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10th Asia and Oceania Thyroid Association Congress
October 24, 2012
Discovery Kartika Plaza Hotel, Bali, Indonesia
Practical Approaches to Regional Needs in Thyroidology
Symposium 9: Subclinical thyroid dysfunction
Subclinical hypothyroidism
○Koshi Hashimoto, Masanobu Yamada and Masatomo Mori
Department of Medicine and Molecular Science
Gunma University Graduate School of Medicine
Maebashi, Gunma, Japan
normal
Subclinical
hypothyroidism
low
Serum TSH
high
Subclinical hypothyroidism
Subclinical
thyrotoxicosis
low
normal
Free T4
high
Dyslipidemia in subclinical
hypothyroidism is controversial
Lancet. 2012 379:1142-1154.
J Clin Endocrinol Metab. 2012 97:326-333
J Clin Endocrinol Metab. 2012 97:326-333
In consistent findings regarding lipid metabolism in SCH could be due to…
1) Lack of large-scale clinical studies
2) Inconsistent exclusion criteria that may include patients treated
with medications for dyslipidemia
3) Variation in blood drawing time
Background of the current study
7494 participants in a complete medical check-up
in Gunma prefecture, Japan
including 4756 males and
2738 females
Exclusion criteria
We have excluded …
242 males, 92 females under medication for dyslipidemia
38 males, 59 females under medication for thyroid disease
32 males, 21 males administered glucocorticoid,
and those who have a past history of thyroid disorders, liver
cirrhosis or collagen disease.
The mean age of the participants was 48 years old
in both male and female
4756 males (6939)
Mean age (48±9 years-old）
male
female
2738 female (4290)
Mean age (48±9 years-old)
Age
Q
What percent of the participants have SCH?
7
(0.09 %)
normal
0
4
(0.05 %)
6979
(94.2 %
)
2
(0.02 %)
low
Serum TSH
high
Thyroid status of 7403 participants （4726 males, 2677 females）
0
94
(1.2 %)
19
(0.2 %)
low
normal
high
Free T4
normal
4
(0.15 %)
2
(0.07 %)
low
Serum TSH
high
Thyroid status of 2677 females
0
low
6% of females
156
have SCH ! 0
(5.8 %)
2476
(92.5 %
)
28
(1.0 %)
normal
Free T4
0
10
(0.04 %)
high
Prevalence of SCH in each decade of life
20
18
About
20% of females over
16
14
70
years old have SCH !
12
10
Male
Female
男性
女性
8
6
4
2
0
21-30
31-40
41-50
51-60
61-70
71-
Age
About 15% of males over 74 years old have SCH in the US
Q
Is SCH more prevalent with age due to
a decrease in thyroid hormone levels?
Serum TSH levels increase after the age of 30
TSH
Male
Age
TSH
Female
Age
Free T4 levels decrease with age
freeT4
Male
男性
freeT4
Female
女性
The elevation in serum TSH levels with
age is attributed to the concurrent
decrease in T4 levels
Age
Age
Q
Do patients with SCH have elevated serum LDL-C levels?
LDL-C levels are comparable between
euthyroid participants and SCH patients
LDL-C
(mg/dl)
121.4
122.6
Normal：121.4. ± 0.5 mg/dl (mean ± SE)(n=4236)
SCH: 122.6 ± 2.8 mg/dl (n=123)
Not significant
LDL-C levels are significantly elevated in SCH females
LDL-C
(mg/dl)
111.5
mg/dl
125.0
normal：111.5 ± 0.6 mg/dl (mean ± SE)(n = 2286)
SCH: 125.0 ± 2.7 mg/dl (n = 133)
p<0.0001
LDL-C levels and age are significantly correlated,
especially in females
(mg/dl)
(mg/dl)
Male
p<0.05
Female
p<0.001
Age-adjusted LDL-C levels in SCH females
are significantly elevated
LDL-C
(mg/dl)
Mean
SCH
111.9 ± 0.6 mg/dl
normal 119.6 ± 2.5 mg/dl
Age
Q
What happens to serum triglyceride levels in patients
with SCH?
SCH is a risk factor for increased Triglyceride and LDL-C
Q
Are the patients with SCH susceptible
to metabolic syndrome(MetS) ?
