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Serum negative autoimmune thyroiditis
displays a milder clinical picture compared with
classic Hashimoto’s thyroiditis
Mario Rotondi
1
, Luca de Martinis
1
, Francesca Coperchini
1
, Patrizia Pignatti
2
,
Barbara Pirali
1
, Stefania Ghilotti
1
, Rodolfo Fonte
1
, Flavia Magri
1
and Luca Chiovato
1
1
Unit of Internal Medicine and Endocrinology, Fondazione Salvatore Maugeri I.R.C.C.S., Laboratory for Endocrine
Disruptors, Chair of Endocrinology and
2
Allergy and Immunology Unit, Fondazione Salvatore Maugeri I.R.C.C.S.,
University of Pavia, Via S. Maugeri 10, I-27100, Pavia, Italy
Correspondence
should be addressed
to L Chiovato
Email
lchiovato@fsm.it
Abstract
Background: Despite high sensitivity of current assays for autoantibodies to thyroperoxidase (TPO) and to thyroglobulin (Tg),
some hypothyroid patients still present with negative tests for circulating anti-thyroid Abs. These patients usually referred to
as having seronegative autoimmune thyroiditis (seronegative CAT) have not been characterized, and definite proof that
their clinical phenotype is similar to that of patients with classic chronic autoimmune thyroiditis (CAT) is lacking.
Objective: To compare the clinical phenotype of seronegative CAT (SN-CAT) and CAT as diagnosed according to a raised
serum level of TSH with negative and positive tests for anti-thyroid Abs respectively.
Methods: A case–control retrospective study enrolling 55 patients with SN-CAT and 110 patients with CAT was performed.
Serum free triiodothyronine (FT
3
), free thyroxine (FT
4
), TSH, Tg Abs, and TPO Abs were measured in all patients.
Results: Patients with SN-CAT displayed significantly lower mean levels of TSH (6.6G3.4 vs 10.2G9.8 mU/ml; PZ0.009),
higher mean FT
4
levels (1.1G0.2 vs 0.9G0.2 ng/dl; PZ0.0002), and similar FT
3
levels when compared with CAT patients.
Mean thyroid volume was significantly greater in patients with CAT when compared with SN-CAT patients (11.2G6.5 vs 8.1
G3.7 ml; PZ0.001). Logistic regression demonstrated that FT
4
(0.123 (0.019–0.775); (PZ0.026)) and thyroid volume
(1.243 (1.108–1.394); (PZ0.0002)) were significantly and independently related to the diagnosis (CAT/SN-CAT). Patients
with SN-CAT had a similar prevalence of thyroid nodules and female gender but a lower prevalence of overt hypothyroidism
(5.4 vs 20.9%; PZ0.012) as opposed to patients with CAT.
Conclusions: These results suggest an autoimmune etiology of SN-CAT, which, however, seems to have a milder clinical course
when compared with CAT.
European Journal of
Endocrinology
(2014) 171, 31–36
Introduction
Chronic autoimmune thyroiditis (CAT) is the main cause
of hypothyroidism in the general population (1). Auto-
antibodies to thyroperoxidase (TPO) and to thyroglobulin
(Tg) are the circulating hallmark of this autoimmune
thyroid disease (1, 2). Positive tests for TPO Abs are present
in w90% (TPO Abs) and 50% (Tg Abs) of hypothyroid
patients with CAT (1, 3, 4). Their prevalence in the general
population is highly variable, given the strong gender and
age effect, but it may reach a rate of 12–15% in females in
their third to fourth decade of life (5, 6). Early studies
supported the hypothesis that TPO Abs would play a
pathogenic role in the development of autoimmune
thyroiditis (7). Indeed, they fix complement and, at least
in vitro, can produce antibody-dependent cell cytotoxicity
(8). However, the high prevalence of positive tests for
TPO Abs in euthyroid subjects and the observation that
neonates born to mothers with circulating TPO Abs have a
normal thyroid gland (9) have made it clear that TPO Abs
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 31–36
www.eje-online.org Ñ2014 European Society of Endocrinology
DOI: 10.1530/EJE-14-0147 Printed in Great Britain
Published by Bioscientifica Ltd.
are more likely markers and/or risk factors for the
subsequent development of autoimmune thyroid disease
rather than pathogenic factors (10).
In spite of the high sensitivity of modern assay
methods for TPO Abs and TG Abs, a consistent percentage
of hypothyroid patients present with negative tests for
these thyroid autoantibodies (11).Asmostofthese
patients display a hypoechoic pattern of their thyroid at
neck ultrasound (US) examination, the diagnosis of ‘serum
negative autoimmune thyroiditis’ (seronegative CAT) is
commonly used to define the underlying thyroid disorder.
