© 2016 American College of Physicians

The information contained herein should never be

used as a substitute for clinical judgment.
BEYOND THE GUIDELINES:
Would you treat this patient for subclinical hypothyroidism?

Medicine Grand Rounds

January 7, 2016

Discussants BIDMC Series Editor Moderator

Pamela I. Risa B. Burns, MD, Gerald W.

Hartzband, MD MPH Smetana, MD

Carol K. Bates, MD

The Series Editors have no conflicts of interest to disclose.

 Conflict of Interest Disclosure

The speakers have no financial

relationships with a commercial entity
producing healthcare-related products
and/or services.
Risa B. Burns, MD, MPH
Pamela I. Hartzband, MD
Carol K. Bates, MD
Gerald W. Smetana, MD
OUR PATIENT
Medical History — Ms C is a 60 yo woman 2013

2012

TSH 5.9 uIU/mL

2003
TSH 5.8 uIU/mL c/o fatigue

c/o sweating Free T4 0.93 ng/dL

2001
3/3 sisters thyroid
TSH 3.5 uIU/mL ‘problem’ *Treatment not initiated:
TSH level stable
c/o fatigue
TSH 2.5 uIU/mL
*Treatment not initiated:
symptoms not consistent w/
c/o constipation
hypothyroidism
OUR PATIENT
Recent and Past Medical History
• Ms C returned in 2015
• weight gain despite trying to eat a good diet and exercise
• fatigue
• constipation

• Past medical history

• hyperlipidemia treated with atorvastatin 10mg daily
• cervical radiculitis
OUR PATIENT
Social and Family History

• Social History
• Married
• Primary care giver for her chronically ill husband
• Adult children and grandchildren whom she visits frequently
• Does not smoke cigarettes or drink alcohol

• Family History
• 3/3 sisters thyroid ‘problem’, 2 on thyroid medication
• Brother is well
OUR PATIENT
Periodic Health Examination

• Blood pressure 136/79

• Heart rate 77
• Weight up 9 pounds from preceding year to 156 pounds, BMI
29.6
• Normal thyroid gland and no adenopathy
• Repeat TSH 6.5 uIU/mL, free T4 1.0 ng/dL

Both Ms C and her primary care physician wonder whether she

should be started on thyroid replacement.
CONTEXT, EVIDENCE, & GUIDELINES
• Subclinical hypothyroidism defined as
• TSH > 4.5 mIu/L and normal free T4
• Present in about 5% women and 3% men in US
• Risk factor for development of “overt” hypothyroidism
• about 2 - 5% progress to “overt” hypothyroidism
• about 40% revert to normal over time
• May be a risk factor for coronary heart disease and CHF
• May be a risk factor of increased CHD mortality
• Unclear if treatment of subclinical hypothyroidism reduces the risk
for these adverse health outcomes
 THE GUIDELINES :
Screening and Treatment of Subclinical Hypothyroidism - 2011 AHRQ

*Rugge B, Balshem H, Sehgal R, Relevo R, Gorman P, Helfand M. Screening and Treatment of Subclinical Hypothyroidism or Hyperthyroidism. Comparative
Effectiveness Review No. 24. (Prepared by the Oregon Evidence-based Practice Center under Contract No. 290-2007-10057-I.) AHRQ Publication No. 11(12)-
EHC033-EF. Rockville, MD: Agency for Healthcare Research and Quality. October 2011. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm
CONTEXT, EVIDENCE, & GUIDELINES
• AHRQ review found:
• No evidence that treating subclinical hypothyroidism improved
quality of life, blood pressure or body mass index.
• Lipid data were less clear. Reviewers concluded that treatment
of subclinical hypothyroidism may improve lipid measurements
by 5%.
• No formal data on harms making it difficult to balance the
benefits and harms of treatment.
• AHRQ concluded that it is unclear whether screening and early
treatment was better than not screening or watchful waiting when
a TSH was mildly abnormal.
 THE GUIDELINES:
Screening for Thyroid Dysfunction - USPTF 2015

