancy is not recommended

•  Screening of asymptomatic pregnant women with a mildly enlarged thyroid is not warranted.

•  Test only if personal history of thyroid disease or symptoms •  Recommendations have been reaffirmed several times

since

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ACOG 2002 Maternal Thyroid and Kid IQ

•  Studied children of women with undiagnosed hypothryoidism (TSH 13)1

28 Haddow et al, NEJM, 341:549; 1999.

Offspring IQ Age 7

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Maternal Thyroid and Kid IQ •  Antenatal screening at 12w3d gestation

o  21,800 women o  TSH 3-4 o  Treatment for hypothryoidism didn’t improve cognitive

function at age 31

•  Study Flaws o  Fetal thyroid develops at wk 12 o  Median TSH 3.8/3.1 o  Half were enrolled based on a low FT4 o  Age 3 might be to early to study

•  Guidelines don’t recommend antenatal screening however, prenatal screening is likely more beneficial

29 1Lazarus et al, NEJM, 366:493; 2012.

Guideline Recommendations In Pregnancy re Treatment •  Endocrine Society 2012 Guideline1

o  Treat all women with subclinical hypothyroidism •  American Thyroid Association Guideline

20112 o  Treat if TSH > 10 o  Treat if TPO-Ab+

•  American College of Obstetricians and Gynecologists

o  Don’t recommend treating unless overt hypothyroidism

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(evidence against is not the same as lack of evidence….)


o  Prevent progression to frank hypothyroidism o  Improve symptoms o  Improve lipids o  Pregnant/considering pregnancy o  Associated with increased mortality and/or

morbidity •  Reasons not to treat

o  Treatment has not yet been shown to improve mortality in a prospective trial

o  Expense o  Could do harm

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Subclinical Hypothyroidism Long Term Effects – CVD •  CHD

o  Good prospective studies give discordant results for CHD

o  Meta-analysis suggests significant increased CHD risk1 -  Age < 65 OR 1.51 (1.09-2.09); age > 65 OR 1.05 NS -  TSH > 10 OR 1.69 (0.64-4.45); TSH > 4.5 OR 1.06 NS

•  CV Dysfunction o  Diastolic and systolic dysfunction o  Small trials show improvement when made euthyroid

•  CHF Events o  Health ABC2 increased events if TSH > 7 o  CV Health Study3 RR for events 1.9 if TSH > 10

32 1Osch Ann Intern Med, 2008; 2Rondondi Arch Int Med 2005; 3 Rondondi JACC 2008

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Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality By Degree of TSH Elevation!

Bodondi et al., JAMA. 2010;304:1365-1374."

Patient level metananalysis of individual patient data from 11 prospective cohort studies

Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality By Age!

Bodondi et al., JAMA. 2010;304:1365-1374."



•  Reasons not to treat o  Treatment has not yet been shown to improve

mortality in a prospective trial o  Expense o  Could do harm

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Treatment in Subclinical Hypothyroidism •  There are no prospective randomized controlled

treatment trials powered to address this issue •  The lack of evidence is not the same as evidence

against

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Treatment in Subclinical Hypothyroidism •  There are no prospective randomized controlled

treatment trials powered to address this issue •  Such a study would need roughly 2000 patients •  There is little interest in funding such a study

(though they are trying to put together one in Europe)

•  The lack of evidence is not the same as evidence against

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Razvi et al 20121

•  4735 patients in the UK with new subclinical hypothyroidism (TSH 5 -10). •  Patients received usual care and were

followed for 7.6 years. •  Excluded:

o  History of ischemic heart disease o  History of cerebrovascular disease o  Patients on lithium, amiodarone, steroids in

previous year

38 Ravzi et al Arch Intern Med 2012; 172:811.

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Multivariate-Adjusted Cumulative Fatal and Non-Fatal Ischemic Heart Disease Events

AGE 40-70 3093 patients 53% received treatment HR = 0.61 (CI 0.39-0.95)

AGE >70 1642 patients 50% received treatment HR = 0.99 (CI 0.59-1.33)

Ravzi et al Arch Intern Med 2012; 172:811.