(12). Besides the description of some clinical cases, in
which seronegative CAT (SN-CAT) was detected in
association with type 1 diabetes mellitus (13) or rheuma-
toid arthritis (14, 15), no currently published study
evaluated a large series of patients with SN-CAT.
The prevalence of SN-CAT can be estimated indirectly
at w5% taking into account the rate of hypothyroid
patients showing positive tests for thyroid autoantibodies
in the published studies (11). The rather low prevalence of
the condition and the non-routine, at least in previous
years, use of thyroid US scan contributed to the opinion
that these patients have a similar clinical phenotype when
compared with those having classic CAT. In recent years,
the routine use of ultrasensitive thyroid-stimulating
hormone (TSH) measurements, which increased the
detection of subclinical hypothyroidism in patients,
contributed to raise the prevalence of SN-CAT, as it is
known that the rates of positive thyroid Ab tests increase
with increasing levels of TSH (6, 16).
Up to date, the clinical presentation of patients with
SN-CAT was not systematically investigated; in particular,
it is still unknown whether its clinical features are similar
to those of classic CAT.
The aim of this study was to compare the clinical
phenotype of patients who received a diagnosis of SN-CAT
with that of patients with classic CAT.
Subjects and methods
Subjects
The study group encompassed 55 patients who received a
diagnosis of SN-CAT in the Outpatient Clinic of the Unit
of Internal Medicine and Endocrinology of the Fonda-
zione S. Maugeri I.R.C.C.S. (Pavia, Italy) between 2008 and
2011. The diagnosis of SN-CAT was based on the following
criteria: i) presence of subclinical and/or overt hypothyr-
oidism, as assessed by a serum TSH level O4.0 mU/ml
associated with either normal or low FT
4
levels
respectively; ii) negative tests for circulating Tg Abs and
TPO Abs on at least two consecutive measurements; and
iii) a US scan of the thyroid showing a hypoechoic pattern
of its parenchyma. The study group encompassed seven
males and 48 females. Their median (and range) age was
47.7 (17–80) years.
The control group was composed of a double number
of patients (110; 12 males and 98 females) who had
received a diagnosis of CAT. Control patients with CAT
were consecutively and retrospectively selected using a
computerized database. Inclusion criteria were positive
tests for either TG Abs, TPO Abs, or both, accompanied
by clinically overt or subclinical hypothyroidism.
In all patients and controls, the diagnosis of subclinical
hypothyroidism was confirmed on at least two separate
TSH measurements at time intervals ranging from 2 to
6 months. Common exclusion criteria were: i) pregnancy
at diagnosis and/or within 1 year from study entry; ii) a
history of irradiation of the neck; iii) current and/or
previous L-thyroxine (T
4
) treatment; iv) treatment with
corticosteroids, amiodarone, lithium, oral contraceptives,
or other thyroid interfering drugs; v) inter-current chronic
illnesses; vi) a previous diagnosis of thyroid disease, in
particular Graves’ disease and subacute thyroiditis; and
vii) presence of obesity (BMI level R30 kg/m
2
).
The family history, as well as the co-morbidity for
other allergic or autoimmune (allergic rhinitis or asthma,
thyroid diseases, type 1 diabetes mellitus, psoriasis,
vitiligo, alopecia, celiac disease, Crohn’s disease, rheuma-
toid arthritis, atrophic gastritis, and lupus) and non-
autoimmune (thyroid diseases) disorders, was recorded.
The study was approved by the Local Ethics Committee.
Serum assays
Serum concentrations of free triiodothyronine (FT
3
,
normal range 1.5–4.1 pg/ml), free T
4
(FT
4
, normal range
0.8–1.9 ng/dl), and TSH (normal range 0.4–4.0 mIU/l)
were measured using immunochemiluminescent assays
by an automated analyser (Immulite 2000, DPC Cirrus,
Los Angeles, CA, USA) employing commercially available
kits (all from Diagnostic Products Corporation, Los
Angeles, CA, USA). The intra-assay coefficient of variation
(CV) values for these hormones ranged from 4.3 to
8.4% for FT
3
, from 5.2 to 7.5% for FT
4
, and from 5.1
to 12.5% for TSH. Inter-assay CV values ranged from 5.4 to
10.0% for FT
3
, from 7.7 to 9.0% for FT
4
, and from 6.4
to 12.5% for TSH. The analytical sensitivities were
1.0 pg/ml for FT
3
,0.3ng/dlforFT
4
,and0.004mIU/l
for TSH (third-generation TSH assay). The serum
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 32
www.eje-online.org
concentrations of Tg Abs (normal range !60 U/ml) and
TPO Abs (normal range !60 U/ml) were measured using
immunochemiluminescent assays employing commerci-
ally available kits (Brahams, Hennigsdorf, Germany). The
sensitivity of the assay was 33 U/ml for TGAb and 50 U/ml
for TPO Abs. The intra- and inter-assay CV values were
2.6 and 13% respectively for TG Abs and 3.9 and 8%
respectively for TPO Abs. Samples were assayed in duplicate.