*LeFevre ML, U.S. Preventive Services Task Force. Screening for Thyroid Dysfunction: U.S. Preventive
Services Task Force Recommendation Statement. Ann Intern Med. 2015;162:641-650.
CONTEXT, EVIDENCE, & GUIDELINES

• The 2015 USPTF update included an evaluation of those

with a TSH level < 10 mIU/L who are currently being
treated.
• Examined the effectiveness of treatment on
• intermediate outcomes - blood pressure, BMI, lipids
• clinical outcomes - cardiovascular events and mortality,
quality of life and cognitive function
CONTEXT, EVIDENCE, & GUIDELINES

• No evidence that treating subclinical hypothyroidism improved

blood pressure, body mass index, quality of life or cognitive
function
• Lipid Data - mixed results
• Across 8 studies the difference between treatment and no
treatment in mean total cholesterol levels ranged from -0.7 to
0 mmol/L (-28 to 0 mg/dL).
• The difference ranged from -0.6 to 0.1 mmol/L (-22 to 2
mg/dL) for mean low-density cholesterol levels.
CONTEXT, EVIDENCE, & GUIDELINES
Cardiovascular Events and Mortality
• A single fair-quality study examined the association between
treatment of subclinical hypothyroidism and risk for cardiac events.
• In the younger age group (40-70 years) treatment was associated
with a lower risk for fatal or nonfatal ischemic heart disease events
(4.2% vs 6.6%; HR, 0.61 [CI, 0.39 to 0.95].
• There was no statistically significant association between
treatment and cardiovascular outcomes in the older age group
(over 70 years).
CONTEXT, EVIDENCE, & GUIDELINES

• The USPTF found inadequate evidence on the harms of treating

subclinical thyroid dysfunction.
• However, indirect evidence suggests important and frequent
harms including:
• frequent false-positive results
• psychological effects of labeling
• large degree of over diagnosis and over treatment particularly
in persons with TSH levels less than 10
• The USPTF concluded that that current evidence is insufficient to
assess the balance of benefits and harms of screening for thyroid
dysfunction.
 THE GUIDELINES:
Agressive Case Finding

Hennessy et al reiterated the American Association of Clinical

Endocrinologists and American Thyroid Association
recommendation for aggressive case finding.
*Hennessey JV, Klein I, Woeber KA, Cobin R, Garber JR. Aggressive Case Finding: A
Clinical Strategy for the Documentation of Thyroid Dysfunction. Ann Intern Med.
2015;163:311-312.
CONTEXT, EVIDENCE, & GUIDELINES

• Aggressive case finding advocates screening those with certain

clinical conditions or characteristics rather than screening the
general population.
• Aggressive case finding allows for the identification of those who
are most likely to have thyroid disease and benefit from treatment.
• The authors argue that subclinical hypothyroidism has adverse
effects on cardiovascular consequences and merits case finding.
QUESTIONS TO DISCUSSANTS
To structure a debate between our two discussants, we
mutually agreed on the following key questions to consider
when applying the guidelines to clinical practice, in general, and
Ms C in particular:
1. Does treatment of subclinical hypothyroidism reduce
morbidity and mortality
2. What are the harms of treating subclinical hypothyroidism?
3. Balancing the benefits and harms when would you
recommend treating subclinical hypothyroidism, in general,
and for our patient in particular?
OUR MODERATOR & DISCUSSANTS
Gerald W. Smetana, MD (Moderator)
Professor of Medicine, Harvard Medical School
General Medicine and Primary Care, BIDMC

Pamela I. Hartzband, MD
Assistant Professor of Medicine, Harvard Medical School
Medical Director, Thyroid Biopsy Clinic, BIDMC

Carol K. Bates, MD
Associate Professor of Medicine, Harvard Medical School
Associate Dean of Faculty Affairs, Harvard Medical School
General Medicine and Primary Care, BIDMC
Dr. Hartzband
 Does screening for and treatment of subclinical
hypothyroidism reduce morbidity and mortality?
 Screening vs. Case Finding

AHQR/USPSTF AACE/ATA
Focus is on screening asymptomatic Focus is on testing based on
adult population. symptoms, signs, other lab
abnormalities, medications,
*LeFevre ML, U.S. Preventive Services Task Force. Screening for Thyroid
personal and family history.
Dysfunction: U.S. Preventive Services Task Force Recommendation
Statement. Ann Intern Med. 2015;162:641-650.

*Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical
Practice Guidelines for Hypothyroidism in Adults: Cosponsored by the American
Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid.
2012;22:1200-1235.
 Autoimmune Thyroiditis

*Reprinted from The Lancet, Vol. 379, Cooper DS, Biondi B, Subclinical Thyroid Disease,
pp1142-1154, 2012, with permission from Elsevier.
 Not only conflicting data.

Conflicting interpretation of the same data.

 Summary of Lipid Trials

“The previous USPSTF review included 7 trials

on the effect of treatment of subclinical
hypothyroidism and effects on lipid profiles. Six
trials found no improvement in lipid
variables...”

*Rugge JB, Bougatsos C, Chou R. Screening and Treatment of Thyroid Dysfunction: An Evidence
Review for the U.S. Preventive Services Task Force. Ann Intern Med. 2015;162:35-45.
 Summary of Lipid Trials
“Eight placebo-controlled randomized clinical
trials have examined the effects of
levothyroxine on serum lipids in subclinical
hypothyroidism. Levothyroxine did not reduce
total cholesterol in four studies, but exerted a
beneficial effect in the other four studies.”

*Biondi B, Cooper DS. The Clinical Significance of Subclinical Thyroid Dysfunction. Endocr
Rev. 2008;29:76-131.
 Levothyroxine treatment
resulted in a significant
decrease of both TC and LDLc
concentrations (P=0.003) in
direct proportion to the
respective baseline values.
*Caraccio N, Ferrannini E, Monzani F. Lipoprotein Profile in Subclinical Hypothyroidism:
Response to Levothyroxine Replacement, a Randomized Placebo-Controlled Study. J Clin
Endocrinol Metab. 2002;87:1533-1538.
This is the first double blind study to show
that physiological L-thyroxine replacement
in patients with subcinical hypothyroidism
has a beneficial effect on low density
lipoprotein cholesterol level and clinical
symptoms of hypothyroidism. An important
risk reduction of cardiovascular mortality of
9-31% can be estimated from the observed
improvement in low density lipoprotein
cholesterol . *Meier C, Staub JJ, Roth CB, Guglielmetti M, Kunz M, Miserez AR, et al. TSH-
Controlled L-Thyroxine Therapy Reduces Cholesterol Levels and Clinical
Symptoms in Subclinical Hypothyroidism: a Double Blind, Placebo-Controlled
Trial (Basel Thyroid Study). J Clin Endocrinol Metab. 2001;86:4860-4866.
Levothyroxine Treatment of Subclinical Hypothyroidism,
Fatal and Nonfatal Cardiovascular Events, and Mortality

Age Incident IHD Events Incident IHD Events Hazard Ratio (95% CI)
in those treated in those not treated
Younger (40-70 yrs) 68/1634 97/1459 0.61
(4.2%) (6.6%) (0.39-0.95)
Older (>70 yrs) 104/819 88/823 0.99
(12.7%) (10.7%) (0.59-1.33)

Conclusions: Treatment of SCH with levothyroxine was associated

with fewer IHD events in younger individuals, but this was not
evident in older people. An appropriately powered randomized
controlled trial of levothyroxine in SCH examining vascular outcomes
is now warranted. *Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine Treatment of Subclinical
Hypothyroidism, Fatal and Nonfatal Cardiovascular Events, and Mortality. Arch Intern Med.
2012;172:811-817.
 Symptoms/Findings

• Fatigue/malaise • Bradycardia
• Constipation • Hyperlipidemia
• Weight gain • Anemia
• Alopecia • Goiter
• Menorrhagia
• Myopathy
• Depression
What are the harms of screening for
and treating hypothyroidism?
• No evidence base for harm from testing or
treatment.
• Speculation:
– Development of subclinical hyperthyroidism.
• Bone loss
• Atrial fibrillation
– Cost
• Generic medication is available at low cost
– Psychological effects of labeling
 Balancing the benefits and harms, when would you
recommend treating subclinical hypothyroidism, if ever?

