SUBCLINICAL THYROID DYSFUNCTION:A CONUNDRUM

T. Cook FRCPC

Nov 2006

COMMON THYROID PROBLEMS in AMBULATORY IMED

STRUCTURAL Enlargement (goitre)

Diffuse Nodular (multiple vs

solitary)

Nodule Benign Malignant

FUNCTIONAL Hyper Hypo

GRAVE’S EXTRA-GLANDULAR Ophthalmopathy Dermopathy Osteopathy

CASES

A) 67 yo woman presents with palpitations, is found to be in atrial fibrillation. On exam noted to have a goiter, which is long-standing. Echo is normal. The sTSH is <.05 mU/L and T3 & T4 are normal.

1. What is this called & how common is it?

SUBCLINICAL HYPERTHYROIDISM

UK study, 1210 consecutive pts >60, single general practice, NOT on T4

16 (.13) had suppressed TSH Followed for 1 y only 1 developed thyrotoxicosis However, higher progression if MNG (5%) or if

on amiodarone Most studies show prevalence 0.1 – 1%

2) What are the common causes of it?

Same as for thyrotoxicosis

MNG (older age, iodine exposure incl amio) Subacute Thyroiditis Grave’s Disease “Hashitoxicosis” Exogenous T4 (this may be commonest!) Hyperfunctioning “toxic”Adenoma

3) How do you distinguish these?

Clinically History PE

Labs Imaging

DIAGNOSIS Hx

Meds (Li, amio) Goitrogens (cruciferous

veg, dulce) Autoimmune disease

(Type I DM, vitiligo, PA, myasthenia, Addison’s)

PE Diffuse goitre Ophthalmopathy Pretibial myxedema

LABS Free T3 (MNG) Thyrotropin receptor

Ab (absent 5-20% Grave’s)

IMAGING Structure (U/S, Scan) Function (RAI Uptake)

– best to distinguish Grave’s vs thyroiditis

This would be hard to miss!

Nuclear Scans

Cold Nodule Hot Nodule

Ultrasound of a “Complex” Nodule

4) What is the natural history of this problem?

Risk of chronic TSH suppression (<0.1)

What’s the evidence for: Atrial Fibrillation Other cardiac effects (Tachycardia, LVH,

Diastolic dysfunction, reduced exercise capacity)

Osteoporosis Alzheimer’s Dementia

Risk of progression to frank hyperthyroidism

- Esp in MNG

A.FIB

Framingham study Cohort 2007 >60 followed for 10 yrs AF development compared with initial TSH Of 61 < 0.1, AF in 13 RR = 3.1 NNT over 10 y = 4.2

TSH of 0.1 – 0.4 not a risk for AF AF (non-valvular) with thyrotoxicosis

increases risk of embolism

“Subclinical Thyroid Dysfunction as a Risk Factor for Cardiovasc. Disease”

Busselton Health Study, Australia Large longitudinal study 1981 – 2001! No increased risk in subclinical hyperT

OSTEOPOROSIS

2 cross-sectional studies of MNG and subclinical hyperT showed signif lower BMD than age-matched controls, esp femoral neck

Does TSH itself mediate bone remodeling (receptors found on osteoblasts / clasts), Arch Med Research, May 2006

Post-menopausal women with subclinical hyperT have 2% loss of BMD / y

OTHER

Cardiac changes statistically demonstrated but clinically significant??

Increased AD (one study of >55 yo with anti-thyroid peroxidase and suppressed TSH but recent study in Annals -> no incr risk)

5) Should subclinical hyperthyroidism be treated? And if so how?

DEPENDS!

DEFINITELY MNG, toxic adenoma or Grave’s

Esp if assoc with AF / osteoporosis etc

PROBABLY AF / osteoporosis and other cause

TREAT WITH?