Quality control pools at low, normal, and high concen-
trations for all parameters were present in each assay.
Setting the reference limit for thyroid
autoantibodies positivity
Considering that the manufacturer’s cutoff (!60 UI/ml
for both antibodies) might not be adequate, a control
group of 55 age- and sex-matched subjects in whom
thyroid disorders had been excluded by a complete
thyroid work-up (history, physical examination, TSH,
FT
3
,FT
4
, and thyroid US) was recruited. The results
of samples found to be below the limit of detection
(!10 UI/ml for both Tg Abs and TPO Abs) were arbitrarily
estimated to be 10 UI/ml. In a control group, the mean
GS.D. circulating levels of thyroid autoantibodies were
14.11G9.76 UI/ml for Tg Abs and 14.74G8.98 UI/ml for
TPO Abs. On this basis, the cut-off for defining a positive
test was chosen for Tg Abs and TPO Abs at O2S.D. of the
mean level found in the control group (O33.6 UI/ml for
Tg Abs and O32.7 UI/ml for TPO Abs).
According to these in house-established reference
limits, five out of 55 (9.1%) and one out of 55 (1.8%)
patients with SN-CAT displayed above normal titers for Tg
Abs and TPO Abs respectively. Statistical analysis per-
formed after exclusion of these six patients confirmed the
results obtained when the whole study group (nZ55) was
taken into account. Thus, we decided not to exclude the
above-mentioned six patients.
Statistical analysis
Statistical analysis was performed using the SPSS Software
(SPSS, Inc.). Between-groups comparisons were performed
using the Student’s t-test for unpaired data and the Mann–
Whitney U-test according to a normal or a non-parametric
distribution; comparisons were performed using the
Student’s t-test for paired data and the Wilcoxon’s test
according to a normal or a non-parametric distribution.
Frequencies among groups were compared using the
c
2
-test with Fisher’s correction when appropriate. To test
the effects of different variables independent of a
covariate, multivariate logistic regression analysis was
used and partial correlation coefficients were computed.
The multivariate model was constructed by entering the
diagnosis (CAT and SN-CAT) as a dependent variable,
while TSH, FT
4
, and thyroid volume (all factors found to be
significant at P!0.05 in the univariate analysis) were
entered as covariates. A Pvalue of !0.05 was considered
statistically significant. Results are expressed as mean
GS.D., unless otherwise stated.
Results
The clinical and anthropometric data of patients with
SN-CAT and of those with classic CAT are shown in
Table 1. The two groups had a similar M:F ratio (12:98 for
CAT vs 7:48 for SN-CAT), age at first diagnosis (47.3G14.7
vs 47.7G16.6 years), height (161.0G7.8 vs 161.2G
8.4 cm), weight (62.7G10.8 vs 60.7G10.4 kg), and BMI
(24.1G3.4 vs 23.2G2.9 kg/m
2
). As also shown in Fig. 1,
patients with SN-CAT displayed significantly lower levels
of serum TSH (6.6G3.4 vs 10.2G9.8 mU/l; PZ0.009) and
higher FT
4
levels (1.1G0.2 vs 0.9G0.2 ng/dl; PZ0.0002)
compared with those having CAT. The circulating
concentrations of FT
3
were similar in the two groups
(3.2G0.7 vs 3.4G0.9 pg/ml). The prevalence of overt
hypothyroidism was significantly (PZ0.012) higher in
Table 1 Anthropometric and clinical parameters in patients
with CAT and SN-CAT. Data are shown as meanGS.D. unless
otherwise stated.
