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Original Studies |
-Induced Thyroid Autoimmunity and Prognostic Influence of Thyroid Autoantibody Pattern at the End of Treatment
Institute of Endocrinology, "Seconda University" of Naples (C.C., Gh.M., Gi.M., M.R., F.S., G.A.); Department of Food Science, Parco Gussone, Portici (F.M., C.T., N.C.) "Federico II" University of Naples, 80121 Naples, Italy
Address all correspondence and requests for reprints to: Carlo Carella, M.D., Via Crispi, 44, 80121 Naples, Italy. E-mail: carlo.carella{at}unina2.it
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) treatment, but the literature lacks
data regarding the long-term course of these complications, clinical
observation being limited to 6–12 months off therapy. Our
study is the first that has aimed to evaluate the natural history of
IFN-related thyroid autoimmunity during a 6.2-yr follow-up after the
IFN- withdrawal as well as to investigate the potential role of the
autoantibody pattern at the end of treatment to predict the long-term
outcome.
Our study group included 114 patients (79 males, 35 females), mean age
48 yr (range 23–67 yr) with no preexisting thyroid disease, undergoing
a 12-month treatment with recombinant IFN- for C virus-related
chronic active hepatitis. Thyroid autoimmunity (serum TgAb and TPOAb)
and function (serum FT4, FT3, TSH) were
retrospectively evaluated at the end of IFN therapy, 6 months after IFN
withdrawal and after a median period of 6.2 yr (range 5.5–8.4 yr).
At the end of treatment, 78 patients were negative for thyroid autoantibodies (Abs-) and all but one of them remained so for the following evaluations. The remaining 36 patients had thyroid autoantibodies (Abs+) at the end of treatment, and they subsequently showed a heterogeneous behavior: 16 patients remained Abs+ for the whole length of the study (persistent thyroiditis); 10 patients became Abs- 6 months off therapy but were again Abs+ 6.2 yr later (remitting/relapsing thyroiditis); 10 patients reverted to autoantibody negativity at different observation times (transient thyroiditis).
The absence of thyroid autoantibodies at the end of treatment was a protective factor for the successive development of thyroiditis (odds ratio: 0.02, confidence interval (CI) 95%: 0–0.1). On the contrary, the positivity for TgAb and/or TPOAb at high titers at the end of IFN treatment was significantly related to the highest risk of having chronic thyroiditis (odds ratio: 17.3, CI 95%: 3.2–91.7 for TgAb levels > 50 degree percentile; odds ratio: 7.3, CI 95%: 1.5–35.2 for TPOAb levels > 50 degree percentile).
None of the patients showed overt thyroid dysfunction throughout the study, whereas a subclinical hypothyroidism was found in 12 patients. In all 12 cases, the functional abnormality was accompanied by the presence of thyroid autoantibodies. Eight of these 12 patients belonged to the group with persistent thyroiditis (P < 0.05).
The absence of thyroid autoantibodies at the end of treatment was a protective factor for the successive development of thyroid dysfunction (odds ratio: 0.06, CI 95%: 0.01–0.56). On the contrary, the positivity for both TgAb and TPOAb at the end of IFN therapy was significantly correlated with the highest risk of having subclinical hypothyroidism 6.2 yr. later (odds ratio: 38.7; CI 95%: 6.2–242).
Our study demonstrates that in patients undergoing an IFN- therapy
for chronic hepatitis C and with no evidence of preexisting thyroid
disease: 1) the negativity for thyroid autoantibodies after IFN
treatment is a protective factor for the developing thyroid
autoimmunity and/or dysfunction in following years; 2) the
IFN--related thyroid autoimmunity is not a complete reversible
phenomenon because some patients can develop chronic thyroiditis; 3)
high autoantibody levels at the end of IFN therapy are related to the
risk of having chronic thyroid autoimmunity; and 4) the coexistence of
TgAb and TPOAb at the end of treatment is a predictive factor for the
presence of thyroid dysfunction, even if subclinical, many years after
IFN withdrawal.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) HAS become the
standard therapy for chronic hepatitis C (CHC), inducing a biochemical
(persistent normalization of alanine-aminotransferase) and virological
(sustained negativity for hepatitis C virus [HCV] RNA)
response in about 15%–25% of patients treated (1).
