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Department of Pediatrics (A.G.M.), Akershus Central Hospital, N-1474 Nordbyhagen, Norway; Division of Endocrinology, Institute of Medicine (A.G.M, K.L., E.S.H.), Haukeland University Hospital, N-5021 Bergen, Norway; Institute of Immunology (D.E.U.), The National Hospital, N-0027 Oslo, Norway; Department of Medicine (S.U.), Rogaland Central Hospital, N-4003 Stavanger, Norway; Department of Medicine (B.G.N.), Haugesund Hospital, N-5500 Haugesund, Norway; Division of Endocrinology, Institute of Medicine (K.J.F.), University Hospital of Trondheim, N-7006 Trondheim, Norway; Department of Medicine (T.T.), University Hospital of Tromsø, N-9038 Tromsø, Norway; and Department of Medicine (J.I.S.), Stord Hospital, N-5400 Stord, Norway
Address all correspondence and requests for reprints to: Anne Grethe Myhre M.D., Department of Pediatrics, Akershus Central Hospital, N-1474 Nordbyhagen, Norway. E-mail: Anne.Myhre{at}med.uib.no
Abstract
Autoimmune destruction of the adrenal cortex is the most common cause of primary adrenocortical insufficiency (Addison’s disease) in industrialized countries. We have investigated a large Norwegian cohort of patients with Addison’s disease in terms of clinical manifestations, autoantibodies, and human leukocyte antigen (HLA) class II haplotypes. The study comprised 94 patients (54 females) of ages 6–85 yr (mean 45 yr) with, either isolated Addison’s disease or part of autoimmune polyendocrine syndrome type II. Among those diagnosed before the age of thirty, 53% were men, while among those diagnosed at 30 or above, 30% were men. Altogether 77 (82%) of the 94 patients had autoantibodies against 21-hydroxylase (21OH). Thirty-eight of the 40 patients with disease duration 5 yr or less had such autoantibodies. This frequency fell to 60% among patients with a disease duration greater than 35 yr. Five women had gonadal failure. This failure correlated with antibodies against side-chain cleavage enzyme (P = 0.03). Antibodies against glutamic acid decarboxylase and IA2 correlated with the presence of type 1 diabetes (P < 0.005 and P = 0.003, respectively). The frequency of the HLA DRB1*03-DQA1*05-DQB1*02 (DR3-DQ2) and DRB1*04-DQA1*03-DQB1*0302 (DR4-DQ8) haplotypes were positively correlated to Addison’s disease, whereas the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype was negatively correlated. In addition, the DRB1*04 subtype DRB1*0404 was increased among Addison patients relative to controls.
We verify that autoimmunity is the main cause of Addison’s disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis, especially in patients with a short disease duration. Addison’s disease is associated with the DR3-DQ2 and DR4 (0404)-DQ8 haplotypes. A particularly high risk for disease development is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8).
PRIMARY ADRENOCORTICAL INSUFFICIENCY (Addison’s disease) is caused by destruction of the adrenal cortex. In industrialized countries, the majority of cases are attributed to autoimmunity (1, 2, 3). Other causes are tuberculosis, malignant infiltration of primary adrenal tumors, or metastasis. Hereditary diseases such as adrenoleukodystrophy (4) and mutations in the steroid tissue transcription factors DAX1 (5), steroidogenic acute regulatory protein (6), and in steroid factor 1 (7) have also been described as causes of adrenal failure. Women are more often affected with autoimmune Addison’s disease than men are, and the condition is most often diagnosed between the ages of 20 and 40 yr (8, 9). Association to human leukocyte antigen (HLA) DRB1*03-DQA1*05-DQB1*02 (hereafter called DR3-DQ2) and to some extent DRB1*04-DQA1*03-DQB1*0302 (hereafter called DR4-DQ8) haplotypes have been found in different populations (10, 11, 12, 13). Addison’s disease may occur as an isolated entity or as part of a polyendocrine syndrome. The rare autoimmune polyendocrine syndrome type I (APS I) is a monogenic disease (14, 15) caused by mutations in the autoimmune regulator gene (16, 17). It is characterized by a combination of Addison’s disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Autoimmune polyendocrine syndrome type II (APS II) is defined as a combination of Addison’s disease and autoimmune thyroid disease and/or type 1 diabetes (18). Although not one of the criteria for a diagnosis of APS II, premature gonadal insufficiency develops in some of the female patients (19).
