Endocrinol Japon
1992, 39 (6), 533-538
Generalized Resistance Family: Case Studies
to Thyroid
Hormone(GRTH)
in a
KIYOSHITANAKA*,**, AKIRASUGAWARA*, MAKOTOSAKAMOTO*, TATSUHIDEINOUE*, AYUMIYAWATA*, OSAMUKOSHIMURA*, YOSHIYASU SAKO*, SHIGEKAZU SASAKI**, AKIRASHIMATSU**, HIROTOSHINAKAMURA**, ANDHIROO IMURA** *Departmentof Medicine,ShizuokaGeneralHospital,Shizuoka 420, and **SecondDivision,DepartmentofInternal Medicine, KyotoUniversityFacultyof Medicine,Kyoto606,Japan
Abstract.
A
17-year-old and
familial
man
his
11-year
lacked
the
levels.
Their
Their
peripheral
exogenous
old
signs
Key
words:
of who
sister
(case
TSH
levels of
TSH
Thyroid
level
another
2)
hormone
our
not
Even 2. showed
The
for in
suppressed,
T3 two
hormone
in
markedly
were
7
SRL
diagnosed
and
sence by
Received: May 11, 1992 Accepted: September 18, 1992 Correspondence to: Dr. Kiyoshi TANAKA, Second Division, Department of Internal Medicine, Kyoto University Faculty of Medicine, 54 Shogoin-kawaharacho, Sakyo, Kyoto 606, Japan.
function.
after
did
not
to
have
They hormone
TRH
not
loading.
influenced
fully
by
suppress
GRTH.
10%
the
[3].
In
the
Sera
from
order
to
to
TSH,
RIA
which The
described
the
TSH
were
with
subunit
14700
and
determined
the
Case
evaluation regarding
1:
A
of
alpha
and
of
thyroid
treatment
of
and
that age
to the TSH 1ng was
[5].
Results male
Shizuoka
his
that and
Bone
method
by
measured
assuming
5ƒÊU/ml.
TW2
those
subunit
subunit
seventeen-year-old
Clinic
was
respectively,
of
separato
TSH
by
than
analysed
antibody
The
out
less
presence were
alpha
to
Cases
Thyroid
of
the
28000,
by
the
pre-
ruled be
results
calculated
corresponded
was to
out
[4].
of
The
T3
second
alpha
was
or
specimens
comparable
weights
TSH
T4
rule
gave
ratio
1992)
binding
previously
molecular
533-538,
Amersham). to
non-specific
conventional
tion,
39:
TSH;
autoantibodies
autoantibodies by
Japon
Amerwell
of showing
as
Serum T4 and T3 were measured with commercial radioimmunoassay (RIA) kits. Free T4 and free T3 concentrations were determined with analog-based kits (Amerlex Free T4 and Free T3 kits; Amersham). Serum TSH was measured with immunoradiometric assay (IRMA) kits (Sucrosep;
days
A disease
thyroid
were
(Endocrinol
IRMA.
Methods
thyroid serum
and
described. Graves'
abnormalities.
resistance.
THYROID hormone resistance is a syndrome characterized by the relative insensitivity of the pituitary and other peripheral tissues to thyroid hormone action. Since the initial description by Refetoff in 1967 [1], approximately 200 cases have been reported [2]. In this paper we report familial cases of this syndrome.
of
increased
limits for
thus
their high
normal
is
diagnosis
of
extremely
fact
within
patients
the
evaluation of
administration
identical
(GRTH)
under
the
spite but
were
150ƒÊg
thyroid
methimazole
clinic
hormone
case
to
with
thyrotoxicosis
were
in
treated
visited
thyroid
sister
resistance
been
of
administration.
and
generalized had
symptoms
indices
T3
father
1),
and
plasma
TRH-stimulated their
case
(case
General status his
"Graves'
visited Hospital
and
the for
suggestions disease".
He
534
Table
TANAKA
1.
Thyroid
function
tests
of
case
1 at his
initial
visit
et al.
in
height,
55.2kg
axillary
body
palpable goiter ing moistened the
history
aspects
from
a
with
Thyroid
function
hormone
action
tration
of
and in
75ƒÊg
peripheral
case of
indices
1, before T3
for
7
and
of
after
days
size
as
well
a
TRH
for
7
days.
the
tients'
not
TSH
patient
was
obtained.
clinical TSH
Table
3.