Thyroid autoimmunity has been widely reported as a side effect of
IFN- treatment with a percentage variable from 2.5–45.3%
(2, 3, 4, 5, 6, 7, 8), even if its physiopathological mechanisms remain
unclear. The long-term outcome of this event is even less known,
leaving controversial the clinical question of whether to withdraw or
continue the therapy in patients with signs of autoimmunity. On the
other hand, only the knowledge of the real benefits (rate of remission
of the hepatic disease) and the risk (evolution of the induced thyroid
disease) allows a correct guide to therapy. In fact, very few data
about the long-term outcome of such conditions are currently available.
There is no case in which the clinical course of cytokine-induced
thyroiditis has been evaluated more than 1 yr after the completion of
treatment. However, it is not clear whether such thyroid autoimmunity
is temporary or persistent, considering that after IFN-
administration was ended, antibody titers could fall and become
negative, remain elevated, or increase (3, 4, 5, 7, 8, 9).
The aim of this study is to evaluate the clinical course of thyroid
autoimmunity and/or dysfunction in a group of patients with C
virus-related chronic active hepatitis by retrospective analysis of
thyroid status several years after the therapy with human recombinant
IFN- as well as to investigate the potential role of the
autoantibody pattern at the end of treatment to predict the long-term
outcome.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Our study group included 114 patients (79 males, 35 females),
mean age 48 yr (range 23–67 yr), affected by CHC, proven by liver
biopsy and a presence of anti-HCV antibodies detected by enzyme-linked
immunosorbent assay II. All patients underwent treatment with
recombinant IFN- (Roferon-A, Hoffman-LaRoche Inc.,
Basel, Switzerland) for 12 months (3–6 MU, three times weekly).
Long-term response to interferon therapy was defined as the
disappearance of serum HCV-RNA and the normalization of serum
alanine-aminotransferase for at least 12 months after ending
therapy.
Patients with thyroid disease before treatment were excluded from the
study group. Thyroid autoimmunity (serum TgAb and TPOAb) and function
(serum FT4, FT3, TSH) were
retrospectively evaluated on frozen aliquots, drawn before and at the
end of IFN- therapy, 6 months after IFN withdrawal, and after a
median period of 6.2 yr (range: 5.5–8.4 yr). The tests, performed on
aliquots drawn before treatment, confirmed the absence of thyroid
abnormalities in all 114 patients of our study group.
In the period following IFN withdrawal, none of the patients showed clinical findings of thyroid dysfunction and received substances interfering with thyroid function. Moreover, no further trials were undertaken.
Biochemical assays
Serum FT3 and serum FT4 were tested by double-antibody RIA (Technogenetics, Milan, Italy), whereas serum TSH was assayed by an immunoradiometric method (DiaSorin, Inc., Saluggia, Italy). Samples were assayed in duplicate for each hormone. The detection limit of the assays in SI, the intra- and interassay variations expressed as coefficient of variation were: 1.2 pmol/L, 2.9% and 4.7% for FT3; 1.3 pmol/L, 3.0% and 5.7% for FT4; 0.05 mU/L, 3.1% and 4.2% for TSH, respectively. In our laboratory, normal values were 3.8–7.7 pmol/L for FT3, 9.0–23.1 pmol/L for FT4 and 0.3–3.5 mU/L for TSH. TgAb (negative <100 U/mL) was measured using the immunoradiometric assay (BioChem ImmunoSystem, Bologna, Italy) with intraassay, interassay, and limit of 3.9%, 6.9%, and 5.0 U/mL, respectively. TPOAb (negative <10 U/ml) was tested by RIA kit set (DiaSorin, Inc.) with intraassay, interassay, and detection limit of 2.5%, 6.6%, and 0.7 U/mL, respectively. TSH receptor antibodies (TRAb, negative <10 U/mL) were tested by RRA (Henning, Berlin, Germany).
Statistical analysis
Results are expressed as median and ranges. Unpaired data were
compared by Mann-Whitney test and frequencies among different groups
were compared by 
2 and Fisher exact tests.
Friedman’s test was performed to compare repeated measures. A logistic
regression model was used in the statistical analysis of risk factors
for the development of persistent positivity for thyroid autoantibodies
and subclinical hypothyroidism in the years following IFN-
withdrawal. A P value <0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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therapy, 31% of patients showed positivity
for thyroid autoantibodies (Abs+), with TgAb values of 354 U/mL
(126–15.000) and TPOAb values of 850 U/mL (40–1216). Six months after
therapy, the percentage of patients Abs+ decreased to 18% (TgAb: 484
U/mL, range: 116-7420; TPOAb: 180 U/mL, range: 19–1516), but 6.2 yr
later the rate of positivity increased to 23% (TgAb: 345 U/L range:
104–17708; TPOAb: 42.5 U/mL, range: 12–276). None of our patients
showed TRAb neither at the end of IFN- therapy nor during the
following years.
