When and who to screen 54 yr old female with new atrial Take home - - PowerPoint PPT Presentation

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Understanding Subclinical Thyroid Dysfunction

Douglas C. Bauer, MD UCSF Departments of Medicine, Epidemiology & Biostatistics San Francisco Coordinating Center

Disclosure of Financial Relationships

I have no relationships with any entity producing, marketing, re-selling, or distributing health care goods or services consumed by, or used on, patients

Cases

• 66 yr old female with 1 yr of fatigue

and lassitude and no findings except TSH=8.2, nl free T4, anti-TPO positive

• 54 yr old female with new atrial

fibrillation and no other findings except TSH=0.04, normal free T4

Topics Covered

• Rational use of thyroid tests
• Subclinical thyroid dysfunction
• When and who to screen
• Take home messages

Page 2 Thyroid Tests: sTSH

• Very sensitive to circulating thyroid hormone levels
• Excellent correlation with TRH stimulation (sTSH < 0.1)
• Requires intact pituitary-hypothalamic axis;

4-6 weeks to equilibrate

• Falsely low: severe illness, corticosteroids, biotin, and

dopamine

• Normal range 0.5-4.4 mU/L (non-pregnant); $58

Normal TSH in NHANEs

• TSH skewed upwards in elderly: Normal or disease?
• NHANEs: >13,000 people 12 to 80+ years

–Exclude anyone with known thyroid disease or drugs that could effect TSH –Median TSH 1.39 mIU/L

• Upper 97.5th Percentile

< 60 around 4.0 mIU/L

60-69 up to 4.3 mIU/L 70-79 up to 5.9 mIU/L 80+ up to 7.5 mIU/L

Surks, JCEM 2007

Thyroid Tests: Free Thyroxine

• Measures unbound hormone
• Has replaced “index” assays
• Gold standard: Equilibrium dialysis
• Other immunoassays: Improving
• Normal range, 9-24 pmol/L (non-

pregnant); $64

Page 3 Are Both sTSH and Free T4 Necessary?

• American Thyroid Association says “Yes”
• Others recommend sTSH first
• Simultaneous ordering common in clinical practice
• UCSF outpatient data (Bauer, Arch IM 2003)

– Results when both tests ordered on the

same specimen (N=3143) – Each test classified as low, normal or high

Bauer, Archives Intern Med 2003

Diagnostic Redundancy of sTSH and Free T4

sTSH (mIU/L) < 0.5 0.5 – 5 > 5.5 < 9 4 16 49 9 - 24 536 2024 309 > 24 174 30 1 Free T4 (pmol/L) Subclinical (“Mild”) Thyroid Disease

• Subclinical hypothyroidism

“Abnormally high sensitive TSH and normal thyroid hormone levels”

• Subclinical hyperthyroidism

“Abnormally low sensitive TSH and normal thyroid hormone levels”

Thyroid Antibodies

• Anti-thyroperoxidase, TPO (titer<100, $78)

–Similar to “anti-microsomal” –Most sensitive thyroid autoantibody –Specificity a problem

• TSH receptor antibody (absent, $112)

–Causes Grave’s disease –Rarely found in normal individuals

Page 4 Thyroid Scans

• Technetium 99 ($450)

–Low radiation, quick –Useful for nodules in some circumstances –Useful to determine cause of hyperthyroidism

• High uptake: Grave’s, toxic nodule
• Low uptake: thyroiditis, thyroxine use

“High Value” Thyroid Testing Strategy

In outpatients without suspicion of disrupted pituitary-thyroid axis:

– When sTSH is normal, STOP – When sTSH is low, measure T4 (consider T3 if T4 is normal) – When sTSH is high, measure T4 (consider TPO antibodies)

Subclinical Hypothyroidism: Etiology

• Autoimmune (Hashimoto’s)
• Iodine deficiency
• Iatrogenic
• A. Radioiodine/ surgery
• B. Drugs (lithium, amiodarone)

Subclinical Hypothyroidism: Prevalence

• Population based studies:

Author Age Men Women Tunbridge >65 6.0% 10.9% Bagchi >55 1.8% 2.7% Parle >60 2.9% 11.6% Bauer >55 5.4%

Page 5 Subclinical Hypothyroidism: Symptoms

???