The autoimmune process is characterized by the presence of circulating autoantibodies against 21-hydroxylase (21OH), one of the enzymes participating in steroid biosynthesis in the adrenals (20). Some of the patients also have autoantibodies against side-chain cleavage enzyme (SCC) and 17
-hydroxylase (17OH), but these autoantibodies are more frequent in sera from patients with APS I (1, 21, 22). No convincing evidence has been presented that the autoantibodies themselves participate in the autoimmune destruction (23). It is assumed that the autoimmune destruction is mediated by cytotoxic T cells because lymphocytic infiltration has been observed in adrenal tissue from patients with newly diagnosed Addison’s disease (8), and reactivity of T cells against proteins extracted from the adrenal cortex has been reported (24). However, the mechanisms that initiate and propagate the autoimmune adrenalitis are still largely unknown.
In the current report, we present a clinical description of a cohort of Norwegian patients with primary adrenocortical insufficiency. Autoantibodies against autoantigens specific for Addison’s disease and related organ-specific diseases were assayed, and the HLA class II haplotypes were defined.
Subjects and Methods
Subjects
Patients were recruited by contacting departments of internal medicine and pediatrics at all major hospitals in Norway. The doctors were asked to provide information on patients with Addison’s disease and polyendocrine syndromes. Out of this material, a total of 111 persons with Addison’s disease were identified. Their medical history, hereditary disorders, and medication were recorded. Because we had asked for information on persons with autoimmune diseases on the registration form, we assumed that the 111 patients had autoimmune or idiopathic adrenal insufficiency and not adrenocortical failure of other known causes. Seventeen of the patients fulfilled the clinical criteria for APS I, and because this is a well defined, monogenic disease they were excluded and are reported on elsewhere (25). The remaining 94 patients were characterized in this study. A total of 290 randomly selected healthy controls (26) were used in the analysis HLA class II haplotypes and genotypes. In addition, 431 separate healthy controls selected for carrying the DQB1*0302 allele were used in the analysis of DRB1*04 subtypes (27). All control samples were obtained from The Norwegian Bone Marrow Donor Registry.
Clinical data
The diagnoses Addison’s disease, primary hypothyroidism, primary gonadal failure, and diabetes mellitus were based on typical biochemical findings as described by Ahonen et al. (14).
Antibody assays
Antibodies against 21OH, SCC, 17OH, and glutamic acid decarboxylase were assayed by a method based on an in vitro transcription and translation method as described by Ekwall et al. (28). Commercial kits were used to assay antibodies against thyroperoxidase (Diagnostic Products Corp., Los Angeles, CA), thyroglobulin (Brahms Diagnostica GmbH, Berlin, Germany) and IA2 (DLD Diagnostika GmbH, Hamburg, Germany).
Indirect immunofluorescence
Normal bovine adrenals were obtained at a local abattoir and frozen in liquid nitrogen. Bovine adrenals were used since human substrates often produce high background in immunofluorescence and Western blot studies of Addison sera (29). Rat testes were obtained from Rattus Norwegicus BD9 rats and immediately frozen in liquid nitrogen. Unfixed frozen 6-mm sections from bovine adrenal glands and rat testes were incubated overnight at 4 C with patient or control sera diluted 10-fold. After three washes in PBS, the sections were exposed to antihuman FITC-labeled IgG antibodies diluted 1/20 for 30 min (29). Blinded sections were investigated by two independent observers and assigned as positive or negative.
HLA typing
DNA samples were available from 74 of the 94 patients with Addison’s disease, of whom 40 had isolated Addison’s disease and 34 had APS II. None of the patients were related. Patient and control samples were typed for HLA-DRB1 and DQB1 using a reverse dot blot kit (Amplicor, DynAl, Oslo, Norway). The DQA1 alleles and HLA-DRB1-DQA1-DQB1 haplotypes were deduced based on known patterns of linkage disequilibrium in the Norwegian population.
Statistical analysis
P values were calculated using 
2 analysis or Fisher’s exact test when appropriate. Odds ratios were calculated using Woolf’s formula.
The study was approved by the local ethical committee and was conducted in accordance with the Declaration of Helsinki.