Thyrotropin case 1
and T3 responses
to TRH
loading
2,
in
not
respond
The
data,
shown
obtained
six
appointment.
thyroid
At
hormone
obtained
levels.
from
abnormalities
his
former
in
sella
the
patient in
Table
and
other
and
the
paThe
follow-up set
in
of
could
column his
the
patient's
presence
Table
of
3 are
attending
of
after
time, the
and
data
right
months
In
75ƒÊg
loading.
to
in
per-
of
TRH
that
suppressed
of
were
T3,
lost additional
the initial
indices
(BMR)
to
quite
his
shown
by
of
question
period,
rate
one
not
was
to
As
only
were
was
test
temporarily
consequently
Table
the
lack thyroid
action
influenced
did
A
administration
metabolic
were
1.
of
medication.
for
laboratory
measurement
During
basal
methi-
after
hormone
other
markedly
elevated
us
be
surgery
months
after
to
taking
which
led
few
and
and
no
indices
be
A
before
received
and
history,
thyroid
formed
for alkaline phosphatase respectively.
his
disease,
test
peripheral
Alp and ACE are abbreviations angiotensin converting enzyme,
as
diagnosis.
goiter
of
no in
began
Table
face
Graves'
he
Initial
in the
had disease;
and
in
unusual
Graves'
12.
no
includtaking
On
stopped
age
had
some
His he
normal
initially
after
summarized
of
original
2,
only
at
hormone,
T3
as
appendicitis
atypical
visit,
diagnosed
when
suppression
a He
detail,
patient
hospitalization
are
TSH
in
The
during
findings
thyroid adminis-
father
methimazole. in
acute 2.
his
had
36.8•Ž.
of thyrotoxicosis, finger tremor.
developed
decreased mazole
and of
signs and
when
goiter
treated
weight
noticed.
goiter
fact,
Table
or skin
were
visible
in
temperature
last
high
shown
data
physician.
turcica
No
were
observed
younger
sister
radiographically. Case case
2: 1,
goiter.
She
without
body
weight
loss
at age
7 and
was
or
4,
which
Fig.
1,
sis. On
his initial
visit to our clinic,
the
diagno-
he was 171.7cm
of
suppressed
term
and
her
initial
had
sufficiently.
a
thyroid
hormone
TSH
diffuse
soft
of
thyro-
response Even
Her
lack
in of
hormone of
were
doses
of
her
summarized
measurement
graded
her
and
signs
of her
grown
visit,
abnormalities.
shows
high
had
a
no
are
clearly
of
35.8kg,
had
physical
thyroid
plasma
She
findings
and
after
weight
She
despite
evaluation
On
78/min. width.
loading
the the
full
body
which
suppression
indices
for at
other
Table
and
since
in
laboratory
fore
to take
was
initial
TRH
continued
born
147.2cm,
4cm
toxicosis
girl,
clinic
problems.
rate
goiter,
diagnosed as having Graves' disease based upon a high serum thyroid hormone level. Antithyroid drug treatment with methimazole was initiated, he had
our was
was
pulse
experienced
11-year-old
any
height
Data were obtained from his former attending physician. The patients was under methimazole treatment.
An
visited
TSH levels.
peripheral
performed T3. to after
be-
As
shown
TRH
was 150ƒÊg
in not T3,
GENERALIZED
Table
4.
Thyroid
function
THYROID
HORMONE
RESISTANCE
535
tests of case 2 at her initial visit
Fig. 2.
Effects
of exogenous
T3 administration
prolactin responses to TRH loading legend to Fig. 1 for details.
Fig.
1.
Effects
of
TSH
exogenous
responses
shows
the
TSH
exogenous the
patient's
action
The
ated
by
she
was
years
the
old.
our
clinic
every
any
medication. Family
mother
of
study: the was
patient's not
to
was
was
13.5
six
months
Sera
available.
be
0.96,
sella
years
SD
when
was
She
follow-up
specimen
Interestingly
from the
Discussion
13.5 no visited
without
from
and another sister also showed signs of thyroid function abnormalities which were identical to those of the two patients (Fig. 5).
evalu-
revealed
obtained A
1 as
she
turcica.
for
was
tumor
within
11.4
when
were family.
