scholarly journals Residual adrenal function in Addison’s disease

2020 ◽  
Author(s):  
Simon Hs Pearce ◽  
Earn H Gan ◽  
Catherine Napier
Keyword(s):  
Stem Cell ◽  
Clinical Significance ◽  
Disease Duration ◽  
Addison’S Disease ◽  
Adrenal Function ◽  
Stem Cell Population ◽  
Addison's Disease ◽  
Adrenal Failure ◽  
Adrenal Steroidogenesis ◽  
The Moment

Over the last ten years, evidence has accumulated that autoimmune Addison’s disease (AAD) is a heterogeneous disease. Residual adrenal function, characterised by persistent secretion of cortisol, other glucocorticoids and mineralocorticoids is present in around 30% of patients with established AAD, and appears commoner in men. This persistent steroidogenesis is present in some patients with AAD for more than 20 years, but it is commoner in people with shorter disease duration. The clinical significance of residual adrenal function is not fully clear at the moment, but as it signifies an intact adrenocortical stem cell population, it opens up the possibility of regeneration of adrenal steroidogenesis and improvement in adrenal failure for some patients.

scholarly journals Adrenal Steroidogenesis after B Lymphocyte Depletion Therapy in New-Onset Addison's Disease

2012 ◽  
Vol 97 (10) ◽  
pp. E1927-E1932 ◽  
Author(s):  
Simon H. S. Pearce ◽  
Anna L. Mitchell ◽  
Stuart Bennett ◽  
Phil King ◽  
Sukesh Chandran ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Addison’S Disease ◽  
Serum Cortisol ◽  
Adrenal Crisis ◽  
Addison's Disease ◽  
Adrenal Failure ◽  
Lymphocyte Depletion ◽  
Adrenal Steroidogenesis ◽  
Cortisol Levels ◽  
New Onset

Abstract Context: A diagnosis of Addison's disease means lifelong dependence on daily glucocorticoid and mineralocorticoid therapy and is associated with increased morbidity and mortality as well as a risk of unexpected adrenal crisis. Objective: The objective of the study was to determine whether immunomodulatory therapy at an early stage of autoimmune Addison's disease could lead to preservation or improvement in adrenal steroidogenesis. Design and Intervention: This was an open-label, pilot study of B lymphocyte depletion therapy in new-onset idiopathic primary adrenal failure. Doses of iv rituximab (1 g) were given on d 1 and 15, after pretreatment with 125 mg iv methylprednisolone. Patients and Main Outcome Measures: Six patients (aged 17–47 yr; four females) were treated within 4 wk of the first diagnosis of idiopathic primary adrenal failure. Dynamic testing of adrenal function was performed every 3 months for at least 12 months. Results: Serum cortisol levels declined rapidly and were less than 100 nmol/liter (3.6 μg/dl) in all patients by 3 months after B lymphocyte depletion. Serum cortisol and aldosterone concentrations remained low in five of the six patients throughout the follow-up period. However, a single patient had sustained improvement in both serum cortisol [peak 434 nmol/liter (15.7 μg/dl)] and aldosterone [peak 434 pmol/liter (15.7 ng/dl)] secretion. This patient was able to discontinue steroid medications 15 months after therapy and remains well, with improving serum cortisol levels 27 months after therapy. Conclusion: New-onset autoimmune Addison's disease should be considered as a potentially reversible condition in some patients. Future studies of immunomodulation in autoimmune Addison's disease may be warranted.

scholarly journals Residual Adrenal Function in Autoimmune Addison’s Disease—Effect of Dual Therapy With Rituximab and Depot Tetracosactide

2019 ◽  
Vol 105 (4) ◽  
pp. e1250-e1259 ◽  
Author(s):  
Catherine Napier ◽  
Earn H Gan ◽  
Anna L Mitchell ◽  
Lorna C Gilligan ◽  
D Aled Rees ◽  
...  
Keyword(s):  
B Lymphocyte ◽  
Outcome Measure ◽  
Combined Treatment ◽  
Addison’S Disease ◽  
Dual Therapy ◽  
Adrenal Function ◽  
Gas Chromatography Mass Spectrometry ◽  
Addison's Disease ◽  
Open Label ◽  
Main Outcome Measure

