Download Specificity of Sensitive Assays of Thyrotropin (TSH) Used to Screen

CLIN. CHEM.
33/8, 1391-1396
(1987)
Specificity of Sensitive Assays of Thyrotropin (TSH) Used to Screen for Thyroid Disease in
Hospitalized Patients
Carols Spencer,AndreaElgen,Dennis Shen, Marysla Duds, StephanIe Quails, Steven Weiss, and John Nicoloft
Thyrotropin (TSH) concentrations were measured in 1580
hospitalized patients and 109 normal persons. Using the
mean ±3 SD limits of the log values for the controls (0.356.7 milli-int. units/L), the proportion of abnormal TSH results
in the hospitalized patients was 17.2%. TSH was undetectable (<0.1 milli-int. unit/L) in 3.1% of patients, suggesting
hyperthyroidism, and high (>20 milli-int. units/L) in 1.6%,
suggesting hypothyroidism. On follow-up of 329 patients,
62% with abnormal TSH (<0.35 or >6.7 milli-int. units/L) and
38% with normal TSH concentrations, only 24% of those with
undetectable TSH had thyroid disease: 36% of them were
being treated with glucocorticoids and 40% had nonthyroidal
illness (NTi). Although half the patients with TSH >20 millimt. units/L had thyroid disease, 45% of patients had high
TSH values associated with NT1. TSH concentrations usually
returned towards normal when patients’ therapy with glucocorticoids was discontinued or they recovered from NTI. TSH
test sensitivity appeared good when the mean ±3 SD limits
of the reference population were used, i.e., no cases of
hyper- or hypothyroidism, as identified by free thyroxin index
(FT4I), were missed. However, TSH test specificity was
inferior to that of the FT4I test (90.7% vs 92.3%), although
specificity could be improved to 97.0% if the wider TSH
reference limits of 0.1 to 20 milli-int. units/L were used-limits
considered pathological if applied to outpatients. Evidently,
different reference intervals for TSH are needed for hospitalized and nonhospitalized patients. We conclude that a “sensitive TSH assay” is not a cost-effective thyroid screening
test for hospitalized patients as compared with the FT4I.
AdditIonal Keyphrases: thyroid status
screening
effect of
nonthyroidal illness, glucocorticoids
Recently, sensitive immunometric
methods have been
developed for quantifying
thyrotropin
(TSH), for use in
routine clinical laboratories (1,2).’ These new methods offer
substantially
improved sensitivity over conventional clinical TSH assays (3-7), and can completely distinguish
between normal TSH concentrations
and the low values that
typify thyrotoxicosis
(8-16). TSH values in thyrotoxic patients characteristically
fall below the detection limit of 0.1
milli-int. unitlL with these new methods. Consequently,
the
new TSH assays are being widely promoted as first-line
screening
tests of thyroid function on the basis of data
Clinical Research Center, University
of Southern
2025 Zonal Avenue,
Los Angeles,
CA 90033.
Abstract
presented at the American Federation
California,
for Clinical
Research, Western Regional Meeting, February 5, 1987.
1 Nonstandard
abbreviations: TSH, thyrotropin (thyroid-stimu-
lating hormone); NT!, nonthyroidal illness(es); VI’41, free thyroxin
index (total T4 x T3 uptake ratio); T4, total thyroxin; T3, total
triiodothyronine; T3UR, T3 uptake ratio; FT’31,free T3 index (T3 X
T3UR)
Received February 9, 1987; accepted May 22, 1987.
showing good sensitivity and specificity for diagnosing both
hyper- and hypothyroidism
(4, 6, 10, 11, 15-19). Although
there have been some studies of TSH specificity in patients
with nonthyroidal
illnesses (NT!) (20,21), data on the value
of these new sensitive tests for diagnosing
thyroid disease in
unselected
hospitalized
patient
populations
are few. The
recent report of Dubuis and Burger (22), in which 3% of 269
hospitalized
patients
had undetectable
TSH values that
were not due to hyperthyroidism,
suggests that the specificity of these sensitive TSH tests may be impaired
as a result
of NT! or in the presence of complicating drug therapy(s).