The
age,
examination her
was
6.55ƒÊU/ml.
bone
[5],
old,
in
Fig. 3. Basal metabolic rate (BMR) before and after T3 administrationin case 2.
observed.
pituitary
her
method
Radiographic findings
was
curve
and
years
in
peripheral
were
calculated
growth
TW2
11.5
of
4)
by
changes
indices
TSH
height,
abnormal
bers
significant
a TSH-producing
patient's
average
affected
concentration
ratio, of
or
prolactin
little
(Fig.
her
subunit/TSH
from
Plasma
other
after
(•Ÿ-•Ÿ)
days.
also No
and
when
indicative
[6].
3)
2).
curve or
100ƒÊg
serum ƒ¿-subunit
0.63ng/ml alpha
7
was
hormone
The
(• -• ),
for
plasma
Each
(•¡-•¡)
3.69ƒÊU/ml.
(Fig.
(Fig.
thyroid
not
to TRH
T3
BMR
T3
on
loading.
before
50ƒÊg
(•ž-•ž)
to
TRH
response of
responded
response
administration
500ƒÊg
TSH
administration 150ƒÊg
T3
to
on plasma in case 2. See
memtheir father
Thyroid hormone resistance is characterized by insufficient tissue response to thyroid hormone. Since an initial description by Refetoff in 1967 [1], approximately 200 cases have been reported [2]. This syndrome is subdivided into three categories, according to the tissues involved, i.e., (1) the generalized
form
in which
both
pituitary
and
536
TANAKA
Fig.
4.
Changes
in
ferritin,
cholesterol
peripheral
glucose-6-phosphatase verting
enzyme
50ƒÊg; •œ-•œ,
indices (Choi),
et al.
of
thyroid
alkaline
dehydrogenase (ACE),
before
(B)
hormone
action
phosphatase (RBC
and
G6PDH)
after
100ƒÊg; •£-----•£,
(A)
and
administration case
the
In
(•¡----•¡,
is
made
our
study,
case
2
hormone
levels,
the
symptoms
of
thyrotoxicosis.
TSH
spite
levels
tion,
even
suppressed
her
unlikely. the
a
TSH
Thus
generalized
2
form
induced state
Assay
can
be thyroid
of
case
no or
fully
interference
diagnosed
of
to
administra-
metabolic
levels.
case
and
response
150ƒÊg,
her
signs measurable
hormone of
in
had
exaggerated
dose
changes
thyroid
the
She an
diagnostic
high
lacked
thyroid
fulfills
little
extremely
patient
with
at
significant
patient [7].
presented
of
Exogenous
a
criteria
In
TRH.
when
above-mentioned
difficulty.
basal
cell con-
2.
(GRTH)
of
serum
blood
angiotensin
in
hormone
as
red
T3
150ƒÊg)
all
such
(Alp),
was as
having
hormone
resist-
ance. The
metabolic
tent
with
did
Fig. 5.
Result of family study. Data from the mother of the affected subjects were not available.
not
serum
respond to
what
response
to
TRH
few
months
nous
a
patient
at
to
the
have
response trial,
that
thyroid
time.
TSH
was
were
not the
not
high. that
The
pituitary less
insensitive
hormone
than
was
we
by
a
exogein
diagnosed
second
attending
inappropriate thyroid most
to
levels
explanation
thyrotrophs
those
TSH
hormone likely
of
negative of
1
TSH
at his former
this
case
plasma
suppressed patient's
TSH
suppressed.
established
because
showed circulating
the performed
suppression
was
form
clearly
be
visit,
However,
from
when
extremely
patient by
of
TRH
data
secretion
would
lack
was
and
hormone.
however, which
initial
generalized
physician
are
his
inconsislevels,
thyroid
expected,
hormone
to and
exogenous
we
also
hormone
loading,
after
thyroid
1 was
thyroid to
Contrary
Therefore,
peripheral tissues are involved, (2) the pituitaryselective form and (3) the peripheral form. Diagnostic criteria from the Ministry of Health and Welfare of Japan are: (1) a metabolic state inconsistent with circulating thyroid hormones, (2) TSH secretion inappropriate for given thyroid hormone levels, (3) insufficient metabolic changes after exogenous administration of thyroid hormone and (4) lack of TSH suppression after exogenous thyroid hormone administration [6]. A diagnosis of generalized resistance to thyroid
state
his
case
case
1
feedback 2,
and
the
GENERALIZED
THYROID
TSH of case 1 patient could be suppressed by extremely high serum thyroid hormone levels. The goal of therapy for generalized resistance to thyroid hormone (GRTH) is to maintain tissue euthyroidism. We assessed that case 1 patient was in a state of "compensated euthyroidism" because of his better than average mental state and growth as well as his normal peripheral indices of thyroid hormone action. Case 2 patient was examined more carefully because of her youth. We concluded that she was also in a state of compensated euthyroidism from her normal growth curve, normal bone age and mental state. Consequently both patients are being followed up without medication. Pituitary insensitivity to T3 does not seem to be restricted to thyrotrophs in these cases. Basal and TRH-stimulated prolactin levels are negatively influenced by T3 in normal subjects. In the two cases we have discussed, the TRH-stimulated PRL levels were little affected by exogenous T3 admi-
HORMONE
nistration,
showing
insensitive
to
The
to
receptor
(TR).