Results
Patient characteristics
Among the 94 patients with primary adrenal failure (54 of whom were women), 49 had isolated Addison’s disease; these included 4 patients with Addison’s disease and either vitiligo or alopecia. Forty-five patients had APS II, including 4 patients with a combination of Addison’s disease and gonadal insufficiency. The clinical diagnoses are summarized in Table 1
.
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). Thus, among those in whom Addison’s disease was diagnosed before the age of 30, there were slightly more males than females (26 vs. 23). Among those who were over 30 yr of age at diagnosis, females predominated (Fig. 1).
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Altogether 77 (82%) of the 94 patients had autoantibodies against 21OH, the main autoantigen associated with Addison’s disease (20), whereas none of 50 sera from blood donors contained such autoantibodies. These autoantibodies were slightly more prevalent in the group of patients with APS II (39/45, 87%) than in the group with isolated Addison’s disease (38/49, 78%). Similar frequencies of 21OH autoantibodies were found in women (43/54, 80%) and men (34/40, 85%). All except two of the 40 patients with disease duration of 5 yr or less had autoantibodies against 21OH. The frequency showed some decline with increasing disease duration, but still 60% of the patients with disease duration greater than 35 yr were positive (Fig. 2). Autoantibodies against 17OH were detected in sera from 7 patients, whom all but one had APS II.
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Gonadal failure
Altogether 7 patients (5 women) had gonadal failure. Among postpubertal women, autoantibodies against SCC were found in the sera of 3 of the 5 women with ovarian failure, compared with 6 of 48 without ovarian failure (P = 0.03). Two of the 3 women with autoantibodies against SCC and ovarian failure also displayed autoantibodies against 17OH, compared with 4 of 48 without ovarian failure. One of the two men with gonadal failure was the only male among 7 patients with autoantibodies against 17OH. None of the sera from patients with gonadal failure displayed positive immunofluorescence against Leydig cells.
Type 1 diabetes
Sixteen of the 94 patients had type 1 diabetes. Ten of these 16 patients had anti-glutamic acid decarboxylase antibodies, compared with 18 of the 78 patients without type 1 diabetes (P < 0.005). Five of the 16 patients with type 1 diabetes displayed IA2 antibodies compared to three of the 78 patients without type 1 diabetes (P = 0.003). In the majority of cases, diabetes was diagnosed before (9/16) or at the same time as (4/16) Addison’s disease.
Autoimmune thyroid disease
Graves’ disease or primary hypothyroidism, without a history of radiation or surgery against the thyroid gland was present in 33 (73%) of the 45 patients with APS II (6 had Graves’ disease). Six of the 33 patients (18%) had autoantibodies against thyroid peroxidase and/or thyroglobulin, while among the 61 patients whom did not report clinical thyroid disease, 7 (11%) had these autoantibodies. If the latter are considered to have autoimmune thyroid disease, 52 of 94 (55%) had APS II.
HLA associations
The distribution of HLA haplotypes in patients with isolated Addison’s disease and APS II was very similar and no statistical significant differences were observed when comparing these two groups (Table 2). A statistically significant correlation was found between Addison’s disease and DR3-DQ2 (OR = 3.6; Pcorrected < 10-6) and DR4-DQ8 haplotypes (OR = 2.5; Pcorrected = 0.0003). (Table 2). In addition, the DRB1*01-DQA1*0101-DQB1*0501 (DR1-DQ5) haplotype conferred protection against Addison’s disease (OR = 0.1; Pcorrected = 0.001). We also observed a slight decrease in the frequency of the DRB1*13-DQA1*0102-DQB1*0604 (OR = 0.16, Pnc = 0.04), DRB1*07-DQA1*02-DQB1*02 (OR = 0.23, Pnc = 0.03) and DRB1*04-DQA1*03-DQB1*0301 (OR = 0.35, Pnc = 0.04) haplotypes among patients compared with controls (Table 2). However, these associations were not significant after correction for number of comparisons.