We undertook the study reported here to further examine
the specificity and clinical utility of TSH measurement
for
evaluating thyroid function in hospitalized patients.
MaterIals and Methods
Normal Subjects
We obtained sera at 08:00-10:00
h from 109 fasting
normal subjects with no clinical, historical,
or biochemical
evidence of thyroid disease. Fifty-two subjects were apparently healthy physicians and laboratory volunteers from the
LAC/USC Medical Center and 57 were employees of the
Nichols Institute, San Juan Capistrano, CA. The mean age
was 32.9 (SD 9.1) y, the ratio of males to females was 1/1.5.
Subjects with positive titers for antimicrosomal
antibody or
antithyroglobulin
antibody, suggestive of autoinunune
thyroid disease (23), were excluded. The log-transformed
TSH
values of the samples followed the expected gaussian distribution, having a mean of 1.56 milli-int. units/L (1 SD limits
0.96 to 2.54,2 SD limits 0.59 to 4.12,3 SD limits 0.35 to 6.72
milli-int. unitsfL).
Hospitalized Patients
Sera remaining
after morning (06:00-11:00 h) SMAC panel
tests (admission requests) for 1580 patients hospitalized at
the acute medical facility of the LACIUSC Medical Center
(outpatients
were excluded) were selected on the basis of
sufficient volume for the thyroid and TSH tests. The mean
age of these patients was 43.7 (SD 17.4) y, the male/female
ratio 1/0.6. TSH values were determined
within 24 h and
were grouped with reference
to the mean, ± 1 SD, ±2 SD
and ±3 SD values of the log normal distribution
of the
normal subjects shown below in Figure 1. Group A (n = 49)
had undetectable (<0.1 milli-int. unit/L) TSH. Group B (n =
137) had detectable
but subnormal (<-3 SD, 0.1 to 0.35
milli-int. unitiL) values. Group C (n = 139) had values
between the -2 SD and -3 SD normal limits (0.36 to 0.59
milli-int. unitiL). Group D (n = 1061) had values within the
normal reference interval (±2 SD normal limits, 0.60 to 4.1
milli-int. units/L). Group E (n = 107) had values between
the +2 and +3 51) normal limits (4.2 to 6.7 milli-int.
unitsfL). Group F (n = 61) had values exceeding the +3 SD
normal limit but <20 milli-int. units/L (6.8 to 20.0 milli-int.
units/L). Group G (n = 26) had high values suggestive of
hypothyroidism (>20 milli-int. unitsIL).
CLINICALCHEMISTRY, Vol. 33, No. 8, 1987 1391
We performed clinical and biochemical follow-up examination(s), measuring
total thyroxin (T4), total triiodothyronine (T3), T3 uptake ratio (T3UR), free T4 index, free T3
index, and antimicrosomal antibody in a subgroup of 329
patients. Of these, 172(52%) had abnormal TSH values (i.e.,
outside 3 SD from the mean): 45 of the 49 from Group A,
70/137 from Group B, 35/61 from Group F, and 22/26 from
Group G; and 157 (48%) were patients with normal values
for TSH: 54 of 139 from Group C, 70/1061 from Group D, and
33/107 from Group E, the members in these latter groups
being selected at random. A complete drug history, including exposure to iodide, was taken at each examination. On
the basis of follow-up studies we classified these patients as
either (a) having a thyroid problem; (b) receiving drugs
known to affect TSH secretion, such as glucocorticoids (24)
or dopamine (25); or (c) having solely NT! (26). The major
nonthyroidal diagnoses were trauma (9.1%), renal disease
(8.8%), liver disease (7.0%), pulmonary
disease (5.8%), cardiac disease (5.5%), central nervous
system lesions (5.5%),
carcinoma
(3.6%), gastrointestinal
problems (3.3%), and
infection (2.7%).
Twenty-nine patients were classified as having thyroid
disease, on the basis of both the clinical examination and an
abnormal
FT4I (<4.5 or >12.0) or a high FF31 (>200) value,
whether at the initial evaluation or on subsequent restudy
after recovery and discharge from the hospital. Patients who
were receiving therapy with thyroid hormone or who had a
history of thyroid surgery or radioiodide thyroid treatment
were also classified as having thyroid disease, as were two
patients being treated with a combination of thyroxin and
glucocorticoid. Most (n = 45) of the drug-treated
patients
were receiving glucocorticoids; however, four patients receiving dopamine were also included in this classification.
