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Clinical Studies |
Chair of Clinical Immunology and Allergy (C.B., M.V., B.P., F.P.), and Chair of Endocrinology (M.B.) from the Institute of Semeiotica Medica; Department of Pediatrics (N.A.G.), University of Padova, Padova; Chair of Immunology (F.T.), Institute of General Pathology, University of Trieste; Department of Laboratory Medicine, Padova General Hospital (M.S.), Padova, Italy; FIRS Laboratories (B.R.S., J.F., S.C.), RSR Ltd, Parc Ty Glas, Llanishen, Cardiff CF4 5DU and Department of Medicine, University of Wales, College of Medicine, Heath Park, Cardiff CF4 4XN, United Kingdom
Address all correspondence and requests for reprints to: Professor Corrado Betterle, Istituto di Semeiotica Medica, Cattedra di Immunologia Clinica e Allergologia, Università di Padova, Via Ospedale 105, 35128 - Padova, Italy.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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-hydroxylase (17-OH) and cytochrome P450 side
chain cleavage enzyme (P450scc) were measured by immunoprecipitation
assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also
carried out and adrenal function assessed by ACTH test. On enrollment,
75% of ACA-positive patients had a normal adrenal function, while 25%
revealed a subclinical hypoadrenalism. 21-OH antibodies were positive
in 91% of ACA-positive sera. Eleven patients were positive for
steroid-cell antibodies by immunofluorescence, and 9 revealed a
positivity for antibodies to 17-OH and/or P450scc. During the
prospective study, overt Addison’s disease developed in 21% and
subclinical hypoadrenalism in 29% of ACA-positive patients, while 50%
maintained normal adrenal function. Progression to Addison’s disease
was more frequent in patients with subclinical hypoadrenalism, high
titers of ACA and higher levels of 21-OH antibodies, complement-fixing
ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were
also negative for antibodies to 21-OH, 17-OH, and P450scc, and all
maintained normal adrenal function during follow-up. In conclusion, the
detection of ACA/21-OH antibodies in adults is a marker of low
progression toward clinical Addison’s disease. . |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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In adult autoimmune disease patients without Addison’s disease, the prevalence of ACA varies greatly, being 0.2–13.5% (3, 4, 5, 6), while occurence is up to 5% in the general population (7). Follow-up studies of ACA-positive patients have suggested that only a few patients (3, 4, 5, 6) or none (7) progress to overt hypoadrenalism. Furthermore, it has been reported that ACA can disappear spontaneously or after treatment with corticosteroids, with remission of a subclinical Addison’s disease (6, 7, 8).
To clarify and extend these earlier observations we carried out a prospective study of 48 ACA-positive autoimmune diseases patients who did not have overt adrenal failure.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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Sera were obtained from 8840 adults with organ-specific
autoimmune diseases but without overt hypoadrenalism (see Table 1
for details). Out of 40 patients with
hypoparathyroidism, 30 developed the disease over 15 yr and 10 under 15
yr of age; the disease was isolated in 37 patients, and in the context
of autoimmune polyendocrine syndrome (APS) Type 1 in 3 cases. In
addition, sera were collected from 338 healthy subjects without
personal or family history of autoimmune diseases.
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Adrenal cortex (ACA) and steroid-producing cell autoantibodies (StCA). ACA of immunoglobulin (Ig) G class (ACA-IgG) were detected by the classical indirect immunofluorescence technique on human adrenal tissue, as previously described (4, 5). Titers of ACA-IgG were defined by doubling dilution up to the end point. ACA-IgA and -IgM were investigated by the same technique, using fluorescein-isothyocianate conjugated polyclonal antibodies against human IgA and IgM, respectively (Wellcome, Beckenham, U.K.). Complement-fixing ACA (CF-ACA) were detected by indirect immunofluorescence complement-fixation test (4, 5). The ability of ACA-positive sera to assemble the terminal complement complex was evaluated by indirect complement fixation immunofluorescent test using normal human serum as source of complement, followed by IgG2 mouse monoclonal antibodies directed against C9 (aE11) neoantigen (kindly supplied by T. E. Mollnes, Oslo, Norway), and by antimouse IgG rabbit FITC-serum (Sigma Co., St. Louis, MO). Steroid-producing cell autoantibodies (StCA) were tested on cryostat sections of human ovary and testis by indirect immunofluorescence complement-fixation test (9).