a to
This
point
TR
[11-13]
is
genetic
domain
of
TR ƒÀ to
TR ƒÀ
it
basis. which
in
of
a lvsine of
thyroid
to
potential
resulting
in
[14]
glutamic
was
identified
the
subtypes
resistance problems
of may
of
hormone diagnostic inappropriate
comparison
abnormalities
its
made
[15]. of
understanding
of
10]
binding
cases,
T3
without
a molecular reported
T3
438
subjects.
Careful
[9,
deletion
our
codon
restricted
[16].
the
been
identification
on been
major
In in
occasionally
and
a
been
nuclear
has when
GRTH have
significance
not
also
has
the
product
at
or
affected The
in
gene
mutations
mutation
were
syndrome
recently, A
identified.
acid
this
hypothesis
analyze a few cases
single
were
of
c-erb
possible Recently,
lactotrophs
abnormality
until
as
the
[8].
an
confirmation
in
that
T3
pathogenesis
ascribed
TR
537
RESISTANCE
therapy
clinical
greatly
functional
data
and
facilitate
our
significance
of
TR
[17].
References 1.
Refetoff lial
S,
ble
goiter
target
mone.
Clin
Franklyn
4.
against
onines.
Ann
Houssein
A,
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5.
a and
TSH-ƒÀ
an
vivo
Tanner WA,
ment
of
Height
T,
Skeletal
H,
patients
RH,
c-erb-A
protein
thyroid
hormone.
H
and 2nd
10.
11.
Mar-
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Doppman
Oldfield
mical
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EH,
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ated
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the
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H, is
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a
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generalized
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the
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USA
the
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point
kindred
T,
74:
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the
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Y, of
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1992, 39 (6), 533-538
Generalized Resistance Family: Case Studies
to Thyroid
Hormone(GRTH)
in a
KIYOSHITANAKA*,**, AKIRASUGAWARA*, MAKOTOSAKAMOTO*, TATSUHIDEINOUE*, AYUMIYAWATA*, OSAMUKOSHIMURA*, YOSHIYASU SAKO*, SHIGEKAZU SASAKI**, AKIRASHIMATSU**, HIROTOSHINAKAMURA**, ANDHIROO IMURA** *Departmentof Medicine,ShizuokaGeneralHospital,Shizuoka 420, and **SecondDivision,DepartmentofInternal Medicine, KyotoUniversityFacultyof Medicine,Kyoto606,Japan
Abstract.
A
17-year-old and
familial
man
his
11-year
lacked
the
levels.
Their
Their
peripheral
exogenous
old
signs
Key
words:
of who
sister
(case
TSH
levels of
TSH
Thyroid
level
another
2)
hormone
our
not
Even 2. showed
The
for in
suppressed,
T3 two
hormone
in
markedly
were
7
SRL
diagnosed
and
sence by
Received: May 11, 1992 Accepted: September 18, 1992 Correspondence to: Dr. Kiyoshi TANAKA, Second Division, Department of Internal Medicine, Kyoto University Faculty of Medicine, 54 Shogoin-kawaharacho, Sakyo, Kyoto 606, Japan.
function.
after
did
not
to
have
They hormone
TRH
not
loading.
influenced
fully
by
suppress
GRTH.
10%
the
[3].
In
the
Sera
from
order
to
to
TSH,
RIA
which The
described
the
TSH
were
with
subunit
14700
and
determined
the
Case
evaluation regarding
1:
A
of
alpha
and
of
thyroid
treatment
of
and
that age
to the TSH 1ng was
[5].
Results male
Shizuoka
his
that and
Bone
method
by
measured
assuming
5ƒÊU/ml.
