12/16/2008

Who should be treated?

A: 76-year-old woman with L-spine T score -3.0 SD.
FT3 2.6 (1.6-4.0) pg/ml, TSH 0.2 (0.3-4.1) mIU/l.

Subclinical hyperthyroidism

..

Definition of

Subclinical hyperthyroidism
Persistently suppressed serum TSH
with
normal FT3 and FT4 concentration.
Third-generation assays: functional
sensitivity of 0.01-0.02 mIU/l.
Normal range : 0.3-4.1 mIU/l.
Pagi G. Am J Med 2005,118:349-61.
Biondi B. and Cooper D. Endocrine Rev 2008,29:76-131.

Glucocorticoid

B: 45-year-old man with septic shock was

received dopamine 4 g/kg/min, developed AF.
FT3 1.6(1.6-4.0) pg/ml, TSH 0.04(0.3-4.1) mIU/l.
C: 56-year-old woman was received cordarone for
AF for 3 months.
FT3 3.2 (1.6-4.0) pg/ml, TSH 0.02(0.3-4.1) mIU/l.

Differential diagnosis
Nonthyroidal illness
Clue !!
Detectable serum TSH ( >0.1 mIU/l)
Serum FT4 low normal
u FT3
3 dec
eased
Se
Serum
decreased

Drugs

Dopamine
Dobutamine
High dose glucocorticoids
Iodinated contrast media or excessive
iodine exposure
Somatostatin analogue
Bromocriptine
Pagi G. Am J Med 2005,118:349-61.
Biondi B. and Cooper D. Endocrine Rev 2008,29:76-131.

Dopamine

Normal range (0.5-4 ) mIU/L

No hydrocortisone
hydrocortisone
0.5 mg/kg/d

Infusion 5 micrograms/kg/min.
Suppressed axis in 24 hours (15-21 hours).
Recovery within 24 hours,
hours even prolonged
infusion (83-296 hours).

hydrocortisone
2 mg/kg/d
Time (am)
Serum TSH levels (mean + SE) in 12 patients
with Addisons disease.
Hangaard J.JCEM 1996.
Functional assay 0.5 mIU/L.

Berghe V. Clin Endcrinol(Oxf)1994.

12/16/2008

Candidate for treatment of

Conditions /diseases

subclinical hyperthyroidism

Pregnancy
Trophoblastic disease

STEP 1 - Detailed medical history and detail

clinical evaluation.
STEP 2 - Repeat
p
measurement.

Psychiatric illness
Subacute, silent or postpartum thyroiditis
Pituitary or hypothalamic insufficiency
Delayed recovery of thyrotroph after treatment
of hyperthyroidism

4-6 months

Pagi G. Am J Med 2005.

2,4,6 months

Biondi B. and Cooper D.

Endocrine Rev 2008.

4 weeks for pateints with serum TSH <0.1mIU/L

2 weeks for patients with AF, cardiac disease

ATA/AACE /ECS conference

in 2002, JAMA 2004.

STEP 3 - Risk vs Benefit.

Biondi B. and Cooper D. Endocrine Rev 2008,29:76-131.

Subclinical thyrotoxicosis
TSH

Endogenous causes
Exogenous causes

- FT3
- FT4

mIU/L

Tissue thyrotoxicosis

0.4
0.3
0.2
01
0.1
0

Low but detectable TSH

Undetectable TSH
20

30

40

50

60

70

age

80

years

HR

PAC

AF

Cardiovascular
mortality

Cardiomyopathy

LVH
Osteopenia
Osteoporosis

Natural history of
Subclinical Hyperthyroidism

Endogenous causes
Graves disease
Autonomously functioning thyroid adenoma
Multinodular goiter

Progression
g
to overt hyperthyroidism??
yp
y

Parle JV.
1991

- more common
Excessive thyroid hormone replacement therapy
Intentional thyroid hormone suppressive therapy

Age(y)

F/U
(y)

>60

50 0.1
0.1--0.5

TSH (mIU/l)

Reverse to
euthyroid

Subclinical
hyperthyroid

Overt
hyperthyroid

38(76%)

12(24%)

1(6%)

16 <0.1

Graves
35-82(55)
disease by TSI

MNG

Exogenous causes

Fracture

1-3 7

34-74(61)

14(88%)

1(6%)

<0.03-0.09 5 (70%)
3-19
3 19 mo

0.11-0.25

9(100%)

Woeber KA. Thyroid 2005.