In all, 251 patients without evidence of thyroid disease and
not receiving glucocorticoid or dopamine therapy were classified as having NTI.
We also measured retrospectively T4 in the remaining
1251 patients not evaluated
as part of the 329-patient
subgroup. We then measured T3UR and calculated FF4! for
the 12.4% of the patients’ sera that had abnormal T4 values
(<45 or >120 j.zgfL). In 7.8% of these patients, FT4I values
were also abnormal (<45 or >120). When possible, these
patients were evaluated by recall, or otherwise by chart
review, to exclude the presence of thyroid disease, and these
data were used in calculating test specificity and sensitivity
Data Reduction
Student’s unpaired-t analysis of group data was made
relative to the NTI patients with normal TSH (Group D).
When analyte concentrations
were undetectable,
we used
the value of the detection limit for the statistical analyses.
Results
Figure 1 illustrates
the distribution
of TSH values obtained for the normal subjects and the hospitalized
patients.
Clearly, the range of concentrations for the hospitalized
patients was wider than that for the normal reference
population, with only 67% of the patients’ values falling
within the 2 SD limits of the reference values, and only 84%
falling within the 3 SD limits. Some (3.9%) of the patients
had borderline high TSH values (Group F) and 1.6% had
clearly above-normal
values suggestive of hypothyroidism
(Group G). In contrast, 8.6% of the patients had subnormal
but detectable TSH values (Group B), and 3.1% of patients
(Group A) had undetectable
values suggestive of hyperthyroidism.
Figure 2 and Table 1 show details of the diagnostic and
biochemical values, by group (A-G), for the subgroup of 329
patients who received clinical and biochemical follow-up
evaluation(s). Surprisingly,
thyroid disease did not appear
to be the principal cause of the abnormal TSH values in
these patients. Indeed, only 24% of Group A patients were
classified as having thyroid disease; more of them were
being treated with glucocorticoids (36%)-dose 732, SE 316,
range 870-2500 mg-equivalents of hydrocortisone
daily-or
simply had NTI (40%). Note that TSH became detectable
(0.39, SE 0.08 milli-int. unitfL) in 9/14 of these glucocorticoid-treated patients upon re-study after glucocorticoid therapy had been discontinued.
Glucocorticoid-treated
patients
(dose 579, SE 176, range 80-1600 mg daily) also accounted
for a significant
proportion of patients with subnormal
values (27% of Group B).
40
35
30
25
(27).
Assays
The sensitive TSH immunoenzymometric
assay used (Abbott, North Chicago, IL) was as previously described (16).
The interassay precision (CV) at 0.6, 1.7 and 15.3 milli-int.
unitslL was 10.5%, 4.3%, and 4.3%, respectively. Samples
with TSH values >60 milli-int. units/L were diluted 10-fold
with the zero standard.
TSH was measured, in duplicate, in
batches of 30 to 40 serum specimens.
Some sera with
undetectable
(<0.1 milli-int. unitlL) TSH values by this
assay were re-assayed with a sensitive TSH immunoradiometric assay (Boots Celltech, Hanover, NJ), courtesy of Dr.
E. C. Ridgway (University of Colorado, Denver, CO).
Concentrations
of T4 (detection limit <2.5 g/L) and T3
(detection limit 250 ng/L), the T3UR, and the antithyroglobulin antibody titer were measured in sera as previously
described (16, 28). Antimicrosomal
antibody titers were
measured by a hemagglutination
technique (Ames, Elkhart,
IN).
1392
CLINICAL CHEMISTRY, Vol. 33, No. 8, 1987
NORMAL REFERENCE
POPULATION
%
HOSPITALIZED
PATIENTS
20
TOTAL
5
10
.\
N
S
I TSI
uU/mII
I
II .1_.351
36-.5.6-
GROUPI AIB[C
11.1-1.611.7
-2.52.64.
