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Prevalence of thyroid disease and abnormal thyroid function test results in patients with systemic lupus erythematosus.

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Although thyroid disease has been associated
with other autoimmune conditions, it is not well recognized in systemic lupus erythematosus (SLE) patients.
We found that in 332 SLE patients hospitalized during a
5-year period, the overall prevalence of diagnosed thyroid disease (7.5%) was similar to that in other female
populations, but the prevalence of diagnosed hypothyroidism (6.6%) was unexpectedly high. There was also a
high frequency of abnormal thyroid function test results
in 175 SLE patients without diagnosed thyroid disease
who underwent laboratory screening. More than 45% of
these patients had elevated levels of thyroid-stimulating
hormone, 34% had low T3 determinations, and 18%
had high antimicrosomal antibody titers. When patients
were categorized into “functional groups,” some
showed evidence of the “euthyroid sick syndrome’’
(15%), but many more had laboratory test results
suggestive of true (5%) or incipient (39%) primary
hypothyroidism. We conclude that abnormal thyroid
function test results are common in patients with SLE
and that hypothyroidism, especially, should be considered when evaluating symptoms and signs in SLE
From the Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and the
Molecular, Cellular and Nutritional Endrocrinology Branches, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland.
Frederick W. Miller, MD, PhD; Gerald F. Moore, MD
(current address: Section of Rheumatology, Department of Internal
Medicine, University of Nebraska Medical Center, Omaha, NE);
Bruce D. Weintraub, MD; Alfred D. Steinberg, MD.
Address reprint requests to Frederick W. Miller, MD, PhD,
Building 10, Room 9N240, National Institutes of Health, Bethesda,
MD 20892.
Submitted for publication November 24, 1986; accepted in
revised form April 9, 1987.
Arthritis and Rheumatism, Vol. 30, No. 10 (October 1987)
Although thyroid disease has been associated
with rheumatoid arthritis ( 1 4 ) , Sjogren’s syndrome
(5,6), progressive systemic sclerosis (7), and other
autoimmune conditions (&13), little is known about
thyroid abnormalities in patients with systemic lupus
erythematosus (SLE). Since SLE is a multisystem
disorder with a wide variety of manifestations, and
because thyroid pathology is generally associated with
autoimmune disease, we suspected that SLE patients
would be a population at high risk for the development
of thyroid dysfunction. The scant reference to this
problem in the literature suggests that either the prevalence of thyroid disease in SLE is lower than that in
other rheumatic conditions, or that its presence has
been under-recognized.
To investigate this problem, we initiated a prospective study of thyroid disorders in patients with
SLE. We present here the first report of the prevalence of thyroid disease and abnormal thyroid function
test results in lupus patients. Our study shows that
although the clinical diagnosis of thyroid disease is
uncommon, abnormal thyroid function test results are
frequently found in SLE patients. Some of these abnormalities appear to reflect what has become known as
the “euthyroid sick syndrome” (14). However, a
larger number of SLE patients had thyroid test values
that were consistent with incipient or true biochemical
primary hypothyroidism (15,16). Our results suggest
that many patients with SLE have thyroid dysfunction
that has not been clinically recognized, possibly because of an overlap between the symptoms of lupus
and those of thyroid diseases. Further evaluation of
our patients will be necessary to understand the longterm clinical relevance of the finding of frequent
biochemical hypothyroidism in SLE patients.
Patients. All patients eligible for the study had been
diagnosed as having SLE, according to American Rheumatism Association criteria (17,18), and had been hospitalized
in the NIH Clinical Center between December 1979 and
January 1985.These 332 patients made up the study population that was used to determine the prevalence of diagnosed thyroid disease in hospitalized SLE patients. Of these,
175 randomly selected patients underwent routine screening
tests; none of these 175 patients had a history or clinical
diagnosis of thyroid disease. This population was used to
determine the prevalence of abnormal thyroid function test
The patients’ mean age was 35.4 years, with a range
of 11-74 years. One hundred sixty-five of them were female
(94.3%);66.3% of the females were white, 30.3% were black,
and 3.4% were of other ethnidracial groups.