Thyroid Function in the Elderly •  Increased T1/2 of T4 •  Reduction in the amount of T4 replacement

needed •  Most studies show with age

o  Increased TSH independent of antibody status o  Decreased free T3 o  Increased rT3

•  Decreased thyroid function likely a normal part of aging

•  Chronic disease increases with age

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Mortality in 85 Year Olds Based on TSH

41 Gussekloo, J. et al. JAMA 2004;292:2591-2599

High TSH





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Do No Harm Thyrotoxicsosis During Hormone Replacement

•  Colorado Study o  21% of patients with TSH < 0.3 o  1% with TSH <0.01

•  Whickham Study o  36% of the patients on thyroxine therapy had TSH < 0.5 o  6% with TSH < 0.05

•  Framingham Heart Study o  48%

•  Cardiovascular Health Study o  41% TSH < 0.45 o  8% TSH <0.1 and high FT4

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Do No Harm Cardiovascular Health Study > 65 y

45 Somwaru, L. L. et al. J Clin Endocrinol Metab 2009;94:1342-1345

Conclusions Subclinical Hypothyroidism •  There is an increase in CHD events and CHD mortality with TSH >

10 and there is likely a continuum •  Relationship between age and outcomes is unclear, treat younger? •  In the elderly, higher TSH is associated with decreased mortality

and may be part of normal aging •  Treating

o  Always recheck TSH with a Free T4 before treating o  Generally treat for TSH >10 o  TSH ULN – 10 base on patient, provider desire o  Treating younger patients maybe justified o  Treating women interested in getting pregnant seems like a good idea o  Always start with low dose l-thyroxine and go up slowly (do no harm) o  Use caution in patients with CAD

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Case 35 yow complains of fatigue, documented weight gain, cold intolerance and amenorrhea.

TSH 1 (0.45-4.20) FT4 0.3 L (0.65-1.78)

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What now? a) Order imaging and get an endocrine consult b) Treat with levothyroxine c) Treat with levothyroxine and get an endocrine consult d) Recheck labs in 6 months e) Get an endocrine consult

Case

35 yow complains of fatigue, documented weight gain, cold intolerance and amenorrhea.

TSH 1 (0.45-4.20) FT4 0.3 L (0.65-1.78)

•  Treat with 50 mcg daily of l-thyroxine (70 kg x 1.4 mcg/kg/d = 98 mcg)

•  Get a call from ED that your patient came in with nausea, vomiting and hypotension.

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MRI Pituitary Tumor

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Case

50 yom with hypertension, HIV, depression and obesity was admitted with substernal chest pain.

Hospital course included a NSTEMI and hypertensive emergency with diastolic BPs in the 140s. Coronary lesion was not amenable to stenting.

He was discharged on medical therapy on HD 4.

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Labs on HD #2

6/15/07 TSH (0.37-4.42) 1.12 FT4 (0.65-1.80) 0.46 L

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What could be going on? a)  Euthyroid sick b)  Lab error c)  Pituitary tumor d)  Other e)  All of the above

Subsequent Course •  Patient continued to have intermittent CP with

visits to ED but no further admissions •  1.5 yrs later referred to endocrine because of

concern for hyperthyroidism with suppressed TSH 0.02

•  Expedited into endo clinic over concern for a pituitary process given low FT4 of 0.49 and presumed history of hypogonadism as patient on testosterone.

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Labs

6/07 8/07 10/08 1/09

TSH (0.37-4.42) 1.12 0.46 0.02 0.03 FT4 (0.65-1.80) 0.46 0.48 0.52 0.49

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Further History – Endo visit

•  In the setting of severe depression 2 years prior (6 mths prior to MI) patient had been started on thyroid medication by his psychiatrist for an elevated TSH.

•  Had had a steady dose increase since then. •  Current meds:

o  L-thyroxine 75 mcg am o  Liothyronine 75 mcg bedtime (cytomel)

•  Exam: tremor, lid lag, stare

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Labs

6/07 8/07 10/08 1/09 1/09

TSH (0.37-4.42) 1.12 0.46 0.02 0.03 0.02 FT4 (0.65-1.80) 0.46 0.48 0.52 0.49 0.57 FT3 (2.30-4.20) 5.00

A TTE performed earlier in the month showed intermittent atrial fibrillation.

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Subclinical Hypothyroidism

11/99 2/01 2/07 1/09

TSH (0.37-4.42) 6.17 3.81 4.56 0.03 FT4 (0.65-1.80) 0.84 0.76 0.83 0.49

No TPO/antimicrosomal antibodies. Had spontaneous normalization of subclinical

hypothyroidism in the past. Patient was made thyroxic contributing to MI and

a.fib.