Autoantibodies to steroid 21-hydroxylase (21-OH Abs),
17-hydroxylase (17-OH Abs), and to P450 side chain cleavage
(P450scc Abs).35S-21-OH, 35S-17-OH,
and 35S-P450scc were prepared using an in
vitro transcription/translation system and analyzed by
SDS-PAGE, as previously described (10, 11). The immunoprecipitation
assay (IPA) was carried out using the method of Colls (10). The results
of 21-OH Abs were expressed as an index, and an index value of 2.6 or
greater (based on a mean + 3 SD of 26 healthy blood donors)
was considered to indicate the presence of 21-OH Abs. The results of
17-OH and P450scc Abs were expressed as arbitrarily defined units
(U/mL), as previously reported (11).
Functional study
Adrenal cortex function was evaluated by measuring basal plasma levels of cortisol (normal values 138–550 nmol/L), aldosterone (normal values 277–831 pmol/L), ACTH (normal values 4–22 pmol/L), and PRA (normal values 2–6 ng/L per 3 h). Plasma concentrations of cortisol were also measured 60 min after an iv bolus of 0.25 mg synthetic ACTH (rapid ACTH-test). Normally, cortisol increase is greater than 200 nmol/L with respect to basal values. Plasma ACTH was measured by a two-site immunoradiometric assay (Euro-Diagnostic, Apeldoorn, Holland). Plasma cortisol and aldosterone were detected by RIA (Diagnostic Products Corporation, Los Angeles, CA, and Sorin, Vercelli, Italy). PRA was determined according to Stockigt (12) with the omission of the boiling step. Functional tests were performed approximately once a year from entry into the study.
According to the values obtained, five distinct grades of adrenocortical dysfunction were recognized, as previously reported (5). Stage 0 was characterized by a normal adrenal function; Stage 1 by an increase in plasma renin activity, along with a normal or low serum aldosterone level; Stage 2 by a decreased plasma cortisol response to ACTH; Stage 3 by an increased basal plasma ACTH level; Stage 4 by a decreased plasma cortisol level with appearance of overt symptoms of adrenocortical failure.
Genetic study
Forty-three ACA-positive patients and 153 normal controls were typed for human leucocyte antigens (HLA) DRB1, DQA1, and DQB1 alleles, as previously described (13).
Statistical analysis
Actuarial survival rate was employed to estimate the likelihood of progression toward Addison’s disease, according to the Cutler-Ederer method (14). All patients entered the life-table when ACA were first determined in our laboratory. The follow-up ended when overt hypoadrenalism occurred or when adrenal antibodies were last detected for unaffected individuals. The result of the survival analysis was expressed by plotting curves of cumulative risk of morbidity. The log-rank statistic was used to compare the estimates between the selected categories (15). The annual incidence of Addison’s disease was evaluated by dividing the number of Addisonian patients by the patients’ years of follow-up. Each patient contributed to the total sum of patients’ years with a period ranging from the start of the observation until the disease was diagnosed, or until the observation period was ended. Sampling errors and 95% confidence intervals (c.i.) were calculated. Differences in the prevalence of ACA and HLA-DR antigens with respect to controls were evaluated by the Chi-square test. For HLA-DR the P value obtained was corrected multiplying by 9 the number of antigens tested.
Follow-up planning
Sixty-eight patients, 45 ACA-positive (43 females and 2 males) and 23 ACA-negative patients (matched for sex, age, and preexisting autoimmune diseases) were enrolled into a prospective study. The one ACA-positive subject from the normal control group was not followed-up. Informed consent was obtained, and the investigation was performed in accordance with the principles of the Declaration of Helsinki.
At the beginning of the study, all ACA-positive sera were characterized
for ACA-IgG titers, CF-ACA, ACA-IgA, -IgM, and StCA. In addition, sera
were tested for 21-OH, 17-OH, and P450scc Abs. During follow-up, ACA
titers and ACTH-tests were reevaluated at yearly intervals. The mean
follow-up period of ACA-positive patients was 50 months (range 3–163).
All ACA-negative patients were also periodically evaluated for ACA and
by ACTH-test. The mean follow-up period was 45 months (range 6–100).