Graves
disease by
TRAb

35-59(48)

Nodular
disease

50-63(56)

15 <0.1

2(13%)

7(46%)

16(40%)

30 <0.1

6(20%)

18(59%)

6(20%)

10 % per year
TSI = thyroid-stimulating immunoglobulin
TRAb = anti-TSH receptor antibody

Rosario PW. Clin Endocrinol.2008.

12/16/2008

Progression to overt hyperthyroidism

Autonomously functioning thyroid adenoma
18 % developed overt hyperthyroidism.
4.1 % per year.
Age,
Age sex
sex, nodular size not predict
progression.
After iodine excess, 31% developed overt
hyperthyroidism.

Acta Endocrinol (Copenh)1993.

Quality of Evidence on the

Strength of Association and Benefits of Treatment

Good

Transient subclinical thyrotoxicosis after

treatment of

Graves disease

The remission rate 61.8%

In remission group, 41.2% experienced transient thyrotoxicosis
Overt thyrotoxicosis 11.8%
Subclinical thyrotoxicosis 30% (18% of all patients)
The duration of the transient
thyrotoxicosis was 7 months.
No different in age, FT4, TSH and
TBII between transient
thyrotoxicosis groups and recurrent
groups.

TSH

FT4

TBII

time from drug withdrawal

Kubota S. Thyroid 2008.

Coronary heart disease

:Meta-analysis

Good

Good

Insufficeint
Insufficeint

RR = 1.21 (CI, 0.88 to 1.68)

ATA/AACE /ECS conference in 2002, JAMA 2004.

Ochs N. Ann Intern Med. 2008.
Rodondi N. J Am Coll Cardiol. 2008.
Cappola A. JAMA 2006.
Bauer D. Ann Intern Med. 2001.
Faber J. Clin Endo 1998.

Cardiovascular mortality
:Meta-analysis

RR = 1.19 (CI, 0.81 to 1.76)

Ann Intern Med. 2008;148:832-845.

Total mortality
:Meta-analysis

RR 1.12 (CI, 0.89 to 1.42)

Ann Intern Med. 2008;148:832-845.

Ann Intern Med. 2008;148:832-845.

12/16/2008

Artrial fibrillation
The Cardiovascular Health Study

Congestive heart failure

65-years age at 1989 -1990 and 13th years F/U

Adjusted RR 1.98 (1.29-3.03)
for subclinical hyperthyroidism
Adjusted RR 1.85
for TSH 0.1-0.44 mIU/l

67 per 1000-person-year
31 per 1000-person-year

Adjusted for age, gender, race, clinical cardiovascular disease at baseline, AF at

baseline, alcohol use, smoking status, diabetes mellitus, hypertension, body mass
index, LDL cholesterol, HDL cholesterol, and creatinine

Single time-point may developed overt hyperthyroid

Cappola A. JAMA 2006

J Am Coll Cardiol 2008;52:11529.

Cardiovascular effects
Increased heart rate
Increased premature atrial contraction
Increase atrial fibrillation

Holter monitoring
N= 10
Median age 59 years, TSH 0.05-0.07 mIU/L.
MMI mean dose 12.5 mg/d to achieve 6 months of euthyroid.

No studies report increased arterial

emboism

Increased left ventricular mass index

Increase diastolic time
Reduce exercise capacity

No AF in any subjects.

Biondi B. and Cooper D. Endocrine Rev 2008,29:76-131.

