Background
Addison’s disease (AD) is a rare disorder and among adult population in developed countries is most commonly caused by autoimmunity. In contrast, in children genetic causes are responsible ...for AD in the majority of patients.
Purpose
This review describes epidemiology, pathogenesis, genetics, natural history, clinical manifestations, immunological markers and diagnostic strategies in patients with AD. Standard care treatments including the management of patients during pregnancy and adrenal crises consistent with the recent consensus statement of the European Consortium and the Endocrine Society Clinical Practice Guideline are described. In addition, emerging therapies designed to improve the quality of life and new strategies to modify the natural history of autoimmune AD are discussed.
Conclusions
Progress in optimizing replacement therapy for patients with AD has allowed the patients to lead a normal life. However, continuous education of patients and health care professionals of ever-present danger of adrenal crisis is essential to save lives of patients with AD.
Background
The number of recognised distinct autoimmune diseases (AIDs) has progressively increased over the years with more than 100 being reported today. The natural history of AIDs is ...characterized by progression from latent and subclinical to clinical stages and is associated with the presence of the specific circulating autoantibodies. Once presented, AIDs are generally chronic conditions. AIDs have the tendency to cluster and co-occur in a single patient. Autoimmune thyroid diseases (AITD) are the most prevalent of AIDs in the world population, and about one-third of the AITD patients also present with a non-thyroid AID during their life-span. Furthermore, patient with non-thyroid AIDs often presents with a form of AITD as a concurrent condition. Many of the clusters of AIDs are well characterized as distinctive syndromes, while some are infrequent and only described in case reports.
Purpose
In this review, we describe the wide spectrum of the combinations and the intricate relationships between AITD and the other AIDs, excluding Addison’s disease. These combinations are collectively termed type 3 Autoimmune Polyglandular Syndrome (APS-3), also called type 3 Multiple Autoimmune Syndrome (MAS-3), and represent the most frequent APS in the world populations.
Conclusions
Numerous associations of AITD with various AIDs could be viewed as if the other AIDs were gravitating like satellites around AITD located in the center of a progressively expanding galaxy of autoimmunity.
Primary adrenal insufficiency (PAI), or Addison's disease, is a rare, potentially deadly, but treatable disease. Most cases of PAI are caused by autoimmune destruction of the adrenal cortex. ...Consequently, patients with PAI are at higher risk of developing other autoimmune diseases. The diagnosis of PAI is often delayed by many months, and most patients present with symptoms of acute adrenal insufficiency. Because PAI is rare, even medical specialists in this therapeutic area rarely manage more than a few patients. Currently, the procedures for diagnosis, treatment and follow‐up of this rare disease vary greatly within Europe. The common autoimmune form of PAI is characterized by the presence of 21‐hydroxylase autoantibodies; other causes should be sought if no autoantibodies are detected. Acute adrenal crisis is a life‐threatening condition that requires immediate treatment. Standard replacement therapy consists of multiple daily doses of hydrocortisone or cortisone acetate combined with fludrocortisone. Annual follow‐up by an endocrinologist is recommended with the focus on optimization of replacement therapy and detection of new autoimmune diseases. Patient education to enable self‐adjustment of dosages of replacement therapy and crisis prevention is particularly important in this disease. The authors of this document have collaborated within an EU project (Euadrenal) to study the pathogenesis, describe the natural course and improve the treatment for Addison's disease. Based on a synthesis of this research, the available literature, and the views and experiences of the consortium's investigators and key experts, we now attempt to provide a European Expert Consensus Statement for diagnosis, treatment and follow‐up.
Context
Fludrocortisone (FC) is the mineralocorticoid (MC) replacement treatment for patients with primary adrenal insufficiency (PAI).
Objective
To explore the dose of FC treatment and its ...relationship with glucocorticoid therapy, sodium, potassium, renin and clinical parameters.
Setting
Monocentric cohort.
Patients
Data of 193 patients with PAI (130 autoimmune) were collected during baseline (T0), intermediate (T1) and last follow-up visit (T2, respectively, after a mean of 38 and 72 months).
Main outcome measure
Utility of endocrine and clinical parameters to titrate FC dose.
Results
FC