[PDF] - Case 45 yow comes to see you complaining of fatigue, depressive PDF Document

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Pesky Thyroid Problems

UCSF Internal Medicine Updates May 20th, 2013

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

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3

Cooper 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.

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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

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

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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

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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
Heterophile antibodies
Assay variability

7

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

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

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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) Subclinical Hypothyroidism

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) – Normal for the population

A given individual will have a narrower normal range.

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Relationship of TSH to Free T4

11

Quest Diagnostics, D. Fisher, J. Nelson

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)

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

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Subclinical Hypothyroidism

Prevalence in US
4.3% NHANES III
9.5% Colorado Mall Study
Prevalence
Increased in iodine sufficient areas
Increases with age
Increased in women
Decreased in African Americans
Only 25% of people with subclinical

hypothryoidism have TSH > 10

13

Race and Ethnicity Specific TSH Distributions – NHANES III

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

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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

Newest data is causing a push for more treatment
There is no clear right or wrong answer

15 1JAMA 2004; 291:228-238

Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve

mortality in a prospective trial

Expense
Could do harm

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Progression to Hypothyroidism

Increased likelihood for the development of overt

hypothyroidism :

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

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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 :

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

18

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

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Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve mortality

in a prospective trial

Expense
Could do harm

19

Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve mortality

in a prospective trial

Expense
Could do harm

20

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Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve mortality in a

prospective trial

Expense
Could do harm

21

Maternal Thyroid and Kid IQ

Studied children
f women with

undiagnosed hypothryoidism (TSH 13)1

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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, 21,800

women, TSH 3-4. Treatment for hypothryoidism didn’t improve cognitive function at age 31

Study Flaws
Fetal thyroid develops at wk 12
Median TSH 3.8/3.1
Half of those enrolled had a low FT4
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.

Subclinical Hypothyroidism

Deciding When to Treat

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

morbidity

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

in a prospective trial

Expense
Could do harm

24

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Subclinical Hypothyroidism

Long Term Effects – CVD

CHD
Good prospective studies give discordant results for

CHD

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
Diastolic and systolic dysfunction
Small trials shows improvement when made euthyroid
CHF Events
Health ABC2 increased events if TSH > 7
CV Health Study3 RR for events 1.9 if TSH > 10

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1Osch 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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5/28/2013 14 Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and Mortality By Age

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

Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve

mortality in a prospective trial

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

previous year

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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
Increased TSH independent of antibody status
Decreased free T3
Increased rT3
Decreased thyroid function likely a normal part
f aging
Chronic disease increases with age

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Mortality in 85 Year Olds Based on TSH

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

H i g h T S H

Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve mortality

in a prospective trial

Expense
Could do harm

34

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Subclinical Hypothyroidism

Deciding When to Treat

Reasons to treat
Prevent progression to frank hypothyroidism
Improve symptoms
Improve lipids
Pregnant/considering pregnancy
Associated with increased mortality and/or morbidity
Reasons not to treat
Treatment has not yet been shown to improve mortality

in a prospective trial

Expense
Could do harm

35

Do No Harm

Thyrotoxicsosis During Hormone Replacement

Colorado Study
21% of patients with TSH < 0.3
1% with TSH <0.01
Whickham Study
36% of the patients on thyroxine therapy had TSH < 0.5
6% with TSH < 0.05
Framingham Heart Study
48%
Cardiovascular Health Study
41% TSH < 0.45
8% TSH <0.1 and high FT4

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Do No Harm

Cardiovascular Health Study > 65 y

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

Conclusions

Subclinical 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

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

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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

39

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? Have you changed what you would do? (options were treat, follow, get more information) a) Yes b) No

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

40

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

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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

45

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 on testosterone.

46

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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

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:
L-thyroxine 75 mcg am
Liothyronine 75 mcg bedtime
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.

49

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.

50

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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

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

monitoring”

Safety monitoring recommended in 2011 clinical guidance piece2
Textbooks and 2010 APA guidelines suggest good evidence for the

use of T3 in depression but don’t mention routine monitoring of thyroid function.

“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.

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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
Cytomel (King Pharma (was Jones))

54

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T3 CONTAINING PREPARATION

DESICATED PIG THYROID

Westhroid (RLC labs)
Nature-Throid (RLC labs)
T4:T3 in a ratio of 4.22:1
1 grain = 65 mg, (38 mcg T4, 9 mcg T3)
Armor Thyroid (Forest)
T4:T3 in a ratio of 4.22:1
1 grain (60 mg) TE
Thyroid USP
All generic forms have been discontinued by manufacturers (no

FDA approval), can get compounded forms

SYNTHETIC

liotrix (Thyrolar) (Forest)
T4:T3 in a ratio of 4:1
1 tablet = 50 mcg T4, 12.5 mcg T3

55 56

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57 58

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PRINT THIS OUT AND TAKE TO YOUR DOCTOR

59

National Academy of Hypothryoidism, Dr. Kent Holtorf

Thyroid Disorders Endocrinologists Don’t Know about or Underdiagnose

Euthyroid Hypothyroidism
Wilson’s Syndrome
T3 resistance
Common characteristics
Normal TSH yet patient still hypothyroid
Don’t have enough T3 action
Often have too much rT3
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

39% relative improvement in the placebo group
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 hormone
Not all studies determine if initial treatment was for frank

hypothyroidism.

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

subclinical hypothryoidism

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, 2002 2Jonklaas JAMA 229:769, 2008.

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63 64

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Conclusions

T3 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

Summary

Lisa Murphy Opinion

Given the lack of definitive data, use your

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

Never treat based on a single value
Treat if TSH > 10 or patient interested in pregnancy
Don’t treat if TSH < 10 and age > 65ish
Do no harm
If you have a patient on a T3 preparation,

ensure they are not hyperthryoid and avoid initiating T3

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