Sgarbi A. JCEM 2003.

Haemodynamic parameters

Left ventricular mass

index
Control
79.1 (50.692.3) (g/m2)
Before Rx
89.7 (65.8105.6) (g/m2)
After euthyroid 71.4 (58.390.8) (g/m2)

But all groups were in normal

range at baseline

LVMi, Left ventricular mass index.

LVPWT, Left ventricular posterior wall thickness.
IVST, Interventricular septum thickness.
Sgarbi A. JCEM 2003.

Multinodular goiter 6 patients.

Mean age 64 years.
Baseline TSH 0.027 (0.006-0.09 mIU/L).
I-131 for relieve compressive symptom ( 296-740 MBq)

Heart rate (bpm)

Cardiac output (l/min)
Cardiac index (l/min/m2)
Mean arterialpressure (mmHg)
Systemic vascular
resistant(dyn*s*cm2)

Subclinicalhyperthyroid(n=6)
Before
After
%
f
f
treatment
treatment Reduction
748
668**
11
6.932.15
5.581.94*
19
4.051.34 3.231.22**
%
96.94.0
98.97.4 Increase
1223400

1585594**

**P <0:02; values before compared with values after treatment.

30

Faber J. EJE 2001.

12/16/2008

Fracture

Sketetal system

The Study of Osteoporotic fracture

9,704 white, post-menopausal women
Age 65 years ( 71 years)

Good

Good

Adjusted RR
(95% CI)

Good

Insufficeint
Insufficeint

Premenopause

No effect on BMD, increased bone marker

Postmenopause

Reduced BMD at forearm, hip, spine

Hip fracture

1.9(0.7-4.8)

3.2 (0.9-11.6)

Vertebral fracture

2.8(1-8.5)

4.1(1.2-14.3) *

Non-spine fracture

2(0.9-4.5)

2.2 (0.8-6.6)

Bauer D. Ann Intern Med. 2001.

Prevent bone loss

Prevent bone loss

28 Toxic multinodular goiter, postmenopausal patients.

12 patients received RAI median 555(185-3700) mBq.
Age 52-68 years, TSH <0.01-0.127 mIU/l.
No data on T nor Z-score.

Hip BMD
(% of baseline
values)

Before
-RAI(16) 100
+ RAI(12) 100
-RAI

100

+RAI

100

One year
97.3*
97.3*
(87.6-102.9)
(87 6 102 9)
101.9**
101.9
(97.1-106.1)
94.8**
94.8
(91.8-99.7)
102.3**
102.3
(97.8-106.3)

TSH <0.1
mIU/l
IU/l

Adjusted by previous hyperthyroidism, use of thyroid

hormone, age , current estrogen use and body weight

ATA/AACE /ECS conference in 2002, JAMA 2004.

Bauer D. Ann Intern Med. 2001.
Faber J. Clin Endo 1998.

Spine BMD
(% off b
baseline
li
values)

TSH 0.1-0.5
mIU/l
IU/l

Two year
95.5**
95.5
(90.5-100.5)
(90 5 100 5)
101.5**
101.5
(93.0-105.0)
98.0**
98.0
(92.1-98.6) 7)
101.7**
101.7
(100.0-102.8)

20 MNG and Graves disease, 19 premenopausal woman and one man.

Age 36 (24-48) years

Baseline TSH 0.22 mIU/l
No different in baseline BMD compare with 20 normal matched control
10 patients randomly received PTU (150 mg/d) or RAI
Treatment to euthyroid
6 months

Observation 6 months

(g/cm2)

before

After

before

After

BMD femur

0.828 0.038

0.826 0.042

0.848 0.017

0.868 0.019

BMD
Lumbar spine

0.991 0.046

0.998 0.048

0.968 0.030

0.968 0.031

Prevent spine BMD loss 2 % per years

Hip BMD increased at 1-year but not 2-year
* P<0.005 compare baseline, * P<0.02 compare RAI.

Yonem O. Endocrine J 2002.