CAT (AbC)SN-CAT (AbK)Pvalue
No. of patients 110 55
Sex (M/F) 12/98 7/48 0.730
Age at
diagnosis (years)
47.3G14.7 47.7G16.6 0.869
Weight (kg) 62.7G10.8 60.7G10.4 0.261
Height (cm) 161.0G7.8 161.2G8.4 0.875
BMI (kg/m
2
) 24.1G3.4 23.2G2.9 0.101
FT
3
(pg/ml) 3.2G0.7 3.4G0.9 0.097
FT
4
(ng/dl) 0.9G0.2 1.1G0.2 0.0002
TSH (mU/ml) 10.2G9.8 6.6G3.4 0.009
TSH (mU/ml)
(median and
range)
6.8 (4.2–58.0) 5.8 (4.1–27.0) 0.0007
Overt/subclinical
hypothyroidism
23/87 (20.9%) 3/52 (5.4%) 0.012
Thyroid volume (ml) 11.2G6.5 8.1G3.7 0.001
Thyroid volume (ml)
(median and
range)
10 (3–62) 8 (2–20) 0.00003
Nodule (yes/no) 25/85 (22.7%) 14/41 (25.4%) 0.697
Goiter O20 ml 3 (2.7%) 0 (0%) 0.551
Bold characters indicate significant differences.
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 33
www.eje-online.org
patients with CAT (23/110, 20.9%) as opposed to those
with SN-CAT (3/55; 5.4%). Mean thyroid volume, as
measured by US, was significantly greater in patients
with CAT when compared with those having SN-CAT
(11.2G6.5 vs 8.1G3.7 ml; PZ0.001). Although the statisti-
cal significance was not reached, three patients with CAT
and none with SN-CAT had goiter (diagnosed when the
thyroid volume was O20 ml). A similar prevalence of
thyroid nodules was found in patients with CAT (22.7%)
when compared with those having SN-CAT (25.4%).
To test the independent effect of each variable, a
logistic regression model was constructed with the
diagnosis (CAT/SN-CAT) as a dependent variable and all
factors showing significant differences in the univariate
analysis (TSH, FT
4
, and thyroid volume) entered as
covariates. The results shown in Table 2 demonstrated
that only FT
4
and thyroid volume were significantly
and independently related to the diagnosis of CAT and
SN-CAT.
A positive family history for thyroid diseases was
present in 33.6% of patients with CAT and 43.6% of those
with SN-CAT (PZ0.21). However, patients with CAT
displayed a significantly higher prevalence of positive
family history for autoimmune diseases when compared
with patients having SN-CAT (44.5 vs 25.4%; PZ0.017).
The thyroid disease-free control group also served
to assess whether patients with SN-CAT had a higher
than normal frequency of autoimmune diseases
(including autoimmune thyroid diseases) or non-
autoimmune thyroid diseases in their family. A positive
family history of autoimmune diseases was present in
14.5% of thyroid disease-free control subjects. The
correspondent figure for a positive family history of non-
autoimmune thyroid diseases was 10.9%. When these
family histories were compared with those observed in
SN-CAT patients, a strong significant difference (10.9 vs
43.6%; PZ0.00012) emerged for a positive family history
of non-autoimmune thyroid diseases. On the other hand,
despite an w1.5-fold increase, the rate of positive family
history for autoimmune diseases in patients with SN-CAT
did not reach significance compared with controls (25.4 vs
14.5%; PZ0.153).
As a further step, co-morbidities were taken into
account. Patients with SN-CAT showed a significantly
lower rate of co-morbidities for non-thyroid autoimmune
diseases compared with those having CAT (21.8 vs 44.5%;
PZ0.004).
Tabl e 2 Results of logistic regression analysis using the
diagnosis (SN-CAT and CAT) as a dichotomous dependent
variable.
Pvalue Exp(b)
95% CI
Lower Upper
Serum FT
4
(ng/dl) 0.026 0.123 0.019 0.775
Serum TSH (mU/ml) 0.085 1.102 0.987 1.231
Thyroid volume (ml) 0.0002 1.243 1.108 1.394
Covariates were chosen on the basis of Pvalues (!0.05) as a result of the
univariate analysis.
20.00A
18.00
16.00 P=0.009
14.00
Serum TSH (mlU/I)
12.00
10.00
8.00
6.00
4.00
SN-CAT CAT
B 18.0
16.0
14.0
Serum FT4 (pg/ml)
12.0
10.0
8.0
6.0
4.0
SN-CAT CAT
P=0.002
Figure 1
(A) Distribution of the serum levels of TSH in patients with
SN-CAT and CAT. (B) Distribution of the serum levels of FT
4
in
patients with SN-CAT and CAT. The data are expressed as median
and 25th and 75th percentiles in boxes and 5th and 95th
percentiles as whiskers.