D
N
14.2_6.8I6.9_2OI
EF
G
Fig.1. TSH frequency profile in a normal reference population (under
solid cuive) and hospitalized patient population (----)
TSH groups A to G were constructedwithreferenceto the normal reference
population values listed in thetext
100
U HONTHTHOIO*t
their initial evaluation, after recovery and discharge from
the hospital. TSH values only returned to normal in the two
antimicrosomal
antibody-negative
patients
(2.1 and 2.3
milli-int. units/L) but remained
high in the remaining five
antimicrosomal
antibody-positivepatients (9.9, 21.7, 10.1,
11.5, and 28.5 milli-int.
units/L).
As shown in Table 1,
except for thyroid-disease
patients in Groups A and G, T4
and FF4! values did not appear to be related to TSH status.
In fact, in all but Group C, T4 values in the NT! and the
glucocorticoid-treated
patients did not differ notably from
those of NT! Group D patients. Mean T3 and FF3! values
were low or low normal for all seven groups and classifications, although the NT! and glucocorticoid patients in Group
F had significantly lower T3 values than did the other NT!
patient groups.
The prevalence of low T4 in NT! (29) also did not appear
to relate to the TSH concentrations;
in fact, the prevalence
of low T4 in NT! appeared similar for all Groups A-G of the
329-patient subgroup (17%, 14%, 8%, 9%, 13%, 16%, and
27%, respectively) as well as for the 1580 hospitalized
patients as a whole, when evaluated according to TSH group
(12%, 7%, 10%, 6%, 7%, 10%, and 9% for Groups A to G,
respectively).
We did find an association between the type of
NT! and the TSH concentration. Of the 30 trauma patients
90% had low TSH values that would place them in Group A
(n = 7) or B (n = 23). This did not appear to be the result of
narcotic administration,
because patients receiving similar
narcotic treatment frequently presented with normal TSH
values. The prevalence of patients with liver disease was
equal in most TSH groups (7%, 6%, 3%, 11%, and 3%, in
Groups A, B, C, D, and G, respectively), except for Group E,
in which 23% of the patients had liver disease. Patients with
renal disease also were about equally prevalent in most
ILLNESS
80
%
#{128}o
TOTAL
PER GROUP
40
20
0
GROUP
n
A
45
B
C
70
54
0
70
E
F
S
33
35
22
329)
Fig. 2. Percentageof patientsin each TSH group (A-G) classified as
having either thyroid disease (S), being treated with glucocorticoid
dopamine (s),or havinga nonthyroidalillness(D)
Only two patients with normal TSH (Groups C to E) had
disease. These patients
were receiving
thyroxinreplacement therapy. Most of the patients with normal TSH
values were #{232}lassified
as having NT! (89%, 96%, and 97% of
thyroid
those in Groups C, D, and E, respectively).
Fewer patients
were receiving glucocorticoid therapy in these groups (9%,
4%, and 0% respectively) as compared with the low-TSH
groups (Groups A and B).
NT! also appeared to be a common cause of abnormally
high TSH values (71% and 48% of those in Groups F and G,
respectively). There was further evidence that the high TSH
abnormality
in these groups was solely due to NT!: the TSH
concentration significantly
decreased from 32.4 (SE 3.6) to
12.3 (SE 3.7) milli-int. units/L in seven of 10 Group G
patients who were re-studied about 88 (SE 34) days after
Table 1. DIagnostic Classltlcatlon vs TSH GFOUPb
A (<0.1)
n
Male/female
Age,y
T4, .rg/dL
FT4I
T3, ng/dL
FT3I
T3UR
TSH, milh-int. units/L
Antimicrosornal
>1:400, %
11
417
49.2 ±5.3
7/9
52.8t3.8
11.1
12.7
160
180
±1.O#{149} 6.7 ±0.5
±1.7k
7.2±0.5
73±11
±24
±33
76±11
1.11 ±0.04
1.12±07
<0.1#{149}#{149} <0.1”
57*.