Methods. Laboratory and immunologic tests were
performed according to standard methods. All thyroid function tests were performed either at the NIH Clinical Pathology Department, using commercial radioimmunoassays
(RIAs), or at commercial laboratories. The tests included
thyroxine (T4), using an Immunophase T4 RIA kit (normal
6-1 1 pg/dl; Corning Medical, Medfield, MA), free thyroxine
by equilibrium dialysis (normal 1.0-2.3 ng/dl; Corning
Medical), 3,5,3’-triiodothyronine(T3), using a Quantimmune
system (normal 111-199 ng/dl; Bio-Rad, Richmond, CA),
thyrotropin (thyroid-stimulating hormone [TSH]), using an
RIA Phase system (normal 0-3.9 pIU/ml; Beckman Instruments, Brea, CA), 3,3‘,5‘-triiodothyronine(reverse T3
[rT3]),by RIA (normal 10-24 ng/dl; Nichols Institute, San
Juan Capistrano, CA), and thyroxine-binding globulin
(TBG), by immunoradiometric bead assay (normal 12-28
pg/ml; Corning Medical).
Statistical analysis. Grouped data were evaluated for
significance using the Wilcoxon rank sum test and the
Bonferroni adjustment for multiple comparisons. Correlation coefficients were determined by least squares linear
regression analysis. Changes in the patients’ “functional
group” assignment over time were analyzed for significance
using 2-sided McNemar testing for correlated proportions,
with the Bonferroni adjustment for multiple comparisons.
Of 332 SLE patients hospitalized during the
period of the study, 25 (7.5%) had a discharge diagnosis of thyroid disease. Of these, 22 (6.6% of the total)
were hypothyroid, and only 3 (0.9%) were hyperthyroid. Two of the hypothyroid patients had a history of
papillary cancer of the thyroid and previous thyroidectomy, and 4 had a diagnosis of Hashimoto’s
thyroiditis (one of whom also had insulin resistance
secondary to anti-insulin receptor antibodies). Of the
3 hyperthyroid patients, 2 were diagnosed as having
Graves’ disease. Seventeen of these 25 patients were
receiving thyroid replacement hormones during the
period of their hospitalization. These 25 were excluded
from further study. Thus, only data from patients who
were not taking thyroid medications and who had no
known thyroid disease were analyzed further.
Of the remaining 307 SLE patients, 175 randomly selected patients had sets of laboratory tests
performed. These tests consisted of at least the TSH,
the T3, and the T4 or FT4, all of which were determined
on the same day. Many of these profiles also contained
concurrent rT3 or TBG values and 58 other routine
chemical, hematologic, and serologic tests.
Table 1, which lists the thyroid function test
findings in this group of 175 SLE patients, shows that
a significant proportion had abnormal thyroid test
results. Over 45% of the patients had an elevated TSH
value, and 10.9% had a TSH value greater than 2 times
the upper limit of the normal TSH range. More than
34% of the patients had low T3 levels. A high frequency of elevated titers of antithyroglobulin (7.1%)
and antimicrosomal antibodies (18.4%) was also
The analysis of all available data (including
repeated thyroid function studies on these 175 patients) showed that thyroxine determinations correlated positively with levels of T3 (P < 0.0001 ; n = 168)
and TBG (P < 0.03; n = 22) and correlated negatively
with levels of TSH (P < 0.0001; n = 188). TSH
determinations correlated positively with antithyroglobulin titers ( P < 0.0002; n = 84) and antimicrosomal
titers (P < 0.01; n = 65).
The patients were categorized into 5 groups on
the basis of concurrent thyroid function test results
(Table 2). Group 1 consisted of 60 patients with normal
FT4 or T4, T3, and TSH values. Group 2 was composed
of 65 patients who had normal FT4 or T4 levels, normal
T3 levels, and elevated TSH values, suggestive of
subclinical hypothyroidism (19,20). The findings in
group 3 were consistent with the laboratory diagnosis
of primary hypothyroidism (i.e., biochemical primary
hypothyroidism). Group 4 consisted of 26 patients who
had normal or low FT4 or T4 values and low T3 levels,
but normal TSH values, which is diagnostic of the
euthyroid sick syndrome. Group 5 patients had normal
TSH values (although our assay could not distinguish
between normal and low TSH values), but elevated
FT4 or T4 levels and increased or normal T3 values
(i.e., hyperthyroxinemidhypertriiodothyroninernia).
