murphy ucsf cme 2014 hawaii thyroid syllabus murphy ucsf... · case for routine screening date tsh...

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Pesky Thyroid Problems

UCSF Primary Care UpdatesApril 6, 2014

Elizabeth J. Murphy, MD, DPhilProfessor of Clinical Medicine

University of California, San FranciscoChief, Division of EndocrinologySan 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?

A) Yes

B) No

4Cooper 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

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Case



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TSH 8.9 H (0.45-4.20)

What now?a) Treat with levothyroxineb) Order thyroid peroxidase antibody (TPO)c) Recheck a TSHd) 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)

Hypothyroid - Treat

Case


Exam: 80 kg, BMI 32, dry skinThyroid: 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)

Subclinical Hypothyroidism

Case



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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

12Quest Diagnostics, D. Fisher, J. Nelson

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Case



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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 levothyroxineb) Order thyroid peroxidase antibody (TPO), treat if

positivec) Recheck a TSH in 6 monthsd) Recheck a TSH and Free T4 in 6 months


• 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

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

Subclinical HypothyroidismDeciding 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

161JAMA 2004; 291:228-238

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• Reasons to treato Prevent progression to frank hypothyroidismo Improve symptomso Improve lipidso Pregnant/considering pregnancyo Associated with increased mortality and/or morbidity

• Reasons not to treato Treatment has not yet been shown to improve

mortality in a prospective trialo Expenseo 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

18Tunbridge et al., Clinical Endocrinology 7:481, 1977; Vanderpump et al., Clinical Endocrinology43:55, 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

19Tunbridge et al., Clinical Endocrinology 7:481, 1977; Vanderpump et al., Clinical Endocrinology43:55, 1995; Walsh et al., JCEM 95:1095, 2010



• Reasons not to treato Treatment has not yet been shown to improve mortality

in a prospective trialo Expenseo Could do harm

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• Reasons to treato Prevent progression to frank hypothyroidism

o Improve symptoms

o Improve lipids

o Pregnant/considering pregnancyo Associated with increased mortality and/or morbidity


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 beforepregnancy 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

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• Reaffirmed in several times since

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ACOG 2002

Maternal Thyroid and Kid IQ

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

27Haddow et al, NEJM, 341:549; 1999.

Offspring IQ Age 7

Maternal Thyroid and Kid IQ

• Antenatal screening at 12w3d gestationo 21,800 womeno TSH 3-4o Treatment for hypothryoidism didn’t improve cognitive

function at age 31

• Study Flawso Fetal thyroid develops at wk 12o Median TSH 3.8/3.1o Half of those enrolled had a low FT4o Age 3 might be to early to study

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

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

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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 > 10o 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….)


• Reasons to treato Prevent progression to frank hypothyroidismo Improve symptomso Improve lipidso Pregnant/considering pregnancyo Associated with increased mortality and/or

morbidity



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Subclinical Hypothyroidism Long Term Effects – CVD

• CHDo Good prospective studies give discordant results for

CHDo 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 Dysfunctiono Diastolic and systolic dysfunctiono Small trials show improvement when made euthyroid

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

311Osch Ann Intern Med, 2008; 2Rondondi Arch Int Med 2005; 3 Rondondi JACC 2008

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

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

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



• Reasons not to treato Treatment has not yet been shown to improve

mortality in a prospective trialo Expenseo Could do harm

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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

36Ravzi et al Arch Intern Med 2012; 172:811.

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

AGE 40-703093 patients53% received treatmentHR = 0.61 (CI 0.39-0.95)

AGE >701642 patients50% 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 statuso Decreased free T3o 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

39Gussekloo, J. et al. JAMA 2004;292:2591-2599

High

TSH





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Do No HarmThyrotoxicsosis During Hormone Replacement

• Colorado Studyo 21% of patients with TSH < 0.3

o 1% with TSH <0.01

• Whickham Studyo 36% of the patients on thyroxine therapy had TSH < 0.5

o 6% with TSH < 0.05

• Framingham Heart Studyo 48%

• Cardiovascular Health Study

o 41% TSH < 0.45

o 8% TSH <0.1 and high FT4

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Do No HarmCardiovascular Health Study > 65 y

43Somwaru, L. L. et al. J Clin Endocrinol Metab 2009;94:1342-1345

ConclusionsSubclinical Hypothyroidism• There is increased CHD events and CHD mortality with TSH > 10

and there is likely a continuum

• Relationship between age and outcomes is unclear

• In the elderly, higher TSH is associated with decreased mortality and may be part of normal aging

• Treatingo 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 consultb) Treat with levothyroxinec) Treat with levothyroxine and get an endocrine consultd) Recheck labs in 6 monthse) 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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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

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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 andpresumed 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 amo 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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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 4.22:1o 1 grain = 65 mg, (38 mcg T4, 9 mcg T3)

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

• Thyroid USPo 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 4:1o 1 tablet = 50 mcg T4, 12.5 mcg T3

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Thyroid Disorders Endocrinologists Don’t Know about or Underdiagnose

• Euthyroid Hypothyroidism

• Wilsons Syndrome

• T3 resistance

• Common characteristicso 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 T3Weston 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 baselineo 39% relative improvement in the placebo groupo No difference between groups

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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 hormoneo Not all studies determine if initial treatment was for frank

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

subclinical hypothryoidismo 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

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1Woeber J Endocrinol Invest 25:106, 20022Jonklaas JAMA 229:769, 2008.

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SummaryLisa 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 Treatmento 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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murphy ucsf cme 2014 hawaii thyroid syllabus murphy ucsf... · case for routine screening date tsh...

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