6
NIl
18
9/9
NT)
T
CC
Nil
CC
19
51
1
0/1
5
48
31/17
3
3/0
14/5
33/18
43.6±3.8
7.8 ±0.7
8.1 ±0.8
6.4 ±0.5
6.8±0.5
94±10
97±10
1.04 ±0.4
<0.1”
17
Age, y
T4, rg/dL
50
9.4
8.8
F141
13,
ngldL
<25
<25
FT3I
T3UR
TSH,
rn,lli-int.units/L
Antlmicrosomal >1:400,
.94
6.31
%
100
59
7.5
6.6
68±9
69±9
1.07 ±04
0.21 ±.01**
11
254
224
0.88
88±5
1.05 ±02
0.22 ±.01**
0
0.50
0
4/1
54.7±15.5
43.3±2.0
4.5 ±0.4”
4.7±0.6
54±19
55±19
1.03 ±05
0.55 ±08
0
6.7 ±0.3
6.7±0.3
96±8
93±7
1.01 ±02
0.60 ±01”
4
4.8 ±1.6
4.9 ±1.4
7.0 ±0.3
7.0 ±0.3
NT)
32
5
5
25
17/15
1/4
4/1
11/14
±3.7
49.2 ±10.3
6.0 ±1.1
5.9 ±1.1
94 ±9
89±8
0.99 ±03
5.2 ±0.2**
19
62 ±27
55±20
.98 ±06
12.8 ±0.9’
80**
48.8 ±8.5
5.4 ±1.5
44.8 ±3.5
6.0 ±0.5
6.3 ±1.8
35 ±10”
6.3 ±0.4
74 ±8’
78±8
1.10 ±.03’
9.6 ±0.6”
12
36±11”
1.17 ±04’
11.9 ±2.1’
20
88±36
96±6
84±33
1.10 ±0.14
1.26 ±.05**
0
94±5
1.01 ±01
1.9 ±0.1
7
G(>20)
CC
6.8 ±0.4
6.5 ±0.3
67
39/28
43.7±2.6
F (6.8-20)
44.5
Nil
33.6±3.7
T
1
0/1
42.5±2.4
6.6 ±0.3
6.8±0.2
89±6
E 14.2-6.7)
Male/female
0 (0.6-4.1)
OC
44.6±4.2
I
n
C (0.36-0.59)
B (0.1-0.35)
OC
16
I
T
CC
11
5/6
53.3
±4.4
1
0/1
64
NTI
10
5/5
43.2 ±5.7
1.8 ±0.4”
5.2
6.6 ±0.6
1.8 ±0.5**
4.6
6.3 ±0.6
39±9”
37±8”
.97 .08
65.6 ±21.2”
64’
65
57
0.88
39.4
0
75 ±14
68±11’
0.96
±04
35.8 ±3.3”
40”
Results are given as mean ± SE where applicable.
‘I, thyroid disease
GC,glucocoilicoid treated
NTI, nonthyroldal
illness.
GrOUpS A-G (see text); values In parenthesesare the range of TSH concentrations (milli-int. unlts/L) in each group.
* P <0.001
vs NTI patients of
“P<005
JGroupD
CLINICAL CHEMISTRY, Vol. 33, No. 8, 1987
1393
Groups (7%, 4%, 11%, 4%, 8%, and 6% in Groups A, B, C, D,
E, and G, respectively), except for Group F, in which 28% of
the patients had renal disease.
The prevalence of antimicrosomal
antibody positivity
(titer >1:400) tended to be higher in the abnormal
TSH
groups (20%, 23%, and 61%, for Groups A, F, and G,
respectively, as compared with 10% for combined Groups C
to E). Antimicrosomal
positivity was especially prevalent in
patients with thyroid disease in Groups A, F, and G (57%,
80%, and 64%, respectively).
In the 1580 hospitalized patients, the prevalence of T4
and FF4! abnormality
was 12.4% and 7.8%, respectively.
Thirteen of these patients had high FF4! values, of whom
nine (seven from Group A, two from Group D) had been
studied as part of the 329-patient subgroup. None of the
other four Group D patients with high FF4! had evidence of
thyroid disease, so the probable cause of the high FF4! was
familial
dysalbuminemic
hyperthyroxinemia
(30) or NT!
(26).
Thus, the sensitivity of the TSH test was good for detecting hyperthyroidism.