Abstract Context In autoimmune Addison’s disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid replacement have increased morbidity, reduced life expectancy, and poorer quality of life. Objective The objective of this article is to restore adrenocortical steroidogenic function in recent-onset AAD. Design An open-label, multicenter trial of immunotherapy and trophic stimulation in new-onset AAD was conducted. Serial measurement of serum and urine corticosteroids at baseline and throughout a 72-week follow-up period was performed. Setting This study was conducted at the endocrine departments and clinical research facilities at 5 UK tertiary centers. Patients Thirteen participants (9 female, 4 male; age 19-64 years) were included with AAD confirmed by high adrenocorticotropin, low circulating cortisol (basal < 100 nmol/L or post-tetracosactide < 300 nmol/L), and positive serum 21-hydroxylase antibodies. Intervention All participants received dual therapy with B-lymphocyte–depleting immunotherapy (rituximab 1 g given twice) and repeated depot tetracosactide (1 mg on alternate days for 12 weeks). Main Outcome Measure Restoration of normal GC secretion (stimulated cortisol > 550 nmol/L) at week 48 was the main outcome measure. Results Ten of 13 (77%) participants had detectable stimulated serum cortisol (26-265 nmol/L) at trial entry. Following intervention, 7 of 13 (54%) had an increase in stimulated cortisol measurement, with a peak response of 325 nmol/L at week 18 in 1 participant. Increased steroid metabolites, assayed by urine gas chromatography–mass spectrometry at week 12 and week 48, was detected in 8 of 13 (62%) individuals, reflecting an increase in endogenous steroidogenesis. Four of 13 had residual adrenal function at 72 weeks. Conclusion Combined treatment with rituximab and depot tetracosactide did not restore normal adrenal function. Nevertheless, adrenocortical plasticity is demonstrated in some patients, and this has the potential to be exploited to improve adrenal function.

scholarly journals The Substrate-Binding Domain of 21-Hydroxylase, the Main Autoantigen in Autoimmune Addison’s Disease, Is an Immunodominant T Cell Epitope

Endocrinology ◽  
2006 ◽  
Vol 147 (5) ◽  
pp. 2411-2416 ◽  
Author(s):  
Eystein S. Husebye ◽  
Eirik Bratland ◽  
Geir Bredholt ◽  
Mati Fridkin ◽  
Molly Dayan ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Proliferative Response ◽  
Substrate Binding ◽  
Cell Epitope ◽  
Addison’S Disease ◽  
Addison's Disease ◽  
Adrenal Failure ◽  
Lymph Node Cells

The steroidogenic enzyme 21-hydroxylase (21OH) is the main autoantigen in autoimmune primary adrenal failure (Addison’s disease). Autoantibodies against 21OH are immunological markers of an ongoing autoimmune process but are not directly involved in the tissue destruction. Autoreactive T cells are thought to mediate tissue damage, but the T cell antigen(s) has not been identified. To find out whether 21OH contains important immunodominant epitopes for T cells, we first immunized BALB/c and SJL inbred mouse strains with recombinant 21OH and showed that lymph node cells proliferated effectively following in vitro stimulation with recombinant 21OH (stimulation indices (SI) 20–40). We further synthesized a series of peptides based on 21OH with amino acid sequences with propensity to bind to major histocompatibility complex class II molecules. Only a few peptides could trigger lymphocytes of 21OH-primed mice to proliferate. One of these, 21OH (342–361), stimulated effectively 21OH-primed lymph node cells of SJL mice (SI = 4–8) and also, although to a lesser extent, of BALB/c mice (SI = 2.5). When SJL mice were immunized with 21OH (342–361), the immunizing peptide as well as peptide 21OH (346–361) triggered a significant proliferative response (SI = 24). A peptide from another part of 21OH, namely 21OH (191–202), did not stimulate the 21OH (342–361)-primed cells. Moreover, stimulation of lymph node cells of mice immunized with 21OH (342–361) with 21OH resulted in a significant proliferative response. We conclude that 21OH (342–361) is an immunodominant determinant for T cells in SJL and probably BALB/c mice. 21OH (342–361) corresponds to the substrate binding site of the enzyme. The p342–361 region may be involved in the pathogenesis of autoimmune adrenal failure in humans.