Figure 1
shows that at the end of
treatment, 78 patients were negative for thyroid autoantibodies (Abs-)
and 36 patients were Abs+. Following evaluations showed that all but
one of the 78 Abs- patients remained so for the entire length of the
study (no thyroiditis). On the contrary, the 36 Abs+ patients showed
heterogeneous behavior: 16 patients remained Abs+ for the whole length
of the study (persistent thyroiditis); 10 patients became Abs- 6
months off therapy but were again Abs+ 6.2 yr later
(remitting/relapsing thyroiditis); and 10 patients reverted to
autoantibody negativity at different observation times (transient
thyroiditis).
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). However, a
significant reduction of serum TgAb and TPOAb values during the
follow-up was found in patients with persistent thyroiditis but not in
those with remitting/relapsing thyroiditis; patients with transient
thyroiditis, instead, showed a significant reduction of serum TgAb but
not in TPOAb values (Table 1).
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At the end of IFN therapy, eight patients showed a subclinical
hypothyroidism; in five of them, the thyroid function normalized 6
months later and remained so until the last observation, and in the
other three patients, the subclinical hypothyroidism was present for
the entire length of the study. Four patients with normal thyroid
function at the end of therapy and 6 months later demonstrated a newly
appeared subclinical hypothyroidism after a 6.2-yr IFN withdrawal
(Table 2).
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Logistic regression analysis showed that the positivity for TgAb and/or TPOAb at high titers at the end of IFN therapy was associated with the highest risk of having chronic thyroid autoimmunity (odds ratio: 17.3, CI 95%: 3.2–91.7 for TgAb levels > 50 degree percentile; odds ratio: 7.3, CI 95%: 1.5–35.2 for TPOAb levels > 50 degree percentile). The positivity for TgAb at low titer, on the contrary, was not significantly linked to the risk of developing chronic thyroid autoimmunity. Moreover, the highest risk for the development of persistent or newly appeared subclinical thyroid dysfunction was associated with the coexistence of TgAb and TPOAb at the end of IFN therapy (odds ratio: 38.7, CI 95%: 6.2–242.0). The absence of thyroid autoantibodies at the end of treatment was a protective factor for developing thyroiditis (odds ratio: 0.02, CI 95%: 0.01–0.1) and thyroid dysfunction (odds ratio: 0.06, CI 95%: 0.01–0.56) in the following years.
A long-term remission of CHC was shown in 30 of 114 patients (26.3%),
with no statistical difference between Abs+ patients and Abs- patients
at the end of IFN- therapy (36.1% vs. 21.8%; NS).
Comparable percentages of response to IFN were found in patients with
persistent thyroiditis (30.8%), remitting/relapsing thyroiditis
(40.0%), and transient thyroiditis (40%).
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Discussion |
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|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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treatment is widely reported (2, 3, 4, 5, 6), but the literature
lacks data regarding the long-term course of these complications,
the clinical observation being limited to 6–12 months off therapy. Our
study is the first that has aimed to evaluate the natural history of
IFN-related thyroid autoimmunity during a 6.2-yr follow-up after the
end of IFN- treatment. Our long-term retrospective analysis is
critical for the observation of the different courses of such
IFN-related thyroiditis as well as the identification of predictive
markers of this disease.
In our study the percentage of positivity for thyroid autoantibodies
decreased in the 6 months following IFN withdrawal. Subsequently, from
6 months off therapy to the last observation, such percentage increased
from 18% to 23%. This last finding is according to the
epidemiological studies that have reported a progressive increase of
positivity rate for thyroid autoantibodies through the years
(10). It is, however, interesting to find that the
increase found in our work was observed only in patients who have shown
thyroid autoimmunity after cytokine therapy. On the contrary, the
patients without thyroid autoantibodies at the end of treatment
remained so for the entire length of the study. It seems reasonable to
hypothesize that this group of patients could not have a susceptibility
with regards to the development of thyroid autoantibodies: IFN-
should induce thyroid immunity only in patients with an immunological
predisposition, such as reported in clinical and experimental studies
(11, 12, 13).