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 34
www.eje-online.org
Discussion
The results of this study, which investigated the so far
largest series of patients with SN-CAT, indicate significant
differences in the clinical presentation of patients with
SN-CAT compared with those having classic CAT.
First, a prevalence of female gender was observed both
in patients with SN-CAT and in those with CAT. This is a
strong argument pointing toward an autoimmune etiol-
ogy of SN-CAT. Indeed, in conditions such as morbid
obesity, in which the raised serum levels of TSH are not
sustained by an autoimmune process, no gender effect is
observed.
Secondly, the age at presentation was similar in
patients with SN-CAT and those with CAT. This finding
would contrast with the common belief that a hypoechoic
pattern of the thyroid at US anticipates the appearance of
circulating thyroid Abs (17, 18, 19, 20).
Thirdly, lower serum TSH levels and higher serum FT
4
levels are found in patients with SN-CAT when compared
with patients having classic CAT, even if the results of the
multivariate analysis clearly indicate that the effect should
be mainly ascribed to FT
4
. Although the cross-sectional
design of this study does not allow drawing conclusions as
to the natural history of SN-CAT, given that the age at
diagnosis was similar in the two groups, it could be
speculated that the course of SN-CAT is less aggressive
than that of CAT. This hypothesis would be further
supported by the significantly lower rate of overt
hypothyroidism observed among patients with SN-CAT.
The absence of goiter in patients with SN-CAT and the
observation that their thyroid volume was smaller might
suggest that the autoimmune inflammatory infiltrate is
less severe. Indeed, in the classical description of auto-
immune thyroiditis by Hashimoto (21), most patients
had goiter.
Fourthly, patients with SN-CAT had the same preva-
lence of thyroid nodules when compared with patients
having CAT. This observation implies that, compared with
CAT, no nodule-dependent selection bias affected the
recruitment patients with SN-CAT.
The last finding to be discussed is the lower prevalence
of a positive family history for autoimmune diseases and
associated autoimmune conditions in patients with
SN-CAT as opposed to those with classic CAT. Given that
autoimmune diseases result from the interplay between
genetic and environmental factors, it could be speculated
that patients developing SN-CAT would have a weaker
genetic predisposition, while environmental factors play a
more relevant role in their pathogenesis (22, 23). In this
regard, it is also important to recall that two previously
described cases of patients with SN-CAT were found to
be associated with serum negative rheumatoid arthritis
(14, 15). Thus, it could be speculated that patients with
SN-CAT might be more prone to develop other serum
negative autoimmune diseases, the diagnosis of which
might be more cumbersome.
The retrospective design of this study does not allow
grading the echogenicity of the thyroid parenchyma at
US, and this can be viewed as a limitation of this study.
Therefore, it is impossible to compare the degree of
hypoechogenicity in patients with SN-CAT with those
with CAT. Future specifically designed studies will be
required to address this issue.
The design of this study does not allow drawing firm
conclusions about the prevalence of SN-CAT, but the
following consideration could be proposed. The preva-
lence of SN-CAT can so far be estimated indirectly at
w5% according to the rate of positive tests for thyroid
Abs reported by previous clinical studies in patients with
hypothyroidism (3, 4, 11). However, these early studies
enrolling patients with raised serum levels of TSH did
not take into account the presence of clinical conditions
associated with an increase in circulating TSH levels
recently proven not to be indicative of thyroid failure.
In particular, morbid obesity has recently been identified
to cause an increase in the serum levels of TSH often
associated with the presence of a hypoechoic pattern
of the thyroid at US, which do not imply that hypo-
thyroidism is present (24, 25, 26, 27). Taking into
account the above concepts, it would be reasonable to
assume that the prevalence of SN-CAT might have been
overestimated by earlier studies.
In conclusion, the results of the current study,
performed in the largest series of patients with SN-CAT
investigated so far, suggest an autoimmune etiology of the
disease. Although SN-CAT displays similar clinical features
when compared with CAT, serum negative patients appear
to have a less aggressive disease.
Declaration of interest
The authors declare that there is no conflict of interest that could be
perceived as prejudicing the impartiality of the research reported.
Funding
This research did not receive any specific grant from any funding agency in
the public, commercial or not-for-profit sector.
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 35
www.eje-online.org
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Received 18 February 2014
Revised version received 14 April 2014
Accepted 15 April 2014
European Journal of Endocrinology
Clinical Study M Rotondi and others Clinical phenotype of
seronegative CAT
171:1 36
www.eje-online.org
