The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 2 675-678
Copyright © 2001 by The Endocrine Society
Time Course of 21-Hydroxylase Antibodies and Long-Term Remission of Subclinical Autoimmune Adrenalitis after Corticosteroid Therapy: Case Report
Annamaria De Bellis,
Alberto Falorni,
Stefano Laureti,
Silvia Perrino,
Concetta Coronella,
Francesca Forini,
Elio Bizzarro,
Antonio Bizzarro,
Gianfranco Abbate and
Antonio Bellastella
Institute of Endocrinology and Department of Clinical and
Experimental Medicine F. Magrassi (E.B., A.B., G.A.), Second University
of Naples, 80131 Naples; and Department of Internal Medicine and
Endocrine and Metabolic Sciences, University of Perugia (A.F., S.L.,
F.F.), 06126 Perugia, Italy
Address all correspondence and requests for reprints to: Dr. Annamaria De Bellis, Istituto di Endocrinologia, Seconda Università di Napoli, Via S. Pansini 5, 80131 Naples, Italy. E-mail:
etxode{at}tin.it
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Abstract
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Subclinical Addison’s disease is characterized by the presence of
adrenal autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies
(21OHAb) with or without adrenal function failure. In our previous
longitudinal study some patients with high titers of ACA and at stage 2
of subclinical adrenocortical failure showed disappearance of ACA with
recovery of normal adrenocortical function after corticosteroid
treatment for Graves’ ophthalmopathy. To investigate whether
corticosteroid-induced modification of the adrenal autoimmune markers
can also involve 21OHAb and to evaluate whether the remission of
subclinical adrenocortical failure can persist over a long period of
time, we followed-up for 100 months the levels of 21OHAb and ACA as
well as the metabolic markers of adrenal function in one patient with
Graves’ ophthalmopathy and at stage 2 of subclinical adrenocortical
failure before and after corticosteroid therapy. A 34-yr-old woman with
Graves’ disease and active ophthalmopathy who was found to be positive
for ACA and to have high PRA, low aldosterone levels, and normal basal
ACTH and cortisol levels, but impaired cortisol response to ACTH was
studied. The patient was treated with oral corticosteroid therapy for 6
months. After corticosteroid therapy, 21OHAb, initially positive,
became negative in concomitance with the disappearance of ACA and the
restoration of normal adrenal function. The disappearance of both
21OHAb and ACA and their prolonged absence during the follow-up suggest
that corticosteroid treatment can induce long-term remission of
subclinical adrenal insufficiency and prevent the onset of the clinical
phase of the disease. Our pilot study may pave the way to future trials
aimed at preventing the onset of the clinical signs of Addison’s
disease in ACA/21OHAb-positive patients.
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Introduction
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THE CLINICAL PHASE of autoimmune endocrine
disease is preceded by a long subclinical period characterized by the
appearance of organ-specific autoantibodies with or without impairment
of target gland function (1, 2, 3, 4). Although several
predictive studies have been performed in subclinical autoimmune
endocrine diseases, only a few therapeutic trials to prevent overt
disease have been carried out to date (5, 6, 7, 8, 9). Subclinical
autoimmune Addison’s disease, with or without metabolic signs of
adrenal function failure, is characterized by the presence of adrenal
cortex autoantibodies (ACA) and steroid 21-hydroxylase autoantibodies
(21OHAb) (10). Several studies have shown that the
presence of ACA and 21OHAb is not necessarily associated with the
progression toward clinical Addison’s disease (11). It
has been reported that the presence of ACA and 21OHAb is a marker of
rapid progression toward clinical adrenal insufficiency in children but
not in adults with endocrine autoimmune diseases (12, 13).
Recently, a prospective study of the levels of adrenal autoantibodies,
in adult autoimmune patients without clinical signs of adrenal
insufficiency showed that the levels of 21OHAb and ACA are strongly
correlated with the degree of adrenal dysfunction and that the
spontaneous remission of early stages of subclinical adrenal
dysfunction along with the disappearance of 21OHAb and ACA can occur
(14). In addition, high levels of ACA and 21OHAb were
associated with an advanced stage of subclinical adrenal dysfunction
and were predictive of the progression toward clinical Addison’s
disease (14). In a previous longitudinal study
(15), some patients with subclinical adrenocortical
failure (stage 2) showed a disappearance of ACA with recovery of normal
adrenocortical function after a 6-month treatment with corticosteroids
for Graves’ ophthalmopathy (GO). Furthermore, the remission of
preclinical adrenal insufficiency persisted after discontinuation of
corticosteroid treatment (15). The aim of this study was
to investigate whether the corticosteroid-induced modification of
adrenal autoimmune markers in subclinical adrenocortical failure also
involves 21OHAb and to evaluate whether the remission of preclinical
adrenal insufficiency can persist over a long period of time. To this
purpose we followed-up for 100 months the levels of both ACA and 21OHAb
as well as the adrenal function reserve in one of the three previously
studied patients (15) in stage 2 of subclinical
adrenocortical failure before and after corticosteroid therapy. To our
knowledge this is the first observation of a
corticosteroid-induced long-term remission of preclinical adrenal
insufficiency.