TW2
those
subunit
subunit
seventeen-year-old
Clinic
was
respectively,
of
separato
TSH
by
than
analysed
antibody
The
out
less
presence were
alpha
to
Cases
Thyroid
of
the
28000,
by
the
pre-
ruled be
results
calculated
corresponded
was to
out
[4].
of
The
T3
second
alpha
was
or
specimens
comparable
weights
TSH
T4
rule
gave
ratio
1992)
binding
previously
molecular
533-538,
Amersham). to
non-specific
conventional
tion,
39:
TSH;
autoantibodies
autoantibodies by
Japon
Amerwell
of showing
as
Serum T4 and T3 were measured with commercial radioimmunoassay (RIA) kits. Free T4 and free T3 concentrations were determined with analog-based kits (Amerlex Free T4 and Free T3 kits; Amersham). Serum TSH was measured with immunoradiometric assay (IRMA) kits (Sucrosep;
days
A disease
thyroid
were
(Endocrinol
IRMA.
Methods
thyroid serum
and
described. Graves'
abnormalities.
resistance.
THYROID hormone resistance is a syndrome characterized by the relative insensitivity of the pituitary and other peripheral tissues to thyroid hormone action. Since the initial description by Refetoff in 1967 [1], approximately 200 cases have been reported [2]. In this paper we report familial cases of this syndrome.
of
increased
limits for
thus
their high
normal
is
diagnosis
of
extremely
fact
within
patients
the
evaluation of
administration
identical
(GRTH)
under
the
spite but
were
150ƒÊg
thyroid
methimazole
clinic
hormone
case
to
with
thyrotoxicosis
were
in
treated
visited
thyroid
sister
resistance
been
of
administration.
and
generalized had
symptoms
indices
T3
father
1),
and
plasma
TRH-stimulated their
case
(case
General status his
"Graves'
visited Hospital
and
the for
suggestions disease".
He
534
Table
TANAKA
1.
Thyroid
function
tests
of
case
1 at his
initial
visit
et al.
in
height,
55.2kg
axillary
body
palpable goiter ing moistened the
history
aspects
from
a
with
Thyroid
function
hormone
action
tration
of
and in
75ƒÊg
peripheral
case of
indices
1, before T3
for
7
and
of
after
days
size
as
well
a
TRH
for
7
days.
the
tients'
not
TSH
patient
was
obtained.
clinical TSH
Table
3.
Thyrotropin case 1
and T3 responses
to TRH
loading
2,
in
not
respond
The
data,
shown
obtained
six
appointment.
thyroid
At
hormone
obtained
levels.
from
abnormalities
his
former
in
sella
the
patient in
Table
and
other
and
the
paThe
follow-up set
in
of
could
column his
the
patient's
presence
Table
of
3 are
attending
of
after
time, the
and
data
right
months
In
75ƒÊg
loading.
to
in
per-
of
TRH
that
suppressed
of
were
T3,
lost additional
the initial
indices
(BMR)
to
quite
his
shown
by
of
question
period,
rate
one
not
was
to
As
only
were
was
test
temporarily
consequently
Table
the
lack thyroid
action
influenced
did
A
administration
metabolic
were
1.
of
medication.
for
laboratory
measurement
During
basal
methi-
after
hormone
other
markedly
elevated
us
be
surgery
months
after
to
taking
which
led
few
and
and
no
indices
be
A
before
received
and
history,
thyroid
formed
for alkaline phosphatase respectively.
his
disease,
test
peripheral
Alp and ACE are abbreviations angiotensin converting enzyme,
as
diagnosis.
goiter
of
no in
began
Table
face
Graves'
he
Initial
in the
had disease;
and
in
unusual
Graves'
12.
no
includtaking
On
stopped
age
had
some
His he
normal
initially
after
summarized
of
original
2,
only
at
hormone,
T3
as
appendicitis
atypical
visit,
diagnosed
when
suppression
a He
detail,
patient
hospitalization
are
TSH
in
The
during
findings
thyroid adminis-
father
methimazole. in
acute 2.
his
had
36.8•Ž.
of thyrotoxicosis, finger tremor.
developed
decreased mazole
and of
signs and
when
goiter
treated
weight
noticed.
goiter
fact,
Table
or skin
were
visible
in
temperature
last
high
shown
data
physician.
turcica
No
were
observed
younger
sister
radiographically. Case case
2: 1,
goiter.
She
without
body
weight
loss
at age
7 and
was
or
4,
which
Fig.
