Autoimmune Addison's Disease Research Articles

Plasma catecholamines in patients with Addison's disease.

Two endocrine tissues are present within the adrenal gland: the steroid producing cortical cells and the catecholamine producing chromaffin cells. Glucocorticoids occur in high concentrations in the adrenal medulla. In vitro, glucocorticoids have been shown to induce the enzyme phenyl-N-methyl-transferase which is necessary for the production of adrenaline in adrenal medullary cells. The purpose of this study was to evaluate the possible significance of a local glucocorticoid effect on adrenomedullary function. Plasma catecholamine levels were measured in patients with autoimmune Addison's disease where local production of corticosteroids is deficient in the presence of intact chromaffin tissue. Catecholamines were measured by high pressure liquid chromatography and ACTH, renin and adrenal steroids by radioimmunoassay. Nineteen Addisonian patients (9 females, 10 males) were treated according to a standard regime with oral cortisone acetate (37.5 mg/day) and fludrocortisone (0.1 mg/day). All patients were clinically well. Mean plasma adrenaline in patients with Addison's disease was significantly reduced compared to a sex and age matched control group (males (n = 10) 143 +/- 36 pmol/l, controls (n = 27) 303 +/- 30 pmol/l, P < 0.01; females (n = 9) 77 +/- 25 pmol/l, controls (n = 27) 293 +/- 21 pmol, P < 0.001). The noradrenaline:adrenaline ratio was clearly higher in patients with Addison's disease (males 24 +/- 4, controls 9 +/- 1, P < 0.01; females 45 +/- 6, controls 9 +/- 1, P < 0.01). We conclude that the physiologically high local glucocorticoid concentration may be responsible for normal adrenaline production under basal conditions.

Autoimmune Addison's disease--evidence for a role of steroid 21-hydroxylase autoantibodies in adrenal insufficiency.

Autoantibodies to steroid 21-hydroxylase (21-OH) are characteristic of adult onset Addison's disease and we have investigated the effects of these autoantibodies on recombinant human 21-OH enzyme activity. Antibody preparations from 11/11 Addison sera inhibited the ability of 21-OH to convert progesterone to deoxycorticosterone with 8 IgGs showing almost complete inhibition, 2 partial inhibition and 1 weak inhibition. Control IgGs from patients with autoimmune thyroid disease and normal blood donors had little or no effect on 21-OH activity. Our results suggest that 21-OH autoantibodies have the potential to contribute to adrenal failure in Addison's disease by inhibiting the 21-OH enzyme.

Autoimmune Addison's disease--evidence for a role of steroid 21- hydroxylase autoantibodies in adrenal insufficiency

Autoimmune Addison's disease--evidence for a role of steroid 21- hydroxylase autoantibodies in adrenal insufficiency

Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease.

Patients with idiopathic Addison's disease are characterized by cytoplasmic adrenal autoantibodies, detectable by indirect immunofluorescence of cryocut sections of human adrenal cortex. Recently, autoantibodies that bind a 55-kilodalton protein in the microsomal fraction of adrenal gland extracts identified to be the cytochrome P450 enzyme 21-hydroxylase have been found in Addisonian patient sera. We confirm the finding and report here the autoantigenic epitopes involved in the autoantibody reactivity using recombinant DNA technology. Six cDNA fragments spanning different regions of the 21-hydroxylase gene were expressed as fusion proteins with glutathione S-transferase in Escherichia coli. Immunoblot analyses were used to evaluate the reactivity of the recombinant proteins with patients' sera to determine the autoepitopes involved. We found that a conserved region (amino acids 164-356) reacted with 25 of 30 adrenal autoantibody-positive sera tested. One serum sample reacted only with the amino portion of the 21-hydroxylase (amino acids 1-162). In addition, 4 other enzymes important to steroid hormone biosynthesis, 11 beta-hydroxylase, 17 alpha-hydroxylase, side-chain cleavage enzyme P450, and 3 beta-hydroxysteroid dehydrogenase, were expressed in E. coli, but none of them gave positive autoantibody reactions by Western blot assays, even using sera from 5 patients with type I autoimmune polyglandular syndrome. The availability of recombinant antigens has permitted structural analysis of the autoepitopes involved in the autoimmune response to 21-hydroxylase in Addison's disease. Our findings should lead to the development of a simple and specific tool for immunodiagnosis of the disease.

Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease

Autoantibody epitope mapping of the 21-hydroxylase antigen in autoimmune Addison's disease

Autoimmune Addison's disease: Analysis of autoantibody binding sites on human steroid 21-hydroxylase

Human steroid 21-hydroxylase (21-OH) expressed in an in vitro translation system was found to react specifically with adrenal autoantibodies from patients with Addison's disease. The epitopes on 21-OH which reacted with autoantibodies were studied by incorporating a series of terminal and internal deletions into the 21-OH gene and analysing the expressed proteins by Western blotting. N-Terminal deletions up to amino acid 280 had no effect on autoantibody binding whereas a series of C-terminal deletions and truncations (amino acids 281–494) showed marked effects. Our results indicate that a central segment (281–379) and a C-terminal segment (380–494) of 21-OH interact to form at least one major autoantibody binding site.

Steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease

An adrenal-specific protein reacting with autoantibodies in the sera of patients with adult onset Addison's disease has been purified from human adrenal glands. The protein, mol.wt. 55K, has the biochemical characteristics of steroid 21-hydroxylase and reacts on Western blots with rabbit antibodies to recombinant 21-hydroxylase. Absorption of the native human 55K adrenal protein with human adrenal autoantibodies prevented the subsequent reaction of the 55K protein with rabbit antibodies to 21-hydroxylase in Western blot analysis. In addition, human adrenal autoantibodies reacted with recombinant 21-hydroxylase expressed in yeast. These data indicate that the adrenal specific enzyme steroid 21-hydroxylase is a major autoantigen involved in adult onset autoimmune Addison's disease.

Le syndrome des antiphospholipides (SAPL) : une nouvelle cause d'hémorragie bilatérale des surrénales

We report 3 cases of bilateral adrenal hemorrhage associated with the antiphospholipid syndrome (APS). In one of primary APS adrenal insufficiency was the presenting feature. The antiphospholipid antibodies must be searched in « auto-immuneAddison's disease, and adrenal hemorrhage must be searched with CT-scan or MRI if hyponatremia and hyperkaliema occur durint the course of APS.

HLA associations with autoimmune Addison's disease

HLA associations with autoimmune Addison's disease

Autoimmune Addison's disease and thyrotoxic thyroiditis presenting as encephalopathy in twins.

An 11 year old boy who presented with neuropsychiatric symptoms including delirium and pronounced agitation was found to have simultaneous onset of autoimmune adrenocortical insufficiency and hyperthyroidism. His identical twin also had hyperthyroidism and six months later developed symptoms of adrenocortical insufficiency. In children presenting with neuropsychiatric symptoms, adrenal (or pituitary) and other endocrine disorders should be considered.

Polyglandular autoimmune syndrome Type II in patients with idiopathic Addison's disease

The frequency of polyglandular autoimmune syndrome Type II, (idiopathic or autoimmune Addison's disease associated with autoimmune thyroid disease, and/or insulin-dependent diabetes mellitus), was retrospectively investigated in 44 patients (26 females and 18 males) with idiopathic Addison's disease (median age at onset 32.5 years, range 8-62; median observation time 17 years, range 0.5-41) evaluated between 1966 and 1988 in the Department of Endocrinology, General Hospital, Malmö. Twenty-two patients (16 females and 6 males) fulfilled the criteria for polyglandular autoimmune syndrome Type II and of these 16 had autoimmune thyroid disease and 9 insulin-dependent diabetes mellitus. In 7 of 9 patients insulin-dependent diabetes mellitus developed prior to Addison's disease, whereas autoimmune thyroid disease was diagnosed before as well as after Addison's disease and with a similar age distribution as Addison's disease. In conclusion, the present study indicates that polyglandular autoimmune syndrome Type II occurs in about 50% of patients with idiopathic Addison's disease and that autoimmune thyroid disease is more common than insulin-dependent diabetes mellitus in these patients. The present study also indicates that insulin-dependent diabetes mellitus precedes Addison's disease in a majority of these patients and usually develops at a young age, whereas autoimmune thyroid disease precedes as well as succeeds Addison's disease and occurs at all ages in these patients.

Class II MHC expression in normal adrenal cortex and cortical cells in autoimmune Addison's disease.

It has been proposed that aberrant expression of class II major histocompatibility complex (MHC) molecules by target cells may be an initiating factor in some forms of organ specific autoimmunity. This hypothesis was tested in relation to the autoimmune form of Addison's disease by studying autopsy adrenal glands from eight patients who had died of recent onset idiopathic Addison's disease. Using an immunohistochemical technique, class II MHC expression was found in a minority of adrenal cortical cells in the zona reticularis in 25 normal and four hyperplastic glands, while in Addison's disease almost all residual cortical cells expressed class II MHC. Three tuberculous adrenals showed increased staining of cortical cells around areas of chronic inflammation. It is concluded that since adrenal cortical cells of the normal gland express class II MHC, aberrant expression of this product cannot be invoked as an initiating mechanism in autoimmune adrenalitis. The increased cortical expression of class II MHC seen in idiopathic Addison's disease and tuberculosis may be due to local release of lymphokines by inflammatory cells.

Inherited susceptibility to autoimmune Addison's disease is linked to human leukocyte antigens-DR3 and/or DR4, except when associated with type I autoimmune polyglandular syndrome.