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) (27). The increase in DRB1*0404 on DQ8 haplotypes was evident in both isolated Addison’s disease patients (77% DRB1*0404) and APS II patients (90% DRB1*0404), and there was no statistically significant difference between the two subsets of patients (P = 0.2 when comparing APS II and isolated Addison’s disease). The DRB1*0401-DQ8 haplotype is not increased in Addison patients compared with random controls (2.0% vs. 2.0%) (27). This means that all the observed increase of DR4-DQ8 haplotypes among Addison patients are caused by the increase in DRB1*0404-DQ8 haplotypes. Interestingly, the increase in DRB1*0404 was evident also among patients with Addison’s disease and type 1 diabetes where 9/10 DQ8 haplotypes carried DRB1*0404. This is in contrast to what is observed in Norwegian type 1 diabetes patients without Addison’s disease where DRB1*0401 is the predominating DR4 subtype (27).
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To get an estimate of the risk of developing Addison’s disease for individuals carrying the high risk DRB1*03-DQA1*05-DQB1*02/DRB1*0404-DQA1*03-DQB1*0302 genotype, we calculated absolute risk according to the formula: (frequency of genotype among patients/frequency of genotype in random controls) x population prevalence. The frequency among random controls were taken from Ref. 27 and the population prevalence of Addison’s disease was estimated to be 1/10,000 (3). This gives an absolute risk of 0.2% for developing Addison’s disease for individuals with this particular genotype.
Discussion
There have been relatively few reports on large series of patient with adrenocortical insufficiency. We describe here 94 patients with Addison’s disease, either isolated or as part of APS II. No studies on the incidence and prevalence of Addison’s disease in Norway have been published. In the last few years the prevalence in England has been found to be about 100 per million population (3, 30). On the basis of these figures, our cohort comprises about 25% of the total number of cases in Norway. Addison’s disease occurs more often in women (1, 3). We found a relatively low female to male ratio (1.3:1), even though patients with APS I (female to male ratio 1:1) had been excluded. Among patients who were diagnosed before the age of 30, there was a close to 1:1 female to male ratio, whereas among those diagnosed after the age of 30, females dominated (Fig. 1
), which has been observed also by others (9). This is also reflected in the finding that Addison’s disease was diagnosed earlier in male patients (Fig. 1). One may speculate that the mechanism behind the development of Addison’s disease is different among young compared with older patients.
The best immunological marker for Addison’s disease is the presence of autoantibodies against 21OH (1, 20, 31). In our cohort, we found that about 80% of the patients displayed such autoantibodies. Among patients with a disease duration less than 5 yr, 95% had anti-21OH antibodies. There was a tendency for decrease in these antibodies with increasing disease duration, as has been noted by others (32). This confirms that autoantibodies against 21OH is a powerful diagnostic tool in Addison’s disease. Autoantibodies against 21OH may be detected several years before symptoms of adrenal failure become manifest (33, 34). However, this analysis should mainly be used as a test to determine the etiology of Addison’s disease. In selected cases, e.g. in patients with other organ-specific autoimmune diseases such as diabetes mellitus type 1 (12, 35), it can be warranted to test for autoantibodies to see if immunological reactivity against the adrenal is present to make an early diagnosis.
Sera from four patients showed positive immunofluorescence against the adrenal cortex, but without autoantibodies against 21OH, SCC, or 17OH. This finding indicates that other, as yet unidentified autoantigens are present. On the other hand, our results also demonstrate that negative immunofluorescence is of limited value when it comes to assessing the possibility of autoimmunity as a cause of adrenocortical failure. Patients without antibodies against 21OH at diagnosis must be examined for other causes of Addison’s disease such as tuberculosis, malignant disease, and adrenoleukodystrophy.
Some of the female patients with Addison’s disease have gonadal failure (1). We found autoantibodies against SCC and 17OH in the sera of about half of these patients in the present cohort. Similar results have recently been published from a study of Italian patients with Addison’s disease (36) and from studies of patients with APS I (21, 22). Some of the women with autoantibodies, but without gonadal failure, may be at increased risk of developing gonadal failure in the future. Because in many of the women gonadal failure develops at childbearing age, analysis for SCC autoantibodies may be a useful tool for evaluating the risk for this event. Gonadal failure is not one of the criteria for APS II as defined by Neufeld et al. (18). We propose that gonadal failure be included in the criteria so that the combination of Addison’s disease and gonadal failure can also be classified as APS II.