Faber J. Clin Endo 1998.

Management
Follow-up

Young, asymptomatic pt with TSH > 0.1 mIU/l.

Grey zone

Management

Young, symptomatic pt with TSH < 0.1 mIU/l.

Older than 60 years with TSH > 0.1 mIu/l.
Cardiovascular evaluation : EKG , Holter EKG
,echocardiogram for LVH and diastolic function.
BMD evaluation.
Treatment
Older than 60 years with TSH < 0.1 mIU/l.
With or increase risk of heart disease, osteopenia or
osteoporosis.
Symptom of hyperthyroidism.
Endocrine Rev 2008,29:76-131.

12/16/2008

Who should be treated?

TSH
0.1-0.1
Age
(mIU/l)
mIU/l) 0.4
(years)

<0.1

Osteoporosis

Heart
disease,
AF,LVH

Young , prepremenopause

ATD B-blocker,
defenite Rx only in
the presence of
beneficial effect of
antithyroid drugs

Radioiodine Rx
if BMD not
improved after
antiresorptive

Radioiodine
Rx,

Radioiodine Rx,
consider preRx
with ATD

Radioiodine Rx

>60
Or postpostmenopausal

F/U

F/U
BMD
consider
Rx #

consider
preRx
with ATD

Plus
Large goiter with significant airway compression consider surgery.
AF consider anticoagulant.
Osteoporosis Antiresorptive therapy.

Endocrine Rev 2008,29:76-131.

1.Follow-up

Treatment

Young, asymptomatic pt with TSH > 0.1 mIU/l.

F/U at 3-12 months interval until

normal TSH or clinically safe.
Beware of iodine-containing
iodine containing drugs.
drugs
2. Treatment
Older than 60 years with TSH < 0.1 mIU/l.
With or increase risk of heart disease, osteopenia or
osteoporosis.
Symptom of hyperthyroidism.

I-131 therapy 150 Ci/g of thyroid tissue.

ATA/AACE /ECS conference in 2002, JAMA 2004.
Cooper D.JCEM 2007.

# expert opinion no evidence. JAMA2004.

Screening
3.Grey zone

organization

Young, symptomatic pt with TSH < 0.1 mIU/l.

Older than 60 years with TSH > 0.1 mIu/l.

Antithyroid drugs 3-6 months to

evaluate
l t the
th possible
ibl beneficial
b
fi i l effect
ff t
on QOL, HR, PAC before definite Rx
Low doses MMI 5-15 mg/d,
PTU 50-150 mg/d.

ATA/AACE /ECS conference in 2002 , JAMA 2004.

Guideline

American Thyroid Association (ATA)-1995

No opinion

American Association of Clinical

Endocrinologists(AACE)-2002

Periodic assessment to determine

individual therapeutic options

Royal College of Physicians-1996

No agreement on benefits of
detecting/treating subclinical
hyperthyroidism

American College of Physicians-1998

ATA,AACE,ESC conference-2004

Treat older individuals or patients with

risks(cardiac, postmenopausal if TSH <0.1
(Categoty B)
TSH >0.1 (Category E)

Screening all patients age 65 years

number need to screen to find 1 subclinical hyperthyroidism
with AF = 2,500
Screening patients,age 65 years with AF
Cooper D.JCEM 2007.
number need to screen 35
Cappola A. JAMA 2006.

Who should be treated?

A: 76-year-old woman with L-spine T score -3.0 SD.
FT3 2.6 (1.6-4.0) pg/ml, TSH 0.2 (0.3-4.1) mIU/l.
B: 45-year-old man with septic shock was
received dopamine 4 g/kg/min , developed AF.
FT3 1.6(1.6-4.0) pg/ml, TSH 0.04(0.3-4.1) mIU/l.
C: 56-year-old woman was received cordarone for
AF for 3 months.
FT3 3.2 (1.6-4.0) pg/ml, TSH 0.02(0.3-4.1) mIU/l.