Idiopathic Adrenal Insufficiency Research Articles

Etiological diagnosis of primary adrenal insufficiency using an original flowchart of immune and biochemical markers.

Approximately 70-80% of cases of primary adrenal insufficiency are classified as idiopathic. An effective protocol for the etiological diagnosis of primary adrenal insufficiency is needed to ensure correct patient management. With the aim of developing an algorithm for the etiological diagnosis of primary adrenal insufficiency, we studied 56 Italian patients with nonsurgical primary adrenal insufficiency and 24 French patients with X-linked adrenoleukodystrophy (ALD) for serum levels of adrenal cortex, steroid-21-hydroxylase (21OHAb), islet cell (ICA), glutamate decarboxylase (GAD65Ab), IA2/ICA512 (ICA512Ab), thyroid peroxidase (TPOAb) autoantibodies, and plasmatic concentrations of very long chain fatty acids (VLCFA). High levels of 21OH and adrenal cortex antibodies were found in 35/42 (83%) and 17/42 (40%) Italian patients with idiopathic adrenal insufficiency, respectively. Levels of adrenal autoantibodies correlated inversely with disease duration (P < 0.0001). Elevated VLCFA were found in 4/42 (10%) idiopathic patients. A total of 34/35 (97%) idiopathic patients with a disease duration of less than 20 yr was positive for either 21OHSAb or elevated levels of VLCFA. None of 14 patients with posttuberculosis adrenal insufficiency had elevated levels of either adrenal antibodies or VLCFA. ICA, GAD65Ab, ICA512Ab, and TPOAb were found in 6/56 (11%), 8/56 (14%), 4/56 (7%), and 23/56 (41%) patients, respectively. None of 24 French ALD patients with adrenal insufficiency was positive for organ-specific autoantibodies. The measuring of 21OH antibodies and plasma VLCFA levels enabled a correct diagnosis of autoimmune (89%) and ALD (8%) in 97% of patients with idiopathic primary adrenal insufficiency of less than 20 yr of duration. The results of our study have important therapeutic and prognostic implications.

Red blood cell ghosts are affected by adrenoleucodystrophy.

X-linked adrenoleucodystrophy is a disorder occurring in different clinical forms, characterized by adrenal, gonadal and nervous system dysfunction. The basis of the illness is a derangement of the peroxisomal system necessary to oxidize very long-chain fatty acids that accumulate in various tissues. The diagnosis relies on clinical signs and symptoms and on biochemical findings. The six reported cases presented idiopathic adrenal insufficiency. We measured the lipid composition of red blood cell (RBC) ghosts of patients and control subjects. The distribution of phosphorus among phospholipid classes was unaffected; we could not demonstrate any differences between the fatty acid patterns of RBC membrane, either in total lipid extracts or in separated lipid classes. However, we found an increase in total lipid (both phospholipid and cholesterol), in membrane viscosity and in the Na+/K(+)-dependent ATPase. Therefore, we report four main findings on ghosts in adrenoleucodystrophy patients: (a) very long-chain fatty acids do not accumulate; (b) the lipid-protein ratio increases; (c) fluidity decreases; and (d) the activity of ATPase increases. The last finding is proposed as a possible biochemical marker of the illness. We conclude that adrenoleucodystrophy affects deeply RBC membranes.

COMPLEMENT-FIXING ADRENAL AUTOANTIBODIES AS A MARKER FOR PREDICTING ONSET OF IDIOPATHIC ADDISON'S DISEASE

In a prospective investigation of the role of adrenal autoantibodies (AA) in predicting the onset of idiopathic Addison's disease, 9 initially non-addisonian AA-positive autoimmune subjects were followed for 42 months. In 4 of these subjects Addison's disease developed within 1-31 months. A fifth had reduced adrenocortical reserve at the start and at the end of the investigation. An AA capable of fixing the membrane attack complex of complement [(C5-C9) F-AA] was detected before onset of the disease in the sera of the 4 patients in whom Addison's disease developed. (C5-C9) F-AA may be involved in the pathogenesis of idiopathic Addison's disease and may be regarded as a marker for individuals in whom idiopathic adrenal insufficiency is likely to develop.

Cortisol suppression test in patients with elevated adrenocorticotropic hormone levels.

Increased adrenocorticotropic hormone (ACTH) levels after bilateral adrenalectomy could be secondary to a pituitary tumor, under replacement with cortisol, or an abnormality in the hypothalamic-pituitary-adrenal feedback loop. To distinguish between these possibilities, ACTH levels were measured before and after cortisol infusion (20 mg/h for 4 hours) in five groups: normal volunteers; patients with idiopathic adrenal insufficiency; and with bilateral adrenalectomy for Cushing's syndrome with no roentgenographic evidence of pituitary tumor, with pituitary tumors, and with equivocal roentgenographic studies (suspect pituitary tumors). Control ACTH levels in all groups of patients were higher than in normal volunteers but there was overlapping. Cortisol infusion suppressed ACTH in all subjects but the reductions in the last two groups were less than in the first three. The cortisol suppression test appears to be useful in determining whether increased ACTH level after adrenalectomy is due to a pituitary tumor.