Apparently no hyperthyroid
patients
were missed when we used TSH as the initial thyroidscreening test. Sensitivity for the detection of hypothyroidism also appeared good, in that all the patients with clinical
and biochemical evidence of hypothyroidism
had high (>20
milli-int.
units/L)
TSH values.
In contrast, the specificity of the TSH test was clearly
compromised
by associated NT!. Specificity was especially
poor (90.6%) when assessed relative to the mean ±3 SD
limits of the normal reference population (as compared with
a specificity
of 92.3% for the FF4! test). Although the
specificity
of this TSH test could be improved to 97.0% if the
wider cutoff limits (0.1 to 20 milli-int. unitafL)
were used,
these limits would be considered as pathological if applied to
an outpatient population.
Discussion
We found that both abnormally low (<0.1 milli-int. unitiL) and high (>20 milli-int unitsfL) TSH values, not due to
thyroid
disease, are frequently encountered
in hospitalized patients. In our study, 17.2% of patients had TSH
values outside the ±3 SD limits of the range in the normal
reference population, and 4.7% had strikingly abnormal
TSH values (<0.1 or >20 milli-int. unitsfL). These findings
contrasted with the prevalence of abnormal FF4! values,
which was 7.8% overall, with 0.8% of patients having high
FF4! and 7.0% having low FF4! values. The specificity of
the TSH test was inferior to that of FF41 (90.7% vs 92.3%)
when the ± 3 SD limits of the normal reference population
were used, but could be improved to 97.0% by using wider
limits of <0.1 and >20 milli-int. unitsfL.
However, these
wider limits would be pathologicalwhen applied to outpatients, so it appears
appropriate
to use different TSH reference limits for hospitalized and nonhospitalized patients.
The prevalence of patients with undetectable TSH owing
to thyroid disease was double (0.7%) that previously reported for hyperthyroidism
in our hospital (31). This was in part
because we classified three thyroxin-treated
patients, patients in whom TSH is commonly undetectable even with a
sensitive assay (32), as having thyroid disease. An additional factor was the improved sensitivity
of the assay for
detecting hyperthyroidism;
two patients with thyroid disease were identified on the basis of TSH being undetectable
on initial evaluation
when thyroid hormone indices were
normal. When these patients were re-studied after recovery
1394
CLINICALCHEMISTRY, Vol. 33, No. 8, 1987
and discharge, their thyroid hormone
indices had became
high and clinical symptoms of hyperthyroidism
had become
apparent. These hyperthyroid patients would have been
missed if the FF4! value had been used as the initial
screening
test, because the FF4! value can become inappropriately normal or low when NT! is superimposed
on preexisting thyrotoxicosis (33).
One striking observation
was that only 14% of Group F
patients had thyroid disease.
All these patients appeared
clinicallyeuthyroid, and all but one patient had a normal
value for FF4!. Three
of these patients had previously
documented hypothyroidism
and were receiving T4 replacement therapy, whereas the remaining two patients had
histories of partial thyroidectomy. Most (7 1%) of these
Group F patients had NTI as the sole cause of high TSH, as
is consistent
with the recovery phase of an NT! (34). One
interesting observation was that 28% of these patients had
renal disease, suggesting that a high TSH may result from
decreased
renal clearance of the hormone (35).
We were surprised to find that 48% of the patients with
strikingly high TSH values (Group G) had NT!. Although
this finding
is in harmony
with another recent report (36),
the influence of NT! on TSH has not generally been thought
to really limit the clinical usefulness of measuring TSH in
serum
for diagnosing
primary
hypothyroidism.
In fact, NH
measurement
currently is widely considered to be the
definitive test for distinguishing
primary hypothyroidism
from low T4 resulting from NTI (26). All the Group G NT!
patients’ values for FF4! were within the normal reference
interval, suggesting that there was no deficiency of circulating thyroxin. Furthermore,
when we re-studied 10 of these
patients about three months later, we found that TSH had
significantly decreased in five and had returned to normal
in the two antimicrosomal
antibody-negative patients. The
40% prevalence of antimicrosomal
antibody positivity in the
Group G NT! patients was higher than that observed for
Group D NT! patients (7.0%), who displayed an antimicrosomal antibody prevalence comparable with that in the general population [6.7% (37)]. This suggested that subclinical
hypothyroidism
(38), possibly owing to chronic
thyroiditis,
may have been a contributing
factor
in producing the
strikingly high TSH concentration
in some patients,
although longer follow-up would be needed to definitively
resolve this issue.