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Case Report
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Several years ago a 34-yr-old Italian woman was admitted to
our hospital because of the recent onset of tachycardia and weight
loss. A severe active ophthalmopathy with proptosis (>24 mm in both
eyes), impairment of ocular movements in upward and lateral gaze,
marked and constant diplopia, photofobia, eyelid edema, and chemosis
were present.
The thyroid function tests showed hyperthyroidism with the following
values: free T4, 53 pmol/L (normal range,
10.8–27 pmol/L); free T3, 18 pmol/L (normal
range, 4–7.4 pmol/L); and TSH, less than 0.001 mU/L. The tests for
thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb),
and TSH receptor antibodies (TSH-R-Ab) were all positive. Thyroid
antibodies were detected by RIA using commercial kits supplied by
DiaSorin, Inc. (Saluggia, Italy), for TPOAb and TSH-R-Ab
and by Ares Serono (Milan, Italy) for TgAb. A thyroid scan revealed a
diffuse goiter with high thyroid radioiodine uptake. On the basis of
these results the diagnosis of Graves’ disease was formulated.
The patient underwent methymazole treatment for 24 months, starting
with a daily dose of 30 mg and thereafter decreasing doses,
subsequently becoming euthyroid 2 months after the start of therapy.
Moreover, the ophthalmopathy was treated with oral corticosteroid
therapy for 6 months (prednisone, 75 mg and decreasing doses
subsequently) as previously described (15). At the end of
corticosteroid treatment, only slight residual ocular findings were
present, remaining unchanged during the subsequent follow-up period.
Levels of both ACA and 21OHAb and adrenocortical function were
evaluated before corticosteroid therapy and periodically over a
100-month span. Informed consent was obtained from the patient for this
study.
ACA and steroid cell antibodies (StCA) assay
ACA and StCA were determined using an indirect immunofluorescence
method on cryostatic sections of monkey adrenal gland, monkey ovary,
and monkey testis, respectively, as previously described
(15). Levels of ACA and StCA were expressed as the
end-point dilution titer.
21OHAb assay
21OHAb were determined in coded samples by a radiobinding assay
that uses in vitro translated recombinant human
[35S]21OH and protein A-Sepharose
(Pharmacia Biotech, Uppsala, Sweden) (16).
21-OHAb levels were expressed as a relative index (21-OHAb index) using
one positive and two negative standard sera, which were included in
each assay (17). The upper level of the normal range of
the 21-OHAb index was estimated as the mean ± 3
SD of the results obtained when analyzing sera
from 200 healthy subjects (mean ± SD,
0.027 ± 0.011; range, 0.02–0.059) and was 0.06. The samples with
a 21-OHAb index more than 0.7 were titrated using 1:100 to 1:500
dilutions.
Adrenocortical functional studies
Adrenocortical function was evaluated by measuring basal plasma
levels of ACTH, cortisol, aldosterone, and PRA as previously described
(15). Plasma cortisol levels were also evaluated 60 min
after iv infusion of 0.25 mg synthetic ACTH (normal peak response,
>550 nmol/L). If adrenal antibodies were present, five stages (from
0–4) of subclinical adrenal dysfunction were recognized in accordance
with previously reported criteria (15).
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Results
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At the beginning of the study, the patient was positive for ACA in
the presence of complement-fixing ACA, StCA, and 21OHAb (Fig. 1
). A high PRA, low aldosterone levels,
normal basal ACTH and cortisol levels, but impaired cortisol response
to ACTH were observed in the absence of clinical signs and symptoms of
Addison’s disease (Table 1). These
findings were consistent with the diagnosis of stage 2 subclinical
adrenocortical failure (15).
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Figure 1. Levels of ACA and 21OHAb before and after
corticosteroid therapy. ACA levels are expressed as the reciprocal of
the end-point dilution titer. The transversal dotted
line shows the upper level of normal of the 21OHAb assay.
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Subsequently, after corticosteroid therapy, the overlapping
disappearance of 21OHAb, and ACA and recovery of normal adrenal
function were observed (Fig. 1
). In particular, PRA levels showed a
significant reduction in both recumbent and upright values, persisting
in the normal range with minimal fluctuation over time (Table 2). The patient remained negative for
21OHAb and ACA for the following 94 months of observation and did not
show findings of adrenocortical dysfunction after discontinuation of
corticosteroid treatment (Fig. 1).