Criteria for metabolic syndrome in Japan
Abdominal obesity, given as waist circumference
Male
>=８５ｃｍ
Female
>=９０ｃｍ
Plus any 2 of the following
１）Plasma triglycerides ≥150 mg/dL
HDL cholesterol <40 mg/dL
２）
High blood pressure
(≥140 mm Hg systolic or ≥90 mm Hg diastolic)
３）
Fasting glucose levels >=110 mg/dL
Prevalence of metabolic syndrome (MetS) in each decade of life
25
Prevalence
of MetS is
20
increased with age in
15females!
male
女性
female
男性
10
5
0
21-30
31-40
41-50
51-60
61-70
71-
age
Comparison of SCH and MetS prevalence in each decade of life
SCH and MetS
are
20
18 age in
increased with
SCH
16
females!
14
MetS
25
20
12
(%)
(%)
15
10
8
10
6
5
4
2
0
0
21-30
31-40
41-50
51-60
Male
61-70
71-
21-30
31-40
41-50
51-60
Female
61-70
71-
SCH is significantly correlated to MetS in females
Summary (1)
1. The prevalence of SCH is about 6 % in middle aged Japanese women and it increases with age.
2. This increase may be due to lowered thyroid hormone
levels with age.
3. SCH increases not only serum LDL-c levels but also
TG levels particularly in women and may be involved
with metabolic syndrome.
Subclinical primary hypothyroidism
TRH
+
TSH
Thyroid gland is
- SCH.
impaired in
+
-
+
T4
T3
Central hypothyroidism
+
TRH
+
-
or
TSH
-
+
T4
T3
‘Subclinical Central hypothyroidism(SCCH)’
In SCCH, hypothalamus
and/or
TRHpituitary should be
impaired
+
-
+
TSH
-
+
T4
T3
Profile of pituitary tumors
No. of
subject
s
Average age
(years,
mean ± SD)
No. of males
(% male)
No. of
microadenomas
Acromegaly
150
47.7±
13.9
70 (46.7%)
53 (37.1%)
Non Functioning
95
52.6 ±
12.8
49（51.6％）
5 (5.3%)
Cushing’s
28
51.9
± 15.6
4（14.3％）
21 (75.0%)
Prolactinomas
18
37.9
± 12.9
7（38.9％）
6 (33.3%)
Rathke's cleft
cyst
9
45.6
± 16.2
3 (33.3%)
2 (22.2%)
total
３００
１３３（４４.
３％）
８７（２９％）
Thyroid status of patients with pituitary tumors
Free T4
Normal
Normal
Group 3
36
12.0 %
Group 1
207
69.0 %
Low
Group 4
11
3.7 %
Group 2
46
15.3 %
47
15.7 %
253
84.3 %
TSH
Low
Total
Serum TSH
Group 2: Normal T4, Low TSH
Free T4
TSH
2
1.8
1.8
1.6
1.6
1.4
1.4
1.2
1.2
1
1
0.8
0.8
0.6
0.6
0.4
0.4
0.2
0
Free T4
0.2
1
Before
After
2
0
1
2
手術前
Before
後
After
0.14
± 0.04 ng/dl
P = 0.009
normal
Subclinical
hypothyroidism
Subclinical
thyrotoxicosis
Subclinical central
Hypothyroidism (SCCH)
low
Serum TSH
high
Some patients with pituitary tumors demonstrate SCCH
low
normal
Free T4
high
Thyroid status of patients with pituitary tumors
Free T4
Normal
Normal
Group 3
36
12.0 %
Group 1
207
69.0 %
Low
Group 4
11
3.7 %
Group 2
46
15.3 %
47
15.7 %
253
84.3 %
TSH
Low
Total
Serum TSH
Group1 : Normal T4 and normal TSH
Free T4
Free T4
TSH
1.6 increased within
Free T4 levels are
1.4
normal range after
the surgery !
6
5
1.2
4
1
3
0.8
0.6
2
0.4
1
0.2
0
0
1
Before
After
2
1
Before
2
After
TRH knockout mouse
Serum T4
TSH biological activity is impaired
in TRH knockout mouse !