Multiple studies find “hypothyroid” symptoms are common among those with and without subclinical hypothyroidism

Subclinical Hypothyroidism: A Real Problem or Just a Lab Abnormality?

• CV disease:

–Increased risk of of CHD, heart failure in some older observational studies –No randomized trials

• Neuropsychiatric:

–Increased fatigue and depression in some but not all observational studies –Inconsistent results in 4 small randomized trials

• Cardiovascular

Health Study

• Health, Aging and

Body Composition Study Pisa cohort

• Leiden 85+ Study
• Birmingham Study
• Whickham Survey

HUNT Study Nagasaki Adult Health Study Busselton Health Study

Thyroid Studies Collaboration, 2010-now

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Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and CHD Events and Mortality

• Individual level data (N=42,000 adults) from 14

prospective cohorts

• 6% had subclinical hypothyroidism
• After adjustment higher baseline TSH associated with

greater CVD risk

–TSH = 4.5-6.9 RR = 1.1 (0.8, 1.4)  –TSH = 7.0-9.9 RR = 1.1 (0.9, 1.4) p trend=0.004 –TSH > 10 RR = 2.0 (1.3, 3.2) 

• Results similar for CVD mortality…

Rodondi, Jama 2010

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Meta-Analysis: Prospective Studies of Subclinical Hypothyroidism and Heart Failure Outcomes

• Individual level data (N=25,000 adults) from 6

prospective cohorts

• 8% had subclinical hypothyroidism
• Higher baseline TSH associated with greater risk

–TSH = 4.5-6.9 RR = 1.0 (0.8, 1.3)  –TSH = 7.0-9.9 RR = 1.7 (0.8, 3.2) p trend=0.05 –TSH > 10 RR = 1.9 (1.3, 2.7) 

• No data on ejection fraction…

Gencer, Circulation 2012

The TRUST Study

• Double blind RCT of 785 adults >65 from

4 EU countries

–2 or more TSH between 5-20, normal T4 –Not currently treated

• Randomized to placebo or levothyroxine

(50 mcg/d unless existing heart disease)

• Titrated to normal TSH in T4 group, mock

titration in placebo group

• 1-3 years of follow-up for QOL and neuro-

psychiatric outcomes

Stott, NEJM 2017

TRUST Results

• Baseline TSH=6.4, fell to 3.6 in treated group
• No effect on hypothyroid symptoms,

tiredness or quality-of-life

–Even among those with greater baseline symptoms

• Effect on CVD: RR=0.9, CI 0.5-1.7 (so too

small to reliably assess)

Stott, NEJM 2017

Subclinical Hypothyroidism: Natural History and When to Treat

• If persists >6 mo. spontaneous resolution rare
• Antibodies predict overt hypothyroidism

–3-5%/yr if TPO pos, 1-3%/yr if TPO neg

• When to treat? Associated with CVD, but

no trials that replacement helps…

–Treat if goiter or considering pregnancy –Many treat if +TPO, or TSH>10 –“hypo symptoms” not improved with treatment (most common reason for Rx…)

Page 7 Subclinical Hypothyroidism: Treatment

• Replace with levothyroxine (T4)

–T3 + T4 benefit unproven

• Typical replacement dose 1.6 mcg/kg

–start lower (25-50 mcg/d), gradually increase if needed

• Maintain TSH within the normal range

–Some data that TSH=1.0-2.5 optimal

–Wait 6 weeks after dose change

• Monitor yearly (noncompliance, reduced T4

clearance)

Subclinical Hyperthyroidism: Etiology

• Iatrogenic

–Over replacement (30-50% given rx) –Suppression of CA, goiters, and nodules

• Autoimmune (Grave’s disease)

–Thyroid stimulating autoantibodies

• Autonomous nodule(s)

–Usually T4, occasionally T3

Subclinical Hyperthyroidism: Prevalence

• Population based studies:

Author Age Men Women Bagchi >55 1.8% 2.7% Falkenberg >60 1.9% Parle >60 5.5 6.3% Bauer >55 5.8%

Subclinical Hyperthyroidism: Cardiac Effects

• Shortened systolic time intervals

–Clinical significance uncertain

• Reduced exercise tolerance
• Increased incidence of atrial

fibrillation

–Prospective cohort (N = 2000)

–3-fold increase if sTSH < 0.1

Swain, Jama 1994

Page 8 Subclinical Hyperthyroidism: Skeletal Effects

• Florid hyperthyroidism causes fractures
• Effect on BMD, bone loss controversial
• Thyroid Studies Collaboration meta-analysis
• 13 cohorts, 73k patients
• TSH < 0.1 vs. normal
• 2-fold increase in hip fracture, 60% higher

risk of non-spine fracture

• Little effect on BMD
• Mediated via accelerated bone turnover?

Blum, Jama 2015

Subclinical Hyperthyroidism: Natural History

• Exogenous: Dose and GFR dependent
• Endogenous: Few longitudinal data

–2024 untreated individuals, 7 yr F/U

–1% developed overt hyperthyroidism –TSH normalized in 17% after 2 yr, 36% after 7 years (particularly if TSH between 0.1 and 0.4)

Vadiveloo, JCEM 2011

Subclinical Hyperthyroidism: Who Should Be Treated?

• Exogenous-subclinical

–Dose reduction to normalize TSH unless contraindicated

• Endogenous-subclinical

–Repeat and follow if uncomplicated –Consider treatment when TSH<0.1 in setting of atrial fibrillation or osteoporosis. No trials.

Subclinical Hyperthyroidism: Treatment

• Anti-thyroid drugs (PTU and methimazole)

–Remission: 30-50% after 12-18 mo if Grave’s –Side effects: rash, fever, arthritis, cytopenias (all rare). Use PTU in 1st trimester

• Radioiodine

–Best treatment for hot nodules –Remission: everyone –Side effects: transient thyroiditis (rare), hypothyroid (50%), fetal hypothyroidism

Page 9 Screening Cost-effectiveness

• Danese and Sawin, Jama 1995

– Cost-utility analysis, sTSH-based screening – Modeled progression, symptoms and CAD – Screening every 5 year from 35-65: $9,223 per QALY in women $22,595 per QALY in men – Sensitivity analysis: cost of TSH key (used $25)

Screening for Subclinical Thyroid Disease

• American Collage of Physicians, 1998

“…reasonable to screen women older than 50 years

• f age for unsuspected but symptomatic thyroid

disease.”

• American Thyroid Association, 2000

“…all adults starting at age 35 and repeated every 5 years.”

• US Preventive Task Force, 2015

“…the current evidence is insufficient to assess the balance of benefits and harms of screening for thyroid dysfunction in nonpregnant asymptomatic adults.

Subclinical Thyroid Dysfunction: Summary Take Home Points

• sTSH is adequate initial test in most outpatients
• Subclinical thyroid dysfunction is common and

associated with morbidity

• Treatment of subclinical hypo is easy but,

–Does not improve symptoms in patients >65 –Tx if TSH>10, but CV benefits unproven…

• When to treat subclinical hyper unclear.

Consider if TSH<0.1 plus a fib or fractures

• Screening with sTSH every 5 yr may be cost-

effective (but is not currently recommended) Additional References

Garber JR, et al. American Thyroid Association Taskforce on Hypothyroidism in Adults. Clinical practice guidelines for hypothyroidism in adults. Endocr Pract. 2012 Nov-Dec;18(6):988- 1028. Biondi B, Wartofsky L. Treatment with thyroid hormone. Endocr

• Rev. 2014 Jun;35(3):433-512.

Cooper DS, Biondi B. Subclinical thyroid disease. Lancet. 2012 Mar 24;379(9821):1142-54. Rugge JB et al. Screening and treatment of thyroid dysfunction: an evidence review for the US Preventive Services Task Force. Ann Intern Med. 2015 Jan 6;162(1):35-45.