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Table 2. Time course of organ-specific autoantibodies and of
recumbent and upright PRA during the follow-up period
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With respect to the other antibodies, StCA and TSH-R-Ab disappeared 12
months after the start of the study, remaining negative. TgAb and TPOAb
levels showed a reduction initially and subsequently fluctuated during
the follow-up (Table 2).
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Discussion
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Here we report the occurrence of long-term remission of
subclinical adrenal failure with disappearance of 21OHAb and ACA in a
patient with GO treated with corticosteroids. Previous studies
(15, 16, 17, 18, 19, 20) have shown that spontaneous disappearance of
21OHAb and ACA can occur in patients with endocrine autoimmune
diseases. However, a large prospective study of the natural history of
autoimmune adrenal insufficiency (14) demonstrated that
the remission of both immune and metabolic markers of preclinical
adrenal insufficiency does not occur spontaneously in subjects with
advanced impairment of the adrenal function (stages 2 and 3). Thus,
even if other hypotheses cannot be excluded, the complete remission of
a stage 2 adrenal insufficiency in our patient with Graves’ disease
and ophthalmopathy could be explained as the result of the high dose
corticosteroid therapy. A good agreement between the presence of
21OHAb, as measured by a radiobinding assay, and the presence of ACA,
as detected by indirect immunofluorescence, has been reported in
several studies (15, 16, 17, 18, 19, 20). Also in the present study we
observed an absolute concordance between the two assays for adrenal
autoantibodies, suggesting that their disappearance, after
corticosteroid therapy, is not due to a technical artifact.
The main finding of our study is the long-term remission of subclinical
adrenocortical insufficiency with full recovery of adrenal function,
after corticosteroid therapy. The prolonged recovery of adrenocortical
function and the persistent absence of ACA and 21-OHAb suggest that the
early administration of corticosteroids in preclinical autoimmune
Addison’s’ disease could induce a remission of subclinical adrenal
insufficiency and prevent the onset of the clinical phase of the
disease.
The effect of short-term glucocorticoid therapy can be attributed
to the well known immunosuppressive activity of steroids
(21). Glucocorticoids could reduce B cell Ig production by
decreasing the synthesis of IL-6 (21, 22). In preclinical
Addison’s’ disease, a short course of glucocorticoid therapy could
prevent progressive adrenal failure by decreasing the B cell function
and subsequently the production of adrenal autoantibodies. However, we
observed not only the disappearance of 21OHAb, but also a complete
remission of the metabolic signs of adrenal dysfunction in our patient
with GO. Most likely, the corticosteroid therapy had a more general
effect on the autoimmune process and also affected T cell-mediated
pathways. It has been demonstrated that corticosteroids decrease both
monocyte-macrophage function and T cell expansion (21, 22), which have been proposed as having a preponderant role in
the pathogenesis of autoimmune Addison’s disease (23).
Destruction of adrenal cortical cells could be mediated by cytotoxic T
lymphocytes. It is possible that a corticosteroid therapy, when carried
out in an early stage of the subclinical adrenocortical failure,
down-regulates cytotoxic T lymphocyte expansion and decreases the
production of adrenal autoantibodies with the final result of a
complete recovery of adrenal function.
A corticosteroid therapy could also act as an isohormonal therapy
in determining the disappearance of and in preventing progressive
adrenal destruction with restoration to the normal state of adrenal
function in subclinical autoimmune Addison’s disease (9, 24). In particular, a feedback inhibition of adrenal gland
function may decrease the exposure of autoantigens (21-OH-related
peptides) to the immune system or decrease the susceptibility of the
adrenal tissue to an immune attack (24). However, a
possible action of methimazole on adrenal antibody levels cannot be
excluded, taking into account the putative immunosuppressive effect of
this drug, as suggested by some researchers (25). In a
previous study we demonstrated a disappearance of ACA and the recovery
of adrenal function after corticosteroid therapy persisting over 60
months in three positive patients (including the present one) treated
for GO. Our present study demonstrates an overlapping behavior of ACA
and 21OHAb before and after corticosteroid treatment; it also indicates
that the occurring complete remission of early adrenal dysfunction can
persist over a very long period, leading to a possible definitive
recovery. This may pave the way to future clinical trials aimed at
testing the efficacy of early corticosteroid therapy in preventing the
onset of the clinical signs of Addison’s disease in subjects
positive for ACA and/or 21OHAb.
Received April 11, 2000.
Revised August 15, 2000.
Revised October 4, 2000.
Accepted October 9, 2000.
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Abstract
Introduction