1,
sis. On
his initial
visit to our clinic,
the
diagno-
he was 171.7cm
of
suppressed
term
and
her
initial
had
sufficiently.
a
thyroid
hormone
TSH
diffuse
soft
of
thyro-
response Even
Her
lack
in of
hormone of
were
doses
of
her
summarized
measurement
graded
her
and
signs
of her
grown
visit,
abnormalities.
shows
high
had
a
no
are
clearly
of
35.8kg,
had
physical
thyroid
plasma
She
findings
and
after
weight
She
despite
evaluation
On
78/min. width.
loading
the the
full
body
which
suppression
indices
for at
other
Table
and
since
in
laboratory
fore
to take
was
initial
TRH
continued
born
147.2cm,
4cm
toxicosis
girl,
clinic
problems.
rate
goiter,
diagnosed as having Graves' disease based upon a high serum thyroid hormone level. Antithyroid drug treatment with methimazole was initiated, he had
our was
was
pulse
experienced
11-year-old
any
height
Data were obtained from his former attending physician. The patients was under methimazole treatment.
An
visited
TSH levels.
peripheral
performed T3. to after
be-
As
shown
TRH
was 150ƒÊg
in not T3,
GENERALIZED
Table
4.
Thyroid
function
THYROID
HORMONE
RESISTANCE
535
tests of case 2 at her initial visit
Fig. 2.
Effects
of exogenous
T3 administration
prolactin responses to TRH loading legend to Fig. 1 for details.
Fig.
1.
Effects
of
TSH
exogenous
responses
shows
the
TSH
exogenous the
patient's
action
The
ated
by
she
was
years
the
old.
our
clinic
every
any
medication. Family
mother
of
study: the was
patient's not
to
was
was
13.5
six
months
Sera
available.
be
0.96,
sella
years
SD
when
was
She
follow-up
specimen
Interestingly
from the
Discussion
13.5 no visited
without
from
and another sister also showed signs of thyroid function abnormalities which were identical to those of the two patients (Fig. 5).
evalu-
revealed
obtained A
1 as
she
turcica.
for
was
tumor
within
11.4
when
were family.
The
age,
examination her
was
6.55ƒÊU/ml.
bone
[5],
old,
in
Fig. 3. Basal metabolic rate (BMR) before and after T3 administrationin case 2.
observed.
pituitary
her
method
Radiographic findings
was
curve
and
years
in
peripheral
were
calculated
growth
TW2
11.5
of
4)
by
changes
indices
TSH
height,
abnormal
bers
significant
a TSH-producing
patient's
average
affected
concentration
ratio, of
or
prolactin
little
(Fig.
her
subunit/TSH
from
Plasma
other
after
(•Ÿ-•Ÿ)
days.
also No
and
when
indicative
[6].
3)
2).
curve or
100ƒÊg
serum ƒ¿-subunit
0.63ng/ml alpha
7
was
hormone
The
(• -• ),
for
plasma
Each
(•¡-•¡)
3.69ƒÊU/ml.
(Fig.
(Fig.
thyroid
not
to TRH
T3
BMR
T3
on
loading.
before
50ƒÊg
(•ž-•ž)
to
TRH
response of
responded
response
administration
500ƒÊg
TSH
administration 150ƒÊg
T3
to
on plasma in case 2. See
memtheir father
Thyroid hormone resistance is characterized by insufficient tissue response to thyroid hormone. Since an initial description by Refetoff in 1967 [1], approximately 200 cases have been reported [2]. This syndrome is subdivided into three categories, according to the tissues involved, i.e., (1) the generalized
form
in which
both
pituitary
and
536
TANAKA
Fig.
4.
Changes
in
ferritin,
cholesterol
peripheral
glucose-6-phosphatase verting
enzyme
50ƒÊg; •œ-•œ,
indices (Choi),
et al.
of
thyroid
alkaline
dehydrogenase (ACE),
before
(B)
hormone
action
phosphatase (RBC
and
G6PDH)
after
100ƒÊg; •£-----•£,
(A)
and
administration case
the
In
(•¡----•¡,
is
made
our
study,
case
2
hormone
levels,
the
symptoms
of
thyrotoxicosis.
TSH
spite
levels
tion,
even
suppressed
her
unlikely. the
a
TSH
Thus
generalized
2
form
induced state
Assay
can
be thyroid
of
case
no or
fully
interference
diagnosed
of
to
administra-
metabolic
levels.
case
and
response
150ƒÊg,
her
signs measurable
hormone of
in
had
exaggerated
dose
changes
thyroid
the
She an
diagnostic
high
lacked
thyroid
fulfills
little
extremely
patient
with
at
significant
patient [7].
presented
of
Exogenous
a
criteria
In
TRH.
when
above-mentioned
difficulty.
basal
cell con-
2.