Rec 16: Treatment based on individual factors for patients with

TSH levels between the upper limit of normal of a given
laboratory’s upper reference range and 10 miu/L should be
considered for treatment particularly if patients have symptoms
suggestive of hypothyroidism, positive anti TPO antibodies or
evidence of atherosclerotic cardiovascular disease, heart failure,
or associated risk factors for those diseases. (Not fully
generalizable/No prospective interventional studies)

*Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical Practice Guidelines for
Hypothyroidism in Adults: Cosponsored by the American Association of Clinical Endocrinologists and the American
Thyroid Association. Endocr Pract. 2012;18:988-1028.
 Recommendations for Ms. C
Offer a therapeutic trial of low dose levothyroxine
with careful monitoring.
• Positive family history
• TSH increased over time
• Anti-TPO?
• Elevated cholesterol
• Symptoms
• No evidence base for harm with
low dose levothyroxine and
careful monitoring
What are the potential benefits of
treatment?
• First, are we sure that she actually has
subclinical hypothyroidism?
• Is there a benefit with respect to heart
disease and mortality?
• How likely is Ms C to experience symptom
relief?
Dr. Bates
How reliable is TSH?

• Mean TSH in paired samples in 20 patients

– 8-10 AM 5.83 mU/L
– 2-4 PM 3.79 mU/L
• Using reference range of 0.4-4.0 mU/L
– 100% hypothyroid range in AM
– 50% in hypothyroid range in PM
• All of Ms C’s TSH values measured in AM
*Sviridonova MA, Fadeyev VV, Sych YP, Melnichenko GA. Clinical Significance of TSH Circadian
Variability in Patients with Hypothyroidism. Endocr Res 2013;38:24-31.
 What is Ms C’s risk of heart disease?

TSH Events People HR (95% CI)

CHD Events 4.5-6.9 264 1344 1.00 (0.86-1.18)

CHD Mortality 4.5-6.9 132 2363 1.09 (0.91-1.30)

*Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al.
Subclinical Hypothyroidism and the Risk of Coronary Heart Disease and
Mortality. JAMA. 2010;304:1365-1374.
 Are classical symptoms predictive of
hypothyroidism?
• Population study >25,000 patients 9% TSH>5.1
• Symptoms statistically significantly more common
in hypothyroid patients, but…
– “drier skin” ~28% hypo TSH ~25% normals
– “more tired” ~18% hypo TSH ~15% normals
– “feeling colder” ~15% hypo TSH ~12% normals
– “more constipation” ~6% hypo TSH ~5%
normals
*Canaris GJ, Manowitz NR, Mayor G, Ridgway EC. The Colorado thyroid disease prevalence study. Arch
Intern Med. 2000;160:526-534.
 Weight loss with levothyroxine in RCTs

Study TSH Dose in Duration in Total Weight

Drug/Placebo mcg months patients change
Duman 2007 10.9/11.0 >100 8 39 -1 kg/m2
Igbal 2006 5.8/5.4 96 12 64 +1 kg/m2
Kong 2002 8.0/7.3 NR 6 40 -0.3 kg/m2
Monzani 2004 6.0/5.7 70 10.5 45 -1 kg/m2
Nagasaki 2009 7.3 26 5 95 0 kg/m2
Razvi 2007 5.4/5.3 100 3 50 -1 kg

*Rugge JB, Bougatsos C, Chou R. Screening for and Treatment of Thyroid

Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force.
Rockville (MD): Agency for Healthcare Research and Quality (US); 2014 Oct.
(Evidence Syntheses, No. 118.)
What’s the harm in treatment (and testing)?