RAI – MNG / Grave’s PTU or methimazole – Grave’s Treatment of thyroiditis controversial

Wait and see! RAI OR

SUBCLINICAL HYPOTHYROIDISM

B) Case59 yo woman has sTSH = 7 on routine

screening. Only symptoms are mild fatigue, present for > 10 yrs, and difficulty losing weight. Exam normal except for a small firm thyroid with a slightly irregular surface. Total T4 is normal but TC = 5.69 mmol/L and LDL = 3.62. Anti thyroid peroxidase is pos.

1) How common is this scenario?

DEPENDS! WHAT’S YOUR DEF’N OF UPPER NORMAL TSH ?

“The Evidence for a Narrower Thyrotropin Reference Range is Compelling”, J.Clin. Endo & Metab, 2005 Sept

Prev reference pop’n “contaminated” by individuals with thyroid dysfunction (esp Hashimotos)

Nat’l Academy Clin. Biochem: >95% normals have TSH < 2.5 (African-Americans’ v. low rates of Hashimoto’s have mean TSH 1.18 = true pop’n mean?)

PREVALENCE (if using < 5)

1-10% worldwide Up to 20% in women > 60 16% in one study of men > 74 75% have TSH in 5-10 range 50-80% positive anti thyroperoxidase RR of goitre = 2

INCREASED RISK

Treated hyperthyroidism Neck irradiation Postpartum thyroiditis Autoimmune diathesis (esp Type 1 DM) Meds: Amiodarone, lithium, interferon alfa

2) What is the natural history / consequences?

POTENTIAL RISKS

Progression to overt hypothyroidism “Whickham survey” – 2800 randomly

selected adults 1972-1992 If baseline TSH high AND Ab +

4.3% /y RR=38! If either TSH up OR Ab +

2.6%/y

NNT range 4.3 – 14.3

DYSLIPIDEMIA

Meta-analysis of effect of Rx for subclinical HypoT on lipids Mean TC reduction 0.2 mmol/L Mean LDL reduction 0.26 “

Risk of CAD and vascular death Data conflicting, probably increased Busselton Health Study – Australia

OR 1.8 (1.0 – 3.1)

SYMPTOMS, MOOD, COGNITION, BMD

Several studies show more symptom prevalence in this population

3 prospective RPCT of Rx for subclinical hypoT 2 reported signif improvements in QOL (in up to 28% of those

treated) NNT ~ 4 If ovulatory dysfunction and infertility present Rx shown

to be helpful BMD signif reduced in women with subclinical hypoT

(Archives of Med Research, 2006 May)

3) Should subclinical hypoT be treated?

PROBABLY… BUT STILL CONTROVERSIAL!

“Society” Consensus guidelines: Amer. Assoc. Clin. Endo, The Endo Society, Amer. Thyroid Assoc. actually CONFLICT with USPSTF (US Preventive Services Task Force)

Routine screening gen pop’n? YES NO Routine screening preg women? YES YES Routine Rx pts with TSH 4.5-10? YES NO

Generally No Rx recommended IF Thyroid Ab Negative AND TSH < 10 AND No symptoms, goiter, dyslipidemia, pregnancy or ovulatory

dysfunction / infertility BUT annual TSH recommended

REFERENCES NEJM REVIEW ARTICLES

Vol 345, No 4 July 26, 2001 Vol 345, No 7 Aug 16, 2001

“Effects of Subclinical Thyroid Dysfunction on the Heart” Ann Intern Med 2002;137; 904-914

“Subclinical thyroid disease: scientific review and guidelines for diagnosis and management”, JAMA. 291(2):228-38, 2004 Jan 14

“Screening for subclinical thyroid dysfunction in nonpregnant adults: a summary of the evidence for the U.S. Preventive Services Task Force”,] Annals of Internal Medicine. 140(2):128-41, 2004 Jan 20.

REFERENCES CONT’D

“Subclinical thyroid dysfunction as a risk factor for cardiovascular disease”, Arch Intern Med, 2005 Nov = Busselton health Study

“Relationship between subclinical thyroid dysfunction and femoral neck BMD in women”, Arch Med Research, 2006 May