The patients with biochemical primary hypothyroidism had the highest mean TSH value and the
lowest mean FTk and T4 values. The highest mean T3
Table 1. Distribution of thyroid function test values in systemic lupus erythematosus patients*
Thyroid function
test (normal)
(6-11 &dl)
(I .O-2.3 ngldl)
( I 11-199 ng/dl)
( I 2-28 pglml)
antibody (<loo)
antibody (<loo)
No. of
Range of
No. of
No. of
No. of
Mean t SD
8.0 2.4
8 (11.8)
47 (69.1) 13 (19.1)
1.6 t 0.66
4 (3.6)
102 (9 1 .9)
5 (4.5)
123 ? 44
3 (1.7)
112 (64)
60 (34.3)
< 10-43
18 2 9.8
6 (14.6)
4.92 5.2
79 (45.l)t
96 (54.9)
22 rt 5.0
9 (10.2)
79 (89.8)
0 (0)
3 (7.1)
39 (92.9)
7 (18.4)
31 (81.6)
< 100-6,400
* 238
408 * 1,079
22 (53.7) 13 (31.7)
* Data represent screening of 175 hospitalized lupus patients without diagnosed thyroid disease, as
rT3 =
described in Patients and Methods. T4 = thyroxine; FT., = free T.,; T3 = 3,5,3’-triiodothyronine;
reverse T3, or 3,3’,5‘-triiodothyronine;
TSH = thyrotropin; ND = not defined; TBG = thyroxinebinding globulin. Values for antithyroglobulin and antimicrosomal antibodies are represented as
antibody titer (i.e., 100 = 1:lOO).
t Nineteen determinations (10.9%) were >8 pIU/ml, which is 2 times the upper limit of the normal
TSH range.
value was seen in the hyperthyroxinemia/hypertriiodothyroninemia group, while the lowest mean T3
value was found in patients with the euthyroid sick
syndrome (Table 2). There were no significant differ-
ences (P > 0.05) in the mean age, the sex, or the race
of SLE patients in any of these groups.
A few patients from each group underwent a
thyrotropin-releasing hormone (TRH) stimulation test
Table 2. Grouping of systemic lupus erythematosus patients according to thyroid function test results*
Definition (mean value)
No. of
FT4 (normal 1 .O-2.3ng/dl) or
(normal 0-3.9 patients
Group no.
T4 (normal 6-11 pgldl)
(normal 11 1-199 ng/dl) pIU/ml)t
(5% of total)$
(FT4 1.61)
(T4 8.56)
(T4 7.80)
Normal or decreased
(FT4 0.75)
(T4 4.98)
Normal or decreased
(FT4 1.37)
Results consistent with
No abnormality
Subclinical hypothyroidism
Increased or normal
Biochemical primary hypothyroidism
Euthyroid sick syndrome
Normal or increased
(FT, 3.98)
(T4 12.3)
* See Patients and Methods for descriptions of patient
groups; see Table 1 for abbreviations.
t The TSH assay used does not distinguish between normal values and low values.
$ A total of
175 patients were tested; 6 patients’ laboratory data did not meet the criteria for inclusion in any of the 5 groups.
Table 3. Selected laboratory parameters in systemic lupus erythematosus patients, according to
“functional group”*
Parameter (normal)
Leukocyte count (5,000-10,000/mm3)
Hematocrit (37-47%)
ESR,Westergren (0-20 mdhour)
Serum albumin (3.8-4.9 gm/dl)
Serum IgG (650-1,600 mg/dl)
Anti-native DNA (<25%)
Antithyroglobulin antibodies (<100)
Antimicrosomal antibodies (<100)
< 100
< 100
* Data are nonparametrically distributed and are expressed as means. Values for antithyroglobulin and
antimicrosomal antibodies are represented as antibody titer (i.e., 100 = 1:lOO). Groups are defined in
Table 2. ESR = erythrocyte sedimentation rate.
t P < 0.05 versus group 1 .
S P < 0.05 versus group 2.
3 P < 0.05 versus group 4.
to determine their TSH reserve. All patients tested in
groups 1 (n = I), 4 (n = 5 ) , and 5 (n = 1) had a normal
serum TSH response to TRH injection. Four of the 5
group 2 patients and 2 of the 3 group 3 patients tested
showed an exaggerated TSH response, which is consistent with primary hypothyroidism.
Technetium scans of the thyroid were performed on 15 patients with normal thyroid function
test results. Eight of them had normal results, 5
showed mild, diffuse, increased uptake, and 2 showed
mild, diffuse, decreased uptake. In 8 patients with
subclinical hypothyroidism, technetium scans showed
that 5 were normal, 2 had decreased uptake, and 1 had
increased uptake.
