Case - UCSF CME · 2013-08-23 · Case for Routine Screening Date TSH 6/2002 1.30 10/2004 1.37...

6/25/2013

1

Pesky Thyroid Problems

UCSF Internal Medicine UpdatesJune 24, 2013

Case45 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?

Y es

N o

7%

93%

A. Yes

B. No

3Cooper and Biondi, Lancet, 379:1142; 2012.

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

4

65 yow followed in endocrine for primary hyperparathryoidism and DM2.

6/25/2013

2

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

5



What now?

6

• TSH 8.9 H (0.45-4.20) T r e

a t wi t h

l e v. . .

O rd e r

t h yr o i d

. . . R e

c h ec k a

T S H R e

c h ec k a

T S H . . .

31%

50%

8%12%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 Assay variability

7

Case

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


8

• 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

6/25/2013

3


Exam: 80 kg, BMI 32, dry skinThyroid: firm, normal size

9

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



10

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 rang e.

Relationship of TSH to Free T4

11Quest Diagnostics, D. Fisher, J. Nelson



What now?

12

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

T r ea t w

i t h l e v .

. . O r d

e r th y r

o i d . . .

R ec h e

c k a T S H

. . . R e

c h ec k a

T S H . . .

52%

42%

3%3%

1. Treat with levothyroxine2. Order thyroid peroxidase antibody (TPO), treat

if positive3. Recheck a TSH in 6 months4. Recheck a TSH and Free T4 in 6 months

6/25/2013

4


• 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

13

Race and Ethnicity Specific TSH Distributions – NHANES III

14Hollowell 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

• Newest data is causing a push for more treatment

• There is no clear right or wrong answer

151JAMA 2004; 291:228-238


• 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

16

6/25/2013

5

Progression to Hypothyroidism

� Increased likelihood for the development of overt hypothyroidism :

o Female, older, 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 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

17Tunbridge 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, 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 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

18Tunbridge 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

19

Subclinical HypothyroidismDeciding When to Treat• Reasons to treat

o Prevent progression to frank hypothyroidism

o Improve symptoms

o Improve lipids

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

morbidity


mortality in a prospective trial

o Expense

o Could do harm

20

6/25/2013

6



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

prospective trialo Expenseo Could do harm

21

Maternal Thyroid and Kid IQ

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

22Haddow et al, NEJM, 341:549; 1999.

Offspring IQ Age 7

Maternal Thyroid and Kid IQ

• Antenatal screening at 12w3d gestation, 21,800 women, TSH 3-4. Treatment for hypothryoidism didn’t improve cognitive function at age 31

• Study Flawso Fetal thyroid develops at wk 12

o Median TSH 3.8/3.1

o Half of those enrolled had 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

23

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


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

morbidity



24

6/25/2013

7

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 shows improvement when made euthyroid

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

251Osch 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

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

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




mortality in a prospective trialo Expenseo Could do harm

28

6/25/2013

8

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

29

Razvi et al 2012 1

• 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

30Ravzi et al Arch Intern Med 2012; 172:811.

31

Multivariate-Adjusted Cumulative Fatal and Non-Fata l 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

32

6/25/2013

9

Mortality in 85 Year Olds Based on TSH

33Gussekloo, J. et al. JAMA 2004;292:2591-2599

High

TSH





34





35

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

36

6/25/2013

10

Do No HarmCardiovascular Health Study > 65 y

37Somwaru, L. L. et al. J Clin Endocrinol Metab 2009;94: 1342-1345

ConclusionsSubclinical Hypothyroidism• There is increased CHD events and 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 Treat generally 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/CVD

38



What now? Have you changed what you would do? (options were treat, follow, get more information)

39

TSH 8.9 H (0.45-4.20)

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

Y es

N o

67%

33%

A. YesB. No



What now?

40

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

T r ea t w

i t h l e v

. . . O r

d e r t h y

r o i d . . .

R ec h e

c k a T S H

. . . R e

c h ec k a

T S H . . .

12%

80%

4%4%

1. Treat with levothyroxine2. Order thyroid peroxidase antibody (TPO),

treat if positive3. Recheck a TSH in 6 months4. Recheck a TSH and Free T4 in 6 months

6/25/2013

11

Case35 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)What now?

41

O rd e r

i ma g i n

g . ..

T r ea t w

i t h l e v

. . . T r e

a t wi t h

l e v. . .

R ec h e

c k la b s

i . . . G e

t a n e n d

o c ri . . .

24%

8% 8%

56%

4%

1. Order imaging and get an endocrine consult2. Treat with levothyroxine3. Treat with levothyroxine and get an endocrine consult

4. Recheck labs in 6 months5. 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.

42

MRI Pituitary Tumor

43

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.

44

6/25/2013

12

Labs on HD #2

6/15/07TSH (0.37-4.42) 1.12FT4 (0.65-1.80) 0.46 LWhat could be going on?

45

E u th y r

o i d s i c k

L a b e r r

o r P i t

u i t ar y t

u mo . . . O t he r

A l l o f

t h e a b o

. . .

28%

3%

62%

0%7%

1. Euthyroid sick

2. Lab error

3. Pituitary tumor 4. Other

5. 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 andpresumed history of hypogonadism on testosterone.

46

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

47

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

• Exam: tremor, lid lag, stare

48

6/25/2013

13

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.

49


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.

50

51

TSH FT4 FT3

7/15/11 0.77 1.16 No meds

11/13/12 <0.01 0.70L 8.62H T3 100 mcg daily

12/14/12 0.48 0.56L 2.26L No meds

1/24/13 2.17 0.81 2.98 No meds

54 yom severe depression referred to endocrine for thyroid nodules. At one year follow-up pt was noted to have anxiety, 10 lb weight loss. He had been given adjuvant treatment for his depression with T3.

Meds: citalopram 40 daily, liothyronine 100 mcg daily

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.”

52

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.

6/25/2013

14

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)

53

T3 preparations

• liothyronine

o Cytomel (King Pharma (was Jones))

54

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

55 56

6/25/2013

15

57 58

PRINT THIS OUT AND TAKE TO YOUR DOCTOR

59National Academy of Hypothryoidism, Dr. Kent Holtorf

Thyroid Disorders Endocrinologists Don’’’’t Know about or Underdiagnose

• Euthyroid Hypothyroidism

• Wilson’s 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

60

6/25/2013

16

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

61

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

62

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

63 64

6/25/2013

17

ConclusionsT3 or not T3

• Some patients may feel better on T3• There may be a biologic basis for this in a small

subset of patients.• Populations studied are very prone to placebo

effect• No validated metric for dosing• Chances of hyperthyriodism without a long

acting T3 preparation are significant• Would avoid suppressing TSH• If your patient is put on T3 for depression, it is

up to you to assess for hyperthryoidism

65

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 valueo Treat if TSH > 10 or patient interested in pregnancyo Don’t treat if TSH < 10 and age > 65isho Do no harm

• If you have a patient on a T3 preparation, ensure they are not hyperthryoid and avoid initiating T3

66

San Francisco General Hospital and Trauma Center

Case - UCSF CME · 2013-08-23 · Case for Routine Screening Date TSH 6/2002 1.30 10/2004 1.37...

Documents

Transcript of Case - UCSF CME · 2013-08-23 · Case for Routine Screening Date TSH 6/2002 1.30 10/2004 1.37...