In patients who developed overt Addison’s disease, ACA were further
tested.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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ACA-IgG were found to be positive in 67 of the 8840 (0.8%) adults
with organ-specific autoimmune diseases and in one normal adult control
(0.3%). The prevalence of ACA in the different groups of autoimmune
patients varied from 0.3% in patients with vitiligo to 8.9% in those
with premature ovarian failure (see Table 1
), and only in this last
group was the frequency of ACA significantly greater than in normal
controls (P < 0.0001). StCA were found in 11 patients,
all belonging to the ACA-positive group. The highest prevalence of StCA
was found in premature ovarian failure (6.6%) (Table 1).
Follow-up study
Forty-five ACA-positive and 23 ACA-negative patients were
available for the prospective study. Furthermore, 3 patients in the
ACA-negative group became ACA-positive during the study and were moved
to the ACA-positive group. Consequently, the ACA-positive group
included 48 patients (Table 2).
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. Fifteen patients had Graves’ disease (8 were
receiving antithyroid drugs, 2 were in remission without therapy, while
the other 5 were receiving replacement doses of L-thyroxine for
spontaneous or surgical hypothyroidism). Eighteen patients had
Hashimoto’s thyroiditis (9 were under replacement doses of
L-thyroxine). Thirteen patients had insulin-dependent diabetes mellitus
and were on insulin therapy; 2 ICA-positive patients in this group had
had gestational diabetes mellitus and, after the delivery, were
controlled by oral hypoglycaemic agents. Four patients had premature
ovarian failure (one was treated with estrogens and progestins). One
patient with hypoparathyroidism received vitamin D and calcium. Eight
had vitiligo, 1 chronic liver disease, and 1 ICA-positive patient had
normal glucose tolerance. None of the patients were receiving
corticosteroid therapy. Overall in the ACA-positive group, low titers of ACA (<16) were found in 7 cases, medium titers (16–64) in 17, and high titers (>64) in 24 cases. Persistently positive CF-ACA were present in the sera of 39 patients (81%). CF-ACA showed association with high titers of ACA (P < 0.05, Chi-square test). Terminal complement complex ACA were found to be persistently positive in 20 of the 44 (46%) patients studied. Nine of the 48 ACA-positive patients also had ACA-IgA, and 1 patient had ACA-IgM. Eleven patients were also positive for StCA.
21-OH Abs were detected in 43 of 47 (91%) ACA-positive patients
tested, with a mean index of 33 (range 9–121, Table 2); the mean 21-OH
Abs index value did not show correlation with the titers of ACA. Of the
11 ACA-positive patients who were positive for StCA, all were also
positive for 21-OH Abs, and 9 were positive for 17-OH and/or P450scc
Abs (Table 2).
Among the 20 patients persistently ACA-negative (2 males and 18 females), 12 had thyroid autoimmune diseases (6 with Graves’ disease and 6 with Hashimoto’s thyroiditis), 5 had insulin-dependent diabetes mellitus, 1 had both thyroid autoimmune disease and insulin-dependent diabetes mellitus, and 2 had idiopathic hypoparathyroidism. None of the ACA-negative patients were receiving corticosteroids.
The ACTH test upon entry to the study revealed that out of 48
ACA-positive patients, 36 (75%) were in Stage 0, and 12 (25%) in
Stage 1, 2, or 3 (subclinical hypoadrenalism) (Table 2). During
follow-up, of the 36 patients with normal adrenal function, 5 developed
clinical disease and 7 subclinical adrenal insufficiency. Of the 12
patients with initial subclinical hypoadrenalism, 5 developed overt
Addison’s disease, and 7 maintained the subclinical hypoadrenalism.
Overall, 10 patients (21%) developed clinical Addison’s disease, 14
(29%) developed subclinical adrenal insufficiency, and 24 (50%)
maintained a normal adrenal function (Fig. 1, Table 2).
In the group of ACA-positive individuals who developed clinical or
subclinical Addison’s disease, the mean index value ±SD
for 21-OH antibodies was 42 ± 26, compared with 24 ± 17 in
patients who were maintaining normal adrenal function
(P = 0.01, t test).
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; no. 3a, 6a,
7a, 9a, 10a).
During follow-up none of the patients with ACA lost antibody reactivity
or revealed any restoration in their functional adrenal status. Only
one female, initially in Stage 1, showed first a progression up to
Stage 3, but then she partially improved to Stage 2 (Table 2; no. 9b).
