Understanding Common Thyroid Disorders Douglas C. Bauer, MD UCSF - - PDF document

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Understanding Common Thyroid Disorders

Douglas C. Bauer, MD UCSF Division of General Internal Medicine dbauer@psg.ucsf.edu No Disclosures

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

• 45 yr old female, enlarged thyroid with

dominant nodule since 1999, FNA

• benign. On T4 suppression ever since,

TSH=0.1

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Topics Covered

• Rational use of thyroid tests
• Subclinical thyroid disease
• Other common thyroid problems
• Screening and when to refer…

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Thyroid Tests: sTSH

• Excellent correlation with TRH stimulation

(sTSH < 0.1)

• Requires intact pituitary-hypothalamic axis;

4-6 weeks to equilibrate

• Falsely low: B vitamin biotin, severe illness,

corticosteroids, dopamine

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

TSH Levels and Age

• TSH is higher in elderly: Normal or not?
• NHANEs: >13,000 people 12 to 80+ years

–Exclude anyone with known thyroid disease

• r drugs that could effect TSH
• 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

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Thyroid Tests: Free Thyroxine

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

pregnant); $64

Are Both sTSH and Free T4 Necessary?

• American Thyroid Association says “Yes”
• Simultaneous ordering common
• Among outpatients without CNS surgery:

–If TSH normal, T4 and T3 will be normal –If TSH low or high, many will have normal T4 and T3…

Bauer, Archives Intern Med 2003

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“High Value” Thyroid Testing Strategy

In outpatients without suspicion of disrupted pituitary-thyroid axis:

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

Subclinical Thyroid Disease

• Subclinical hypothyroidism

“Abnormally high sensitive TSH and normal thyroid hormone levels”

• Subclinical hyperthyroidism

“Abnormally low sensitive TSH and normal thyroid hormone levels”

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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 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

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Hypothyroidism: Etiology

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

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Billewicz Index*

Symptom/Sign Present Absent Bradykinesia +11

• 3

Cold interance +4

• 5

Coarse skin +7

• 7

Pulse <75 +4

• 4

Delayed AJ +15

• 6

*hypothyroid if > 30

Overt Hypothyroidism in the Elderly

• “Classic” features often missing
• Neuropsychiatric complaints common:

depression, weakness, memory loss

• Other clues: hypercholesterolemia,

elevated CK, pleural effusion

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Subclinical Hypothyroidism: Prevalence

• Population based prevalence of elevated TSH:

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%

Subclinical Hypothyroidism: Symptoms

???

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

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

• CV disease:

–Increased risk of of CHD, heart failure in some older observational studies –Small trials show no effects on lipids, EF

• 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

22

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Meta-Analysis: Subclinical Hypothyroidism and CV Events and Mortality

• Individual level pooled data

–14 prospective cohorts (N=42,000 adults)

• 6% had subclinical hypothyroidism
• CHD and heart failure events:

–Trend toward more events if TSH 7-10 –Two-fold increase if TSH>10

• Similar trends for CVD mortality…

Rodondi, Jama 2010 Gencer, Circulation, 2012

The TRUST Study

• Double blind RCT of 785 untreated adults

>65 from 4 EU countries

–2 or more TSH between 5-20, normal T4

• 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

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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…)

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Hypothyroidism: Treatment

• Replace with levothyroxine (T4)

–T3 + T4 benefit unproven

• Typical replacement dose 1.6 mcg/kg

–>65 or CHD: start lower (25-50 mcg/d) –Bedtime dosing equivalent

• Maintain TSH within the normal range

–Some data that TSH=1.0-2.5 optimal

–Wait 6 weeks after dose change

• Yearly TSH (compliance, T4 clearance)

Pregnancy and Thyroid Dysfunction

• Normal TSH during pregnancy: 1st 0.1-2.5; 2nd 0.2-

3.5: 3rd 0.3-3.0

• Thyroid replacement dose increases 30-50% (check

monthly in first trimester)

• Subclinical hypo (not hyper) associated with

pregnancy loss and neurodevelopmental deficits

–Maybe also be true for positive TPO

• Treatment indications unclear

–Large NIH trial neg negative. Yes if TPO positive?

Chan, Clin Endo 2014; Casey NEJM March 2017

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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

• TSH secreting tumors (rare)

Hyperthyroidism: Prevalence

• Population based prevalence of

suppressed TSH: Author age men women Bagchi >55 1.8% 2.7% Falkenberg >60 1.9% Parle >60 5.5 6.3% Bauer >55 5.8%

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Crook’s Index*

Symptom/Sign Present Absent Palpitation +2 Cold prefer. +5 Hyperkinetic +4

• 2

Weight loss +3 Lid lag +1

*hyperthyroid if 10 or more

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Overt Hyperthyroidism in the Elderly

• Weight loss, palpitations, and

nervousness less common

• Tachycardia, exophthalmos,

tremor less common

• Atrial fibrillation more common
• 8-10% are asymptomatic

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

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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 (higher 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

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Hyperthyroidism: Who Should Be Treated?

• Exogenous (iatrogenic)

–Dose reduction unless contraindicated

• Endogenous-subclinical

–Repeat and follow if uncomplicated –Consider treatment (as if overt) when TSH<0.1 in setting of atrial fibrillation or

• steoporosis. No trials.
• Endogenous-overt

–Rule out thyroiditis. They get beta blocker –Everyone else gets beta blocker and...

Hyperthyroidism: Treatment

• Anti-thyroid drugs (PTU and methimazole)

–Remission: 30-50% after 12-18 mo –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%), worsening exophthalmous (steroids prevent), fetal hypothyroidism

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Thyroid Nodules: Epidemiology and Evaluation

• Nodules are common (cancer is rare, but

incidence is increasing in US) –90% women over age 60 have one or more thyroid nodules at autopsy –Common on neck imaging for other reasons

• Risk factors for cancer: neck irritation, FH
• Evaluation: TSH, sono, +/- FNA

–75% benign, 20% suspicious, 5% malignant –Best centers: false negative 2% false positive 1%

Thyroid Nodules: Treatment

• Cancer
• Histology is important (papillary best)
• Surgery +/- 131I ablation
• T4 suppression? If yes, TSH goal 0.1-0.4
• Benign nodules
• 15% grow, 18% shrink spontaneously
• T4 suppression has little effect
• T4 doesn’t prevent new nodules

Durante, Jama 2015

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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 ($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.

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When to Refer to a Specialist? When Thyroid Tests are Confusing or…

• Hypothyroidism

–Pregnant women –Unstable CV disease –Possible hypothalamic-pituitary etiology

• Hyperthyroidism

–Overt disease (particularly thyroid storm) –Possible hypothalamic-pituitary etiology

• Nodules/Goiter

–Malignant or non-diagnostic FNA –Surgery required

Summary Take Home Points

• sTSH is best test in most patients
• Subclinical thyroid disease is common and

associated with morbidity

• Treatment of subclinical hypo does not

improve symptoms in patients >65. Tx if TSH>10, but CV benefits unproven…

• Treatment for subclinical hyper unclear.

Consider if TSH<0.1 plus a fib or fractures

• Screening with sTSH may be cost-effective

(but is not recommended)

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Cases

• 66 yr old female with 1 yr of fatigue and

lassitude and no findings except TSH=9.0, 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

• 45 yr old female, enlarged thyroid with

dominant nodule since 2010, FNA benign. On T4 suppression ever since, TSH=0.1