scholarly journals Residual Adrenal Function in Autoimmune Addison's Disease: Improvement After Tetracosactide (ACTH1–24) Treatment

2014 ◽  
Vol 99 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Earn H. Gan ◽  
Katie MacArthur ◽  
Anna L. Mitchell ◽  
Beverly A. Hughes ◽  
Petros Perros ◽  
...  
Keyword(s):  
Addison’S Disease ◽  
Adrenal Function ◽  
Addison's Disease

scholarly journals Estimated Risk for Developing Autoimmune Addison’s Disease in Patients with Adrenal Cortex Autoantibodies

2006 ◽  
Vol 91 (5) ◽  
pp. 1637-1645 ◽  
Author(s):  
Graziella Coco ◽  
Chiara Dal Pra ◽  
Fabio Presotto ◽  
Maria Paola Albergoni ◽  
Cristina Canova ◽  
...  
Keyword(s):  
Adrenal Cortex ◽  
Cox Model ◽  
Cumulative Risk ◽  
Human Leukocyte ◽  
Addison’S Disease ◽  
Adrenal Function ◽  
Addison's Disease ◽  
Risk Algorithm ◽  
Functional Factors ◽  
Estimated Risk

Context: Patients with adrenal cortex autoantibodies (ACA) without overt autoimmune Addison’s disease (AAD) are at risk of adrenal failure. Design: To assess the contribution of different clinical, immunological, genetic, and functional factors in the progression to AAD, we followed up 100 ACA-positive and 63 ACA-negative patients without AAD for a maximum of 21 yr (mean 6.0 yr, median 4.8). ACA were measured by immunofluorescence and 21-OH autoantibodies (Abs) by RIA. Adrenal function was assessed by measuring basal levels of cortisol, aldosterone, ACTH, renin activity, and cortisol response to ACTH. The risk of developing AAD was calculated using survival and multivariate analyses. Results: AAD developed in 31 ACA-positive patients and one ACA-negative patient. The cumulative risk of disease in ACA-positive patients was 48.5% [95% confidence interval (CI) 40.8–56.1]. The cumulative risk was higher in children than adults (100 vs. 31.9%; P < 0.0001), males than females (68.6 vs. 42.7%; P = 0.006), patients with subclinical rather than normal adrenal function at entry (87.4 vs. 30.1%; P < 0.0001), patients with hypoparathyroidism and/or candidiasis than patients with other autoimmune or nonautoimmune diseases (100 vs. 29.7%; P < 0.0001), and patients with high rather than low-medium ACA titers (62.8 vs. 41.2%; P = 0.12). The presence of human leukocyte antigen (HLA)-DRB1 did not appear to contribute to the prediction of AAD. Adjusted hazard ratios by Cox model for the development of AAD were 3.37 for males (CI 1.38–8.24), 5.23 for hypoparathyroidism and/or candidiasis (CI 1.53–17.92), 3.33 for high antibody titers (CI 1.43–7.78), and 6.15 for impaired adrenal function at entry (CI 2.79–13.57). Conclusions: These results were used to construct a risk algorithm for estimating the probability of developing AAD from the combination of gender, age, adrenal function, antibody titer, and associated autoimmune disorders at entry. The values of estimated risk could be used to decide appropriate follow-up intervals and future immunointervention strategies.

