4/10/14 1 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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4/10/14
1
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.
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
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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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
21
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
22
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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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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) • 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
Recommendations For Thyroid Screening in Pregnancy
• 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
27
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….)
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
31
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."
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
35
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
37
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
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
42
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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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
46
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.
50
Labs on HD #2
6/15/07 TSH (0.37-4.42) 1.12 FT4 (0.65-1.80) 0.46 L
51
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.
• 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)
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
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
• 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