One patient (Table 2; no. 6c) died of breast cancer after more than 9
yr of follow-up still maintaining normal adrenal function; no autopsy
was performed. Another patient who had IDDM (Table 2; no. 12b)
developed chronic renal failure and underwent transplantation of both
kidney and pancreas. After transplantation she was able to stop the
insulin therapy and was given immunosuppressive treatment with
cyclosporin A, corticosteroids, and azathioprine. This patient was
re-evaluated after 9 months of immunosuppression: ACA and 21-OH
antibodies were still positive and the ACTH test performed 3 days after
the withdrawal of corticosteroids revealed a normal adrenal function.
Nine of the 10 patients (90%) followed after the onset of Addison’s
disease were still positive for ACA after a mean period of 51 months
(range 3–120 months).
All of the 20 persistently ACA-negative patients were also negative for
StCA, 21-OH, 17-OH, and P450scc Abs and maintained normal adrenal
function during the observation period.
The life estimates expressed as cumulative risks of morbidity,
according to ACA status (Fig. 2a), ACA titers (Fig. 2b),
CF-ACA (Fig. 2c), as well as the stage of adrenal function at entry
(Fig. 2d) are plotted. Table 3 summarizes positive
predictive values, annual incidences, and cumulative risks for
Addison’s disease according to the clinical and immunological
features.
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; no. 8a, 10a, 4–5b, 4c, 10c, 16c), maintained
normal gonadal function. Genetic study
Prevalences of the HLA-DR antigens are summarized in Table 4. The frequency of HLA-DR3 and -DR4 was higher in
ACA-positive patients than in controls, but a significantly increased
prevalence of DR3 (corrected P = 0.004) was found only
in the ACA-positive patients progressing to clinical or subclinical
Addison’s disease.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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The follow-up study also showed that, in addition to high levels of ACA/21-OH Abs, CF-ACA, initial impaired adrenal function, as well as HLA-DR3 status, were associated with the highest progression towards clinical Addison’s disease in adults.
These results in adults are in contrast to our observations in children, where the majority of ACA-positive patients developed Addison’s disease independently from HLA, levels of autoantibodies, stage of adrenal function, sex, and age (17). The reasons for these differences in progression to disease between adults and children are not clear at present and reflect our lack of understanding of the mechanisms involved in autoimmune destruction and failure of the adrenal cortex gland (2). Although sera from ACA-positive Addison’s patients appear to react with different epitopes on the 21-OH molecule, the majority of 21-OH Abs bind to central and C-terminal parts of the molecule (18, 19). The different progression to clinical Addison’s disease in children and adults could be related to the heterogeneity of 21-OH Abs reactivity to 21-OH. Consequently, patients who develop antibodies to particular epitopes could go on to develop the clinical disease. These variations in humoral adrenal autoimmunity may reflect variations in cellular immune responses that are likely to be the prime pathogenetic factor (2).
Observation on the ability of 21-OH Abs to inhibit 21-OH enzyme activity in vitro (20) and association of ACA/21-OH Abs with the high progression to adrenal failure in children (17) could suggest a pathogenetic role of 21-OH Abs in Addison’s disease. However, recent hormonal studies in vivo (21) and the present data on low progression to Addison’s disease in ACA/21-OH Abs positive adults appear to indicate that such a mechanism is unlikely.
In our studies ACA/21-OH Abs remained positive in all patients over many years although some fluctuation in titers was observed. This is in apparent contrast to some previous studies on adult population, which have reported a tendency for ACA to disappear during long-term follow-up (6, 7, 8). These discrepancies might be related to differences in the methods employed and to the lack of standardization, rather than to a real seronegativization. International standardization and proficiency of a future program in the detection of ACA and 21-OH Abs will be necessary to correctly compare the results from various laboratories and to define a reference serum.
During our follow-up study the ACTH test was a specific and valuable method for assessing adrenal function and for identifying patients progressing to adrenal failure. As the shortest time period for progression from normal adrenal function to clinical disease in adult population was 23 months, we recommend that full assessment of adrenal function should be carried out on a yearly basis in ACA/21-OH Abs-positive patients, mainly in those with CF-ACA and HLA-DR3. Finally, we suggest the initiation of substitutive therapy when the first stage of impaired adrenal function appears. In this way acute adrenal failure, in patients with ongoing autoimmune adrenalitis, can be prevented in the case of precipitating events such as stress or infections (22).
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Note Added in Proof |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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; no. 3b, 9b).
Received May 14, 1996.
Accepted November 25, 1996.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionNote Added in ProofReferences |
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