Autoimmunity and Multiple Endocrine Abnormalities

Tissue-specific antibodies have been found in the sera of patients with pernicious anemia, chronic lymphocytic thyroiditis, idiopathic adrenal insufficiency, and other endocrine disorders. The role of these autoantibodies in the pathophysiology of such diseases is still uncertain, but the reversal of the histopathological and functional lesions after corticosteroid treatment reported in some patients with pernicious anemia 1,2 and chronic thyroiditis 3 suggests that altered immunological mechanisms may be important in the development of these conditions. In addition, the familial occurrence of many of these diseases and the presence of more than one disorder in some patients suggests that a genetically determined predisposition to develop autoimmune reactions of this type may exist in some individuals. This report describes antibody studies carried out on a patient with chronic lymphocytic thyroiditis, idiopathic adrenal insufficiency, pernicious anemia, and vitiligo. Patient Summary This 36-year-old white man was first hospitalized at the age of 23 years

IMMUNOLOGICAL ASPECTS OF PREMATURE OVARIAN FAILURE ASSOCIATED WITH IDIOPATHIC ADDISON'S DISEASE

Antibodies reactive with the theca interna of the ovary, the interstitial cells of the testis, and the adrenal cortex were detected in the sera of 5 of 77 patients with idiopathic adrenal insufficiency. All 5 of these patients had either complete failure of menstruation or an early menopause. 1 of these 5 patients also had antibody reactive with ova and spermatids, and 3 had antibody reactive with placental trophoblasts. Only 1 of the remaining 72 patients with idiopathic Addison's disease was known to have premature failure of menstruation. Antibody reactive with gonadal tissue was absent in 34 patients with tuberculous Addison's disease, 111 control subjects matched with the Addison's patients for age and sex, 43 patients with gonadal dysgenesis that was not associated with Addison's disease, 50 postmenopausal females, and in 251 subjects with pernicious anæmia or thyroid autoimmune disease. Antibody reactive only with the theca interna of human ovary and with adrenal cortex was found in 1 of 24 patients with Cushing's syndrome. Primary gonadal failure may be part of a polyendocrinopathy of which idiopathic Addison's disease is an integral part and which is characterised by the formation of autoantibodies to the respective tissues.

Extra-adrenal endocrine deficiencies in Addison's disease

The frequency and nature of extra-adrenal endocrine deficiencies in patients with Addison's disease have been studied in an endocrine outpatient population. Of thirty-two patients who had been adequately followed, 41 per cent had evidence of a second endocrine gland deficiency. Six patients, or 19 per cent, had diabetes mellitus. Seven patients, or nearly 23 per cent, had primary gonadal disease. In this small series, extra-adrenal involvement of the endocrine glands was marked in patients with idiopathic adrenal insufficiency (50 per cent), but not significantly increased in those with tuberculous adrenal insufficiency. Premature ovarian failure preceded the development of clinical Addison's disease by five to fourteen years in all three patients in whom this combination of failures occurred. The data suggest that idiopathic Addison's disease represents a generalized tendency toward endocrine organ failure with adrenal insufficiency perhaps the most prominent and life threatening component.

GASTRIC ANTIBODIES STUDIED BY FLUORESCENCE MICROSCOPY.

Antibody specific for the mucosa of the body of human stomach was detected by the method of complement‐fixation in 62 percent of patients with Addisonian pernicious anæmia, in 20 per cent of patients with Hashimoto thyroiditis, in 25 per cent of patients with spontaneous hypothyroidism, and in 3 per cent of blood donors. Using the technique of fluorescence microscopy the specificity of this gastric antibody has been further defined to a particulate component of parietal cell cytoplasm. It is an auto‐antibody that will react equally well with homologous gastric mucosa provided the mucosa contains a normal concentration of healthy parietal cells. The indirect fluorescent antibody technique is a more sensitive test for parietal cell antibody than the method of complementfixation and the incidence of positive results in Addisonian pernicious anæmia, Hashimoto thyroiditis, spontaneous hypothyroidism and blood donors is correspondingly higher at 78, 25, 32 and 4 per cent respectively. Complementfixing gastric antibody is distinct from antibody to intrinsic factor but the latter does not appear to stain any other cell type in the gastric body mucosa with the fluorescent antibody technique.The relationship between pernicious anæmia, chronic thyroiditis and idiopathic adrenal insufficiency is discussed and it is argued that one of the basic factors in the pathogenesis of these three conditions is a genetically determined defect in immunological tolerance.