• Incorrect attribution of symptoms

• The vagaries of treatment
– Thyroid hormone dosing and administration
– Testing and costs
• Risk of overtreatment and hyperthyroidism
– Atrial fibrillation
– Osteoporosis
• Medicalizing a normal phenomenon
The vagaries of levothyroxine

• Color coded across

manufactures
• Testing recommended if
change in manufacturer
• One of only meds where
brand name
recommended
• FDA 2015 draft guidance
narrow therapeutic range
More dilemmas in dosing…
• Half life is…7 days!
– Catch up dosing if missed
– Adherence in 6 weeks prior to testing
– Allows weekly dosing
• Absorption affected by food
– Take 1 hour before meals
– Affected by coffee within 1 hour of dosing
• Absorption decreased by iron, calcium MVI, others with 4 hrs
separation recommended
The burden of testing

• Recommended 6 weeks after dose change

• Charges: TSH $95, free T4 $146 1
• High deductible health plans are now >25%
of employee sponsored insurance2
• If retesting for change in generic
manufacturer, total cost as expensive as
brand name Rx 2
1. Horowitz G. Personal communication
2. Price Waterhouse Coopers: Medical Cost Trend: Behind the Numbers 2015
3. Katz M, Scherger J, Conard S, Montejano L, Chang S. Healthcare Costs Associated with Switching from Brand
to Generic Levothyroxine. Am Health Drug Benefits. 2010;3:127-134.
 The risk of over-replacement

*Somwaru LL, Arnold AM, Joshi N, Fried LP, Cappola AR. High Frequency of and Factors Associated with Thyroid
Hormone Over-Replacement and Under-Replacement in Men and Women Aged 65 and Over. J Clin Endocrinol
Metab. 2009;94:1342-1345.
 Risk of fracture with overtreatment

Women (n =128,428) HR p value

Hip fractures (5994)
Per 6 months TSH >4 0.99 (0.95-1.03) 0.617
Per 6 months TSH <0.3 1.10 (1.03-1.16) 0.002
Major osteoporotic
fractures (15,984)
Per 6 months TSH >4 1.00 (0.98-1.04) 0.452
Per 6 months TSH <0.3 1.10 (1.06-1.14) <.0001

*Abrahamsen B1, Jørgensen HL, Laulund AS, Nybo M, Bauer DC, Brix TH, et al. The Excess Risk of
Major Osteoporotic Fractures in Hypothyroidism Is Driven by Cumulative Hyperthyroid as
Opposed to Hypothyroid Time: An Observational Register-Based Time-Resolved Cohort Analysis. J
Bone Miner Res 2015;30:898-905.
 Atrial fibrillation risk

*From the New England Journal of Medicine, Sawin CT, Geller A, Wolf PA, Belanger AJ, Baker E, Bacharach P,
et al, Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons, Vol. 331,
pp. 1249-1252. © 1994 Massachusetts Medical Society. Reprinted with permission from Massachusetts
Medical Society.
 Is there harm in knowledge of abnormal TSH?

Adjusted self reported Adjusted self reported

QOL in Women QOL in Men
Normal thyroid 1.0 1.0
Unknown 1.84 (1.02-3.33) 1.28 (0.35-4.65)
hypothyroidism
Unknown subclinical 1.48 (1.13-1.94) 1.13 (0.72-1.76)
hypothyroidism
Known hypothyroidism 0.49 (0.65-0.93) 0.69 (0.44-0.84)

*Jørgensen P, Langhammer A, Krokstad S, Forsmo S. Is there an association between disease

ignorance and self-rated health? The HUNT Study, a cross-sectional survey. BMJ Open.
2014;28:4:e004962.
My recommendations for Ms C

• Given absence of benefit of treatment for TSH <10

and harm of inadvertent over treatment favor
treating only if ~ yearly TSH >10 or low free T4
• If Ms C prefers Rx, would start at 25-50 mcg to
avoid risk of overtreatment
• If treating, would monitor weight and other sx and
consider d/c if no affect in 6-12 months
 We would like to thank…

Our Patient, Ms C
Pamela Hartzband, MD & Carol Bates, MD

Howard Libman, MD
Risa Burns, MD, MPH
Eileen Reynolds, MD
Deborah Cotton, MD, MPH
Gerald Smetana, MD
Last Minute Productions
BIDMC Media Services
Lizzie Williamson
 © 2016 American College of Physicians

The information contained herein should never be

used as a substitute for clinical judgment.