TRH
V
A
L
E
Y
Q
V
V
T
I
TRH-R
S R N
Y
Y
S
P
I
Y
L
M
D F G V
F Y V
V P M
I L A
T V L
Y G F I
S F L S S P
N
F
V
Q
E N W F
V V L T
R Y P
L L F C
R I C
MW L
I Y L N
N
L A F
S A I N
L I V
V V A L
P V I
A
M
Y
K
R
N
T
L
I
T V S S R K Q V
M
L
S
S
F
N
Q
L
F C R N S T N V N L N T
K
N
F
N
P
T
F
C
Q
R
I
H
A
P
T
S D P K E N S K T W K N D S
A
F
R
K
E T P K Q K C N C L
D D L E T S F H D S E K I V S Y N L A V S Y N A P K
I
K
K
A
R
S
S
Intracellular
I
T
V
T D T Y L S A T K V S F D D T C L A S E V S F S Q S
TR
TSH
Extracellular
V A R P Q L Q T Q N L E S V T E N E M
V I S C G Y K I
I
G S W V Y G
A
Y
Y
D
I
V
K
S
G
Y
D
C
T
T
S
L
I
I
C
L L V
N L D L
N P L
I T Y
L I I C
G A A V
L Q Y L
L F F W
G L G
G I N
L MC
L V M
I V G N
L D A V
A S S C
Y L S T
I M V
A L S
S I T
F A W
V L V V
A F T
V F I I
V L Y
M
C
I
R
E
N
R
T
T
Y
K
P
I
H M R T
A
I
C
H P I K A Q F L
T3
T3
T3
Α chain
Β chain
conjugation
secretion
T3
TSH
Hypothesis for SCCH with pituitary tumors
TRH
TSH biological activity could be
impaired by the pituitary tumors !
TRH Receptor
Pituitary tumors
Extracellular
V A R P Q L Q T Q N L E S V T E N E M
V
A
V I SC G Y K I S R N
L
I
Y
E
G S WV Y G
A
Y
Y
Y
Y
D
S
Q
I
V
K
P
S
G
V
Y
I
V
D
C
S F L S S P
T
Y
T
T
N
F
S
L
L
I
V
Q
I
I
C
M
E N W F
L L V
N L D L
V V L T
N P L
D F G V
I T Y
L I I C
F Y V
R Y P
L Q Y L
L F F W
L L F C
G A AV
G L G
G I N
R I C
L MC
V PM
MW L
L VM
A S S C
I VG N
L D A V
Y L S T
I Y L N
I L A
L A F
I M V
S A I N
A L S
S I T
F A W
T V L
L I V
V L V V
A F T
V F I I
Y G F I
V V A L
P V I
V L Y
A
M
Y
I
M
C
I
K
N
K
R
R
E
N
T
L
R
K
T
I
V
S
S
R
K
Q
T
V
T
Y
M
K
A
L
P
S
S
I
R
F
H M R T
N
Q
A
S
L
S
F C R N S T N V N L N T
K
N
I
F
N
P
C
F
T
Q
H P I K AQ F L C
R
I
H
A
P
S D P K E N S K TW K N D S T
A
F
R
K
E T P K Q K C N C L
D D L E T S F H D S E K I V S Y N L A V S Y N A P K
Intracellular
I
T
V T D T Y L S A T K V S F D D T C L A S E V S F S Q S
CoA
NcoR
TR
T3 T3
X
Glycosylation
TSH
TSH
TSH
TSH
T3
T3
T3
TSH
βchain
αchain
conjugation
Secretion
T3
T3
T3
T3
normal
Subclinical
hypothyroidism
Subclinical
thyrotoxicosis
low
Serum TSH
high
“Subclinical central hypothyroidism (SCCH)”
low
normal
high
Free T4
10~15 % of the general population have pituitary adenomas
Summary (2)
1) Subclinical central hypothyroidism (SCCH) was found
in about 15% of patients with pituitary tumors.
2) After the removal of pituitary tumors, free T4 levels of
the patients were significantly improved.
3) SCCH in patients with pituitary tumors could
be related to impairment of TRH secretion and
potential biological activity .
Acknowledgment
Gunma University
Department of Medicine and Molecular Science
Tetsurou Satoh
Nobuyuki Shibusawa
Atsushi Ozawa
Sumiyasu Ishii
Takuya Tomaru
Yasuyo Nakajima
Satoshi Yoshino
Emi Ishida
Ryo Taguchi
Akiko Katano-Toki
Takashi Okamura
Department of Neurosurgery
Masahiko Tosaka
Department of Pathology
Jyunko Hirato
Gunma
Tokyo
Toranomon Hospital
Syozo Yamada
National Institute of Genetics
Yumiko Saga
National Institute of Health
Kazuhiko Horiguchi