(GRTH)
of
serum
blood
angiotensin
in
hormone
as
red
T3
150ƒÊg)
all
such
(Alp),
was as
having
hormone
resist-
ance. The
metabolic
tent
with
did
Fig. 5.
Result of family study. Data from the mother of the affected subjects were not available.
not
serum
respond to
what
response
to
TRH
few
months
nous
a
patient
at
to
the
have
response trial,
that
thyroid
time.
TSH
was
were
not the
not
high. that
The
pituitary less
insensitive
hormone
than
was
we
by
a
exogein
diagnosed
second
attending
inappropriate thyroid most
to
levels
explanation
thyrotrophs
those
TSH
hormone likely
of
negative of
1
TSH
at his former
this
case
plasma
suppressed patient's
TSH
suppressed.
established
because
showed circulating
the performed
suppression
was
form
clearly
be
visit,
However,
from
when
extremely
patient by
of
TRH
data
secretion
would
lack
was
and
hormone.
however, which
initial
generalized
physician
are
his
inconsislevels,
thyroid
expected,
hormone
to and
exogenous
we
also
hormone
loading,
after
thyroid
1 was
thyroid to
Contrary
Therefore,
peripheral tissues are involved, (2) the pituitaryselective form and (3) the peripheral form. Diagnostic criteria from the Ministry of Health and Welfare of Japan are: (1) a metabolic state inconsistent with circulating thyroid hormones, (2) TSH secretion inappropriate for given thyroid hormone levels, (3) insufficient metabolic changes after exogenous administration of thyroid hormone and (4) lack of TSH suppression after exogenous thyroid hormone administration [6]. A diagnosis of generalized resistance to thyroid
state
his
case
case
1
feedback 2,
and
the
GENERALIZED
THYROID
TSH of case 1 patient could be suppressed by extremely high serum thyroid hormone levels. The goal of therapy for generalized resistance to thyroid hormone (GRTH) is to maintain tissue euthyroidism. We assessed that case 1 patient was in a state of "compensated euthyroidism" because of his better than average mental state and growth as well as his normal peripheral indices of thyroid hormone action. Case 2 patient was examined more carefully because of her youth. We concluded that she was also in a state of compensated euthyroidism from her normal growth curve, normal bone age and mental state. Consequently both patients are being followed up without medication. Pituitary insensitivity to T3 does not seem to be restricted to thyrotrophs in these cases. Basal and TRH-stimulated prolactin levels are negatively influenced by T3 in normal subjects. In the two cases we have discussed, the TRH-stimulated PRL levels were little affected by exogenous T3 admi-
HORMONE
nistration,
showing
insensitive
to
The
to
receptor
(TR).
a to
This
point
TR
[11-13]
is
genetic
domain
of
TR ƒÀ to
TR ƒÀ
it
basis. which
in
of
a lvsine of
thyroid
to
potential
resulting
in
[14]
glutamic
was
identified
the
subtypes
resistance problems
of may
of
hormone diagnostic inappropriate
comparison
abnormalities
its
made
[15]. of
understanding
of
10]
binding
cases,
T3
without
a molecular reported
T3
438
subjects.
Careful
[9,
deletion
our
codon
restricted
[16].
the
been
identification
on been
major
In in
occasionally
and
a
been
nuclear
has when
GRTH have
significance
not
also
has
the
product
at
or
affected The
in
gene
mutations
mutation
were
syndrome
recently, A
identified.
acid
this
hypothesis
analyze a few cases
single
were
of
c-erb
possible Recently,
lactotrophs
abnormality
until
as
the
[8].
an
confirmation
in
that
T3
pathogenesis
ascribed
TR
537
RESISTANCE
therapy
clinical
greatly
functional
data
and
facilitate
our
significance
of
TR
[17].
References 1.
Refetoff lial
S,
ble
goiter
target
mone.
Clin
Franklyn
4.
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Ann
Houssein
A,
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5.
a and
TSH-ƒÀ
an
vivo
Tanner WA,
ment
of
Height
T,
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protein
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Mar-
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Doppman
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ated
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the
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the
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the
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in
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a mutation
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21-22.
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