The HLA class II DR-DQ haplotypes were determined in the patients with isolated Addison’s disease and APS II. There have also previously been several reports on HLA associations in Addison’s disease. A flaw with these reports is that the number of patients has generally been small, reflecting that Addison’s disease and APS II are relatively rare diseases. In fact, our study represents one of the largest cohorts reported to date. We have therefore been able to support several previously suggestive findings. First of all, we found no significant differences in the frequency of HLA class II haplotypes in patients with isolated Addison’s disease compared with APS II. Secondly, in agreement with several previous studies we found an increase of the DR3-DQ2 and DR4-DQ8 haplotypes in Addison’s disease and APS II compared with healthy controls (10, 11, 12, 13). Concerning the latter haplotype, this association is evident also in Addison patients without type 1 diabetes in contrast to a previous report (11). Furthermore, we could confirm the results of Yu and co-workers (12) showing an increase in the frequency of the DR4 subtype DRB1*0404 on DQB1*0302 positive haplotypes among Addison patients. In fact, all the increase of DR4-DQ8 haplotypes could be explained by an increase of DRB1*0404-DQ8 haplotypes. This could imply that DRB1*0404 is primarily involved in genetic susceptibility to Addison’s disease. In contrast, Norwegian patients with type 1 diabetes have a decreased frequency of DRB1*0404 and instead an increased frequency of DRB1*0401 alleles (27).
A very strong increase of the DR3-DQ2/DR4-DQ8 genotype was observed. This genotype is a well known high risk genotype for type 1 diabetes and the associations observed with Addison’s disease seems equally strong or even stronger (OR = 36.7; P < 10-7). A difference is that in Addison’s disease the predominating DR4 subtype is DRB1*0404, whereas in type 1 diabetes DRB1*0401 prevail (27). The particularly high risk conferred by the DR3-DQ2/DR4-DQ8 genotype has been suggested to be caused by trans-encoded high risk DQ-heterodimers (37).
Finally, the DRB1*01-DQA1*01-DQB1*0501 haplotype conferred protection against Addison’s disease. This has not been reported previously. Interestingly, none among 21 American Addison patients carried this haplotype (12), and a European study observed a lower frequency, albeit statistically not significant, of DQB1*0501 among Addison patients compared with controls (38). Taken together, our results suggest that the DRB1*01-DQA1*01-DQB1*0501 haplotype may protect against the development of Addison’s disease.
Our study verifies that autoimmunity is the main cause of Addison’s disease in our cohort. In younger patients, the disease is equally common in men and women. Measurement of autoantibodies against 21OH is a valuable tool in establishing the etiological diagnosis. Assay of antibodies against SCC and 17OH antibodies may be useful for evaluating the risk of developing gonadal failure. Addison’s disease is associated with the DR3-DQ2 and DR4-DQ8 haplotypes. A particularly high risk is observed when these occur in a heterozygous combination (DR3-DQ2/DR4-DQ8). However, in Addison’s disease the predominating DR4 subtype is DRB1*0404, whereas in type 1 diabetes DRB1*0401 prevail. Signs of the disease should especially be looked for in individuals with other autoimmune disorders like type 1 diabetes and in patients with a high risk HLA genotype [i.e. the DR3-DQ2/DR4 (0404)-DQ8 genotype]. In such cases, determination of antibodies against 21OH can be of diagnostic value and help identifying patients in an early or subclinical phase of the disease.
Acknowledgments
We thank Ms. Wenke Trovik and Elin Theodorsen for help with the autoantibody assays. Our thanks are due to Prof. Ole Langeland Myking, Department of Biochemical Endocrinology, Haukeland University Hospital, for providing assays of autoantibody against thyroperoxidase, thyroglobulin, and IA2. Hanne E. Akselsen is thanked for her help with HLA class II typing. Thanks to the Norwegian Bone Marrow Donor Registry for providing control DNA samples for HLA analyses.
Footnotes
This study was supported by grants from the Aagot Giertsen’s Fund, The Juvenile Diabetes Foundation International, The Norwegian Diabetes Association, The Novo Nordisk Foundation, Novartis, Bristol-Myers Squibb Co., and Innovest. A.G.M. was supported financially by the Norwegian Research Council and grants from the Akershus Central Hospital.
Abbreviations: APS, Autoimmune polyendocrine syndrome; 17OH, 17-hydroxylase; 21OH, 21-hydroxylase; HLA, human leukocyte antigen; SCC, side-chain cleavage enzyme.
Received January 19, 2001.
Accepted October 25, 2001.
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