Problems in Diagnosis of Addison’s Disease and its Misdiagnosis as Chronic Kidney Disease (CKD): A Case Report

2020 ◽  
Vol In Press (In Press) ◽  
Author(s):  
Tahereh Sabaghian ◽  
Minoo Heidari Almasi
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Failure ◽  
Kidney Disease ◽  
Addison’S Disease ◽  
Primary Diagnosis ◽  
Adrenal Crisis ◽  
Addison's Disease ◽  
Adrenal Failure ◽  
Case Presentation ◽  
Endocrine Diseases

Introduction: Chronic kidney disease (CKD) rarely occurs at the same time as endocrine diseases such as adrenal failure. There are some reports of cases with acute kidney failure accompanied by Addison’s disease and adrenal crisis. The studied case was a patient with Addison’s disease referring with manifestations of AKI on CKD and hyperkalemia without hypotension. Case Presentation: This report describes a 34-year-old man with the primary diagnosis of CKD and the subsequent diagnosis of Addison’s disease. Conclusions: Since renal failure is accompanied by hyperkalemia, the diagnosis of adrenal failure will be difficult in the case of no obvious hyponatremia and hypotension. Thus, it is necessary to carefully check the clinical and laboratory symptoms and high clinical suspicions in CKD patients.

scholarly journals Clinical Significance of Adrenal Computed Tomography in Addison's Disease.

1992 ◽  
Vol 39 (6) ◽  
pp. 563-569 ◽  
Author(s):  
ZHONG HUA SUN ◽  
KAORU NOMURA ◽  
SHOHZOH TORAYA ◽  
MAKOTO UJIHARA ◽  
NOBUO HORIBA ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Clinical Significance ◽  
Addison’S Disease ◽  
Addison's Disease

The natural history of adrenal function in autoimmune patients with adrenal autoantibodies

1988 ◽  
Vol 117 (3) ◽  
pp. 467-475 ◽  
Author(s):  
C. Betterle ◽  
C. Scalici ◽  
F. Presotto ◽  
B. Pedini ◽  
L. Moro ◽  
...  
Keyword(s):  
Addison’S Disease ◽  
Plasma Renin ◽  
Autoimmune Disorder ◽  
Adrenal Function ◽  
Adrenocortical Function ◽  
Diabetic Patients ◽  
Addison's Disease ◽  
Gonadal Dysfunction ◽  
Insulin Dependent Diabetic ◽  
Low Cortisol

ABSTRACT Adrenal autoantibodies (AA) were found in 23 of 2571 (0·9%) patients with organ-specific autoimmune diseases, in one of 632 first-degree relatives of insulin-dependent diabetic patients, and in none of 375 normal controls. In AA-positive subjects the prevalence of human leucocyte antigens (HLA)-A1, -B8 and -DR3 was significantly higher with respect to the general population. Two groups were followed (15 subjects persistently positive for AA and 51 negative subjects) for a mean period of 3·2 years. Yearly tests were made for AA and adrenal function. Of the 15 subjects persistently positive for AA, six developed Addison's disease after a period varying from 6 months to 10 years. Of the 51 subjects initially negative, two became positive during follow-up, and one of these developed Addison's disease 16 months later. In contrast, all the remaining 49 persistently negative subjects maintained normal adrenal function tests. Overall, of the 17 positive subjects, seven (41%) developed Addison's disease, three (18%) showed various degrees of subclinical adrenocortical failure and the remaining seven maintained normal glandular function. In the positive patients the yearly incidence of detriment in adrenal function was 19%. Patients who developed Addison's disease showed significant association with HLA-B8 phenotype. The development from normal adrenocortical function to overt Addison's disease seemed to progress through four distinct stages of functional impairment: increased plasma renin activity with normal/low aldosterone (stage 1), low cortisol response after i.v. administration of ACTH (stage 2), increased ACTH (stage 3), and low basal cortisol (stage 4). Thus, idiopathic Addison's disease appears to be a chronic autoimmune disorder with a genetic predisposition and a long preclinical period marked by the presence of AA. Steroid-producing cell antibodies were also evaluated but they were not found to be markers of gonadal dysfunction. J. Endocr. (1988) 117, 467–475

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