Analysis of selected laboratory indicators of
disease activity from each of these 5 groups showed
statistically significant differences between groups.
Patients with normal thyroid test results (group 1) had
significantly higher blood leukocyte counts and serum
albumin values, and lower Westergren erythrocyte
sedimentation rates (ESR) and antithyroglobulin antibody titers than did some of the other groups (Table 3).
Patients with biochemical primary hypothyroidism
(group 3) had significantly lower hematocrit levels and
higher ESRs than did group 1 patients. The “euthyroid
sick” SLE patients (group 4) had significantly higher
serum IgG levels and lower serum albumin values than
did some of the other groups. Taken together, these
data suggest that the degree of disease activity, as
manifested by selected laboratory parameters, is associated with thyroid status in predictable ways.
Of the 175 patients studied for the prevalence of
abnormal thyroid function test results, 79 underwent
repeat screening at some time during the 5-year study.
Table 4 lists the initial and final “functional group”
assighments of these 79 patients and illustrates certain
trends in movements of patients from one group to
another over time. While none of the patients with
subclinical hypothyroidism (group 2) changed category
on retesting, patients initially in groups 1 , 3, and 4 were
significantly more likely to be id group 2 on retesting
than in any other group ( P < 0.05). The “euthyroid
sick” population (group 4) was also more likely to be
reassigned to group 1 (no abnormality) with time. It is
possible that some of these changes in “functiohal
group” assignment on repeat testing result from therapy as well as from changes in disease activity.
Since the initial suggestions that patients with
SLE have a higher incidence of autoimmune thyroid
disease than do normal subjects (21-26), there have
been reports of scattered cases of SLE associated with
Table 4. Changes in “functional group” of systemic lupus erythematosus patients after repeated thyroid function testing*
Initial group
1 (n =
2 (n =
3 (n =
4 (n =
5 (n =
Final group assignment
* Data represent rescreening of 79 lupus patients randomly selected
from the 175 patients described in Table 2. Groups are defided in
Table 2.
t P < 0.05 using 2-sided McNemar testing for correlated proportions, with Bonferroni adjustment for multiple comparisons.
both hypothyroidism (27-3 I ) and hyperthyroidism
(32-34). A recent retrospective study of Asian SLE
patients (35) found more thyrotoxicosis (2.8%) than
either hypothyroidism (0.9%) or thyroiditis (0.6%).
Our study suggests that the overall prevalence of
diagnosed thyroid disease in SLE patients (7.5%) does
not significantly differ from that reported in surveys of
women in other populations (36,37). However, in our
SLE population, there was a greater proportion of
diagnosed hypothyroid cases (6.6%) than was found in
women in an English community (1.9%) (36), than in a
population of S L E patients in Norway ( I .4%) (26),
than in a population of Asian SLE patients (0.9%) ( 3 9 ,
and than in a population of hospitalized female patients in a general medical department in Switzerland
(1.4%) (38). The National lnstitutes of Health patient
population is clearly a selected one and does not lend
itself to providing a concurrent control group. A large
community survey would be necessary to determine
whether hypothyroidism is more common in American
SLE patients than in the general population.
There was a very high frequency of abnormal
thyroid function test results in S L E patients who did
not have diagnosed thyroid disease. Elevated TSH
values have been reported in 7.5% of females in a
general population (37). In other studies, 5.9% of
women had TSH values that were above 2 times the
upper limit of the normal range (39), and 13.7% of
women over age 60 had TSH values that were elevated
(40). The data for our SLE patient population suggest
a much higher frequency (10.9-45.1%, depending on
the extent of the TSH elevation). This finding, in
conjunction with the analysis of the grouped thyroid
data (Table 2) and the positive correlations between
antithyroid antibody titers and TSH levels, suggests
that biochemical primary hypothyroidism, perhaps
secondary to autoimmune thyroiditis, is a common
finding in SLE patients. Approximately 5% of all the
grouped thyroid function test results were consistent
with biochemical primary hypothyroidism (low FT4,
Ta. or T1 levels and elevated TSH determinations).,, and
another 39% of these grouped results were consistent
with subclinical hypothyroidism (normal FT4, T4, and
T7 levels but elevated TSH values). In contrast, only
5% of the grouped thyroid test results were consistent
with hyperthyroxinemia/hypertriiodothyroninemia
(high FT4, T4, or T3 values and normal or low TSH
Although our patients could be conveniently
categorized into 5 “functional groups,” the therapeu-
tic implications of these groupings are not clear. Most
physicians would probably not administer thyroid hormone to patients in the “normal” or “euthyroid sick”
groups and would search for symptoms and physical
findings to justify treatment of patients with abnormal
thyroid test results that were consistent with biochemical primary hypothyroidism or hyperthyroxinemid
hypertriiodothyroninemia. However, it is still controversial whether thyroid hormone replacement therapy
would benefit patients in the subclinical hypothyroidism group. Some investigators suggest that a number
of such patients will eventually develop overt hypothyroidism (39,41,42), and there is evidence of clinical
response to L-thyroxine in a subset of such a group of
patients (43).