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T3 for Depression

•  Used as augmentation therapy in major depressive disorder •  STAR*D Trial showed equal to better remission than lithium with

fewer side effects1 o  There was no placebo and no blood monitoring for those placed on T3 o  “T3 also offers the advantage of lack of need for blood level

monitoring” •  Safety monitoring recommended in 2011 clinical guidance piece2

o  Textbooks and 2010 APA guidelines suggest good evidence for the use of T3 in depression but don’t mention routine monitoring of thyroid function.

o  “Many psychiatrists are nevertheless uncomfortable prescribing thyroid hormones to essentially euthyroid patients, and some of our colleagues in endocrinology may also find this practice controversial.”

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1Nierenberg, et al. A Comparison of Lithium and T3 Augmentation Following Two Failed Medication Treatments for Depression, Am J Psychiatry 163:1519, 2006. 2Rosenthal et al, T3 Augmentation in MDD: Safety Considerations, Am J Psychiatry 168:1035, 2011.

T3 Metabolism

•  T3 is about four times as potent as T4 • Ratio of T4:T3 in thyroid gland excretions in

humans is roughly 14:1 •  In pigs this ratio is closer to 4:1 T4:T3 •  In humans about 80% of T3 is made via

peripheral conversion from T4 •  T3 is very rapidly and effectively absorbed

with a much shorter T1/2 (2.5 d) than T4 (7 d)

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T3 preparations

•  liothyronine

o  Cytomel (King Pharma (was Jones))

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T3 CONTAINING PREPARATION DESICATED PIG THYROID •  Westhroid (RLC labs) •  Nature-Throid (RLC labs)

o  T4:T3 in a ratio of 4.22:1 o  1 grain = 65 mg, (38 mcg T4, 9 mcg T3)

•  Armor Thyroid (Forest) o  T4:T3 in a ratio of 4.22:1 o  1 grain (60 mg) TE

•  Thyroid USP o  All generic forms have been discontinued by manufacturers (no

FDA approval), can get compounded forms

SYNTHETIC •  liotrix (Thyrolar) (Forest)

o  T4:T3 in a ratio of 4:1 o  1 tablet = 50 mcg T4, 12.5 mcg T3

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PRINT THIS OUT AND TAKE TO YOUR DOCTOR

64 National Academy of Hypothryoidism, Dr. Kent Holtorf

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Thyroid Disorders Endocrinologists Don’t Know about or Underdiagnose

•  Euthyroid Hypothyroidism • Wilsons Syndrome •  T3 resistance

• Common characteristics o  Normal TSH yet patient still hypothyroid o  Don’t have enough T3 action o  Often have too much rT3 o  Need to treat with T3

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T3 or not T3 Weston Area T4 T3 Study (WATTS)2 •  Same group had previously shown significantly

impaired well-being in patients on T4 replacement with normal TSH1

•  697 hypothyroid patients in England •  Replaced 50 mcg of LT4 with 10 mcg T3 •  Randomized double blind placebo trial •  Significant drop out due to perceived SE in both

groups •  Both groups had significant improvement in

psychological scores compared with baseline o  39% relative improvement in the placebo group o  No difference between groups

66 1Saravanan Clin Endo 57:577, 2002. 2Saravanan JCEM 90:805, 2005.

Summary Of T3 and Replacement Studies

•  Potential selection bias of people studied on thyroid hormone o  Not all studies determine if initial treatment was for frank

hypothyroidism. o  Up to 5 % of adults in iodine-sufficient countries have untreated

subclinical hypothryoidism o  Patients who end up on treatment are the ones more likely to have

symptoms that could be attributable to the thyroid •  Large placebo effect (up to 40%) in these studies •  Several large studies suggest psychological morbidity in

patients on T4 alone •  Some patients feel better hyperthyroid •  Some patients feel better on T3 (only hyperthyroid?) •  Patients on T4 have a higher serum T4:T3 ratio1,2

67 1Woeber J Endocrinol Invest 25:106, 2002 2Jonklaas JAMA 229:769, 2008.

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Summary Lisa Murphy Opinion •  Given the lack of definitive data, use your judgment

and consult with the patient when considering treatment for subclinical hypothyroidism.

o  Never treat based on a single value o  Treat if TSH > 10 or patient interested in pregnancy o  Don’t treat if TSH < 10 and age > 65ish o  Do no harm

•  T3 Treatment o  If you have a patient on a T3 preparation, ensure they

are not hyperthyroid o  Until a long acting T3 preparation is available would

avoid initiating T3

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San Francisco General Hospital and Trauma Center

Documents

11 Murphy Thyroid - UCSF CME Murphy Thyroid.pdf4/10/14 5 Subclinical Hypothyroidism Deciding When to Treat • Reasons to treat o Prevent progression to frank hypothyroidism o Improve