In the literature, the data regarding the short-term evolution of
thyroid autoimmunity induced by IFN- therapy are controversial
(3, 4, 5, 7, 8, 9). Some authors have reported a complete
recovery from thyroid autoimmune disease a few months after IFN
withdrawal (5, 9). On the contrary, others (4, 7, 8), ourselves included (3), reported a partial
reversibility of thyroid autoimmunity 6 months after the withdrawal of
IFN therapy. In the present study, the long-term follow-up confirmed
that the IFN-related thyroid autoimmunity is not a complete reversible
phenomenon because some patients could develop chronic thyroiditis.
Our study demonstrated that the thyroid autoantibody pattern at the end of treatment is a predictive factor for the different outcomes of IFN-related thyroiditis. Recently, it has been reported that the cytokine-induced thyroiditis is characterized predominantly by positivity for TgAb with absent or low TPOAb levels; the authors considered this pattern dissimilar to that observed in patients with Hashimoto’s thyroiditis and Graves’ disease (14). These findings are similar to those found in our patients with transient thyroiditis and remitting/relapsing thyroiditis. In addition to these findings, we also demonstrated high TgAb and TPOAb levels overall in patients who developed persistent thyroiditis, according to the concept that thyroid autoantibody levels could reflect the severity of the underlying autoimmune process (15, 16). The different behavior observed in our experience could be explained by the hypothesis that genetic predisposition to thyroid autoimmunity is provided by several disease-associated alleles at many genetic loci: When a sufficient number of these alleles are inherited and appropriate environmental events take place, thyroid autoimmune disease develops (17). The patients with transient thyroiditis and remitting/relapsing thyroiditis probably inherited only some alleles, such as the environmental factor that induced only a secondary autoimmune phenomenon (14).
In our experience, no patient undergoing IFN- therapy showed overt
clinical thyroid dysfunction; only subclinical hypothyroidism was
observed. The absence of preexisting thyroid autoantibodies in our
patients could explain the lack of the development of overt clinical
hypothyroidism, considering that the positivity for TPOAb at the
beginning of IFN- treatment was reported as a major risk factor for
thyroid dysfunction (18).
The research data concerning the outcome of cytokine-induced
hypothyroidism are controversial (8, 9, 19, 20). The
subsequent outcomes do not seem to be related to the severity of
hypothyroidism: complete reversibility was also reported in
extremely severe hypothyroidism (21). It has been
suggested that thyroid dysfunction is reversible when it is truly
related to IFN- therapy and is not secondary to the patient’s
autoimmune predisposition (5), considering that IFN-
can induce a direct effect on thyroid function, as demonstrated in
experimental (22) and clinical studies (23).
The high autoantibody levels in our patients with persistent
subclinical hypothyroidism suggest an immunological mechanism for such
abnormality. This hypothesis is confirmed also by the observation that
in these patients, as in those with newly occurred hypothyroidism after
IFN withdrawal, the autoantibody pattern was characterized by the
coexistence of TgAb and TPOAb, although this pattern was not observed
in patients with reversible subclinical hypothyroidism. In this regard,
it has been suggested that the presence of both autoantibodies is
associated with a more active autoimmune disease than that observed in
patients with TgAb or TPOAb alone (24).
Though successful interferon treatment in chronic HCV infection seems
to be associated with HCV-specific and HCV-aspecific immune activation
(25), our study did not demonstrate that the control of
HCV infection by the cytokine might require the breaking of
immunological tolerance against self-antigens. In fact, we were unable
to show that the occurrence of thyroid autoimmunity after IFN-
treatment was associated with long-term response to therapy.
In conclusion, our study demonstrates that in patients undergoing
IFN- therapy for CHC and with no evidence of preexisting thyroid
disease: 1) the negativity for thyroid autoantibodies after IFN
treatment is a protective factor for the developing thyroid
autoimmunity and/or dysfunction in following years; 2) the
IFN--related thyroid autoimmunity is not a complete reversible
phenomenon because some patients can develop chronic thyroiditis; 3)
high autoantibody levels at the end of IFN therapy are related to the
risk of having chronic thyroid autoimmunity; and 4) the coexistence of
TgAb and TPOAb at the end of treatment is a predictive marker for the
presence of thyroid dysfunction, even if subclinical, many years after
IFN withdrawal. Therefore, our study shows that the IFN--related
thyroid autoimmunity is not a homogeneous disease but encompasses a
spectrum of disease activities, probably as an expression of different
underlying genotypes.
Received October 4, 2000.
Revised January 3, 2001.
Accepted January 23, 2001.
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References |
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. Immunol Today. 8:73.
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interferon ß, and interleukin-2 have a different thyroid autoantibody
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