The reasons for the large discrepancy between
the prevalence of diagnosed thyroid disease and that of
laboratory abnormalities suggestive of thyroid disease
in SLE patients are not clear. Since the thyroid
function tests were run in a general clinical laboratory
by standard techniques, we do not believe that the
frequent abnormal findings resulted from a greater
sensitivity of the tests used in this study. And, although many SLE patients were taking medications
that might lower their T3 or T4 values (glucocorticoids,
nonsteroidal antiinflammatory agents, P-blocking
drugs, and dilantin), none had recently received
radiopaque dyes or other medications that would
elevate their TSH values (for review see ref. 14).
Thyroid disease is often difficult to diagnose
clinically in a general population and could certainly
be underdiagnosed in SLE patients because of overlapping symptoms of lupus and thyroid disease. Since
both lupus and thyroid disorders can cause fatigue,
focal edema, weakness, myalgias, arthralgias, and a
variety of other nonspecific complaints (44), many
physicians may incorrectly attribute such symptoms
solely to SLE activity rather than to coexistent thyroid
disease in these patients. It is also possible, however,
that the frequent abnormal thyroid test results are not
all caused by a primary thyroid pathology, but rather,
may represent
that are secondary to the
production of thyrotropin by activated lymphocytes
(45), a peculiar metabolism of thyroid hormones in
SLE patients, or autoantibodies directed against the
thyroid, its hormones, or receptors (46,47).
The pathogenesis of thyroid disease in patients
with SLE deserves comment. The HLA type B8;DR3
occurs significantly more commonly among patients
with either S L E or autoimmune thyroid disease than
among the general population (48-20). Therefore,
there may b e a subset of people w h o have a genetic
predisposition to develop both disorders. The genetic
basis of disease has not been determined definitively,
but appears t o include a predisposition t o excessive
antibody production (51). The underlying cause of the
inflammation in autoimmune thyroiditis has recently
been postulated to include local interferon production,
expression of Ia-like antigens on thyroid cells, and
immune responses to those parts of the thyroid immediately adjacent to the Ia-like antigens (52). Since
patients with SLE often have a marked increase in
interferon production, especially when their disease is
active (53), Ia induction might occur in the thyroids of
these patients because of circulating interferon and,
thus, would not require special local conditions.
We suspect that patients with both SLE and
thyroid disease probably have low levels of thyroid
inflammation, some of which may be suppressed by
the immunosuppressive therapy given for SLE symptoms. SLE patients would be especially prone to
express maximum inflammatory disease prior to major
therapy or after immunosuppressive therapy is reduced or discontinued. This possibility is highlighted
by occasional SLE patients w h o , in our experience,
have developed marked thyroiditis after immunosuppressive therapy had been stopped.
In summary, individuals with SLE frequently
have abnormal results of one or more thyroid function
tests. Some of these abnormalities have no implications for thyroid disease. However, a significant subset of lupus patients appears t o be predisposed t o the
development of hypothyroidism, and this should be
considered when evaluating persons with SLE. We
hope that the present report will focus attention upon
potentially treatable thyroid disorders in certain indi-
viduals with SLE.
The authors thank Dr. John Cowdery for help in
initiating this study, Drs. Nicole G. LeRiche and Lori A.
Love for advice and assistance in the completion of this
study, and Dr. Gregory Campbell for help in the statistical
analysis of our data.
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test, lupus, patients, abnormal, systemic, erythematosus, results, disease, thyroid, function, prevalence
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