The inherited susceptibility to autoimmune Addison's disease was found to be strongly associated with human leukocyte antigens (HLA)-DR3 and DR4 alleles. In a study of 45 white patients from the United States with the disease, the relative risks (the number of times that an individual is at risk for Addison's disease if they had a marker, compared to those without such marker) were found to be 6.0, 4.6, and 26.5 for the DR3 allele, the DR4 allele, and for DR3/DR4 heterozygotes, respectively. Frequencies of DR2, DR5, and DR7 in the patients with Addison's disease were significantly decreased in comparison to 265 individuals in the control population. These HLA-DR frequencies in patients with Addison's disease were similar to those for 723 patients with insulin-dependent diabetes (IDD). However, the above HLA-DR associations persisted even when only data from the 37 patients with Addison's disease who did not have IDD were considered. Adrenocortical autoantibodies in 23 patients with IDD who did not have Addison's disease were equally frequent among those with DR4 and DR3 alleles. In contrast, HLA-DR frequencies in 17 patients with type I autoimmune polyglandular syndrome (chronic mucocutaneous moniliasis, hypoparathyroidism, Addison's disease, etc.) were not different from control. We conclude that genetic susceptibility to autoimmune Addison's disease may involve the same HLA-associated genetic determinants as IDD, except when Addison's disease occurs as part of type I autoimmune polyglandular syndrome.

Receptors, antibodies, and disease.

Abnormal antibody production is now recognized as the basis of specific endocrine and neurological diseases and their complications. Among the autoimmune diseases, the best understood from a mechanistic point of view are myasthenia gravis, Graves' disease, several variants of insulin resistance, and a variant of bronchial asthma. In each of these human disorders, the clinical symptoms can be traced to the actions of antireceptor antibodies produced by a deranged immune system. The autoantibodies produced in these diseases are functionally heterogeneous. They may produce the clinical symptoms of hormone or neurotransmitter insufficiency either by blocking the binding of these agents to target cell surface receptors or by accelerating the internalization and degradation of these receptors. In other cases, the autoantibodies may produce the clinical signs of hormone excess by mimicking the actions of the hormone, in an uncontrollable fashion. In some cases, functionally different types of autoantibodies will appear in the same patient at different stages of the disease. For all of these autoantibodies, of whatever function, assays for their presence in serum are available, in forms suitable for clinical chemists, as well as for researchers; these will be described in this review. In addition to the known anti-receptor autoimmune diseases, there are a large number of other autoimmune diseases for which there is fragmentary evidence that their clinical symptoms have an anti-receptor autoantibody etiology. Several examples of this group will be discussed, and assays suitable for establishing the presence of anti-receptor antibodies in the sera of such patients will be provided. The disorders to be considered are: type I diabetes mellitus, chronic atrophic gastritis, autoimmune Addison's disease, autoimmune hypoparathyroidism, type II pseudohypoparathyroidism, resistant ovary syndrome, connective tissue diseases, and the HLA-B8/DR3 antigen haplotype as a potential marker for autoimmune diseases of the anti-receptor type.

HLA Antigens in Two Siblings with Autoimmune Addison's Disease

The diagnosis of autoimmune Addison's disease was established in two siblings by demonstration of serum antibodies against adrenal cortex antigen, elevated P-ACTH combined with a low P-cortisol, and the absence of P-cortisol response to exogenous ACTH. HLA typing in the two siblings and their parents revealed the same HLA phenotype in the two patients. This is compatible with an autosomal recessive mode of inheritance and indicates that a supposed trait for autoimmune Addison's disease may segregate with the HLA complex in the familial form of autoimmune Addison's disease.

Hyperfunction of the Adrenal Cortex

There is evidence suggesting that autoimmune Addison's disease (AD) could be associated with sexual dysfunctions probably caused by gluco‐ and mineralocorticoid deficiency; however, no study has yet treated this subject in males.To evaluate male sexuality and psychological correlates in autoimmune AD before and after gluco‐ and mineralocorticoid replacement therapy.Twelve subjects with a first diagnosis of autoimmune AD were studied before (baseline) and 2 months after (recovery phase) initiating hormone replacement therapy.Erectile function (EF), orgasmic function (OF), sexual desire (SD), intercourse satisfaction (IS), overall satisfaction (OS), depression, and anxiety were studied using a number of questionnaires (International Index of Erectile Function, Beck Depression Inventory, and Spielberger State‐Trait Anxiety Inventory); clinical, biochemical, and hormone data were included in the analysis.At baseline, low values were found for EF, OF, SD, IS, and OS and high values for depression and anxiety; all of these parameters improved significantly in the recovery phase compared with baseline. EF variation between the two phases correlated significantly and positively with the variation of serum cortisol, urinary free cortisol, systolic blood pressure, and diastolic blood pressure and inversely with that of upright plasma renin activity. Multiple linear regression analysis using EF variation as dependent variable confirmed the relationship of the latter with variation of serum cortisol, urinary free cortisol, and upright plasma renin activity but not with variation of systolic and diastolic blood pressure.Our study showed that onset of autoimmune AD in males is associated with a number of sexual dysfunctions, all reversible after initiating replacement hormone therapy; cortisol and aldosterone deficiency seems to play an important role in the genesis of erectile dysfunction although the mechanism of their activity is not clear. Granata A, Tirabassi G, Pugni V, Arnaldi G, Boscaro M, Carani C, and Balercia G. Sexual dysfunctions in men affected by autoimmune Addison's disease before and after short‐term gluco‐ and mineralocorticoid replacement therapy. J Sex Med 2013;10:2036–2043.