Glucocorticoid
therapy was frequently associated with
low TSH values, but glucocorticoid-treated
patients also
appeared in Groups F and G (14% and 4%, respectively).
There was no clear relationship
between TSH and the
glucocorticoid dose or duration of therapy. This observation,
together with previous data (39) showing that normal TSH
concentrations were usually seen in asthma patients receiving equivalent
glucocorticoid
doses, suggests that other
factors besides
glucocorticoid
dose may be involved in the
genesis of the low TSH in these glucocorticoid-treated
patients (40).
Trauma appeared to be the major NT! diagnosis associated with low TSH concentrations.
Although exogenous narcotic administration
did not appear
to be the cause of this
finding, it is still possible that an increased release of
endogenous endorphins may have played some role in this
association.
We were concerned that the high prevalence (3.1%) of
undetectable TSH observed in this study may have reflected
method-sensitivity limitations. In an attempt to resolve this
issue we remeasured TSH in seven glucocorticoid-treated
patients’ sera by a different sensitive TSH technique (Boots
Ceiltech) and found that five of the seven sera had comparably low (<0.08 milli-int. unitfL) values for TSH. Thus, this
finding, together with that of Dubuis and Burger (22)
showing that 3.0% of hospitalized patients had undetectable
TSH by the sensitive Serono TSH method, was evidence
that our high prevalence of undetectable TSH in hospitalized patients was not method related.
Previous reports suggesting that central nervous system
impairment of TSH secretion is associated with the low T4
NT! state (41-43) are not supported by our data. There was
no relationship between the TSH and the prevalence of low
T4 in NT!, in agreement with previous studies in which both
the current TSH technique (39) was used as well as studies
in which the Boots Celltech method was used (3). In the
present study, central nervous system impairment
(pituitary or hypothalamic disease, head trauma, stroke, seizure,
or brain metastases) was not found to be strongly associated
with low TSH (9%, 10%, 15%, 12%, 16%, 0%, and 0% in
Groups A to G, respectively, of the 329-patient subgroup).
Sensitive TSH measurement
had good sensitivity but
poor specificity for screening
or evaluating
hospitalized
patients for thyroid disease when the TSH reference limits
were based on the ±3 SD limits of a normal population. A
high prevalence (3.1%) of undetectable values suggestive of
hyperthyroidism
was found both in this and in another
study in which a differentsensitive TSH assay was used
(22). Patients receiving glucocorticoid treatment or having
trauma were frequently found to have low or undetectable
TSH, a finding that did not appear to be method related.
Both high and low TSH values were found to be frequently
associated with NT! per se. Thus, although the new sensitive TSH tests appear to offer better sensitivity and specificity for screening
for thyroid disease in ambulatory patients
(8-16), their cost effectiveness for use with hospitalized
patients would be impaired by poor specificity, resulting in
expensive and unnecessary follow-up study of patients with
abnormal
values due to glucocorticoid treatment or NTI.
Because the specificity of the TSH test can be improved to
97.0% if wider reference limits (<0.1 and >20 milli-int.
unitsfL) are used, it may be appropriate to use different
reference intervals for TSH when these tests are used for
assessing hospitalized vs nonhospitalized patients. However, at this time, the current specificity and reagent-cost
considerations suggest that the FF4! test may be a more
cost-effective thyroid screening test for evaluating hospitalized patients than is sensitive TSH.
We thank Abbott Laboratories (Chicago, IL) for supplying the
for this study, and the Los Angeles County Hospital
Chemistry Department, especially Dr. Ed Wong, the associate
director of the laboratories, and Eddie Briones and the SMAC
Laboratory staff, for their help and support in this study. We also
gratefully acknowledge the expertise
of Ken Anderson with statistics, Denise Walters in preparing this manuscript, and Anne Santo
in preparing the graphics.
The computer services for this study were provided by the cuiro
Project, funded by the Division of Research Resources of the NIH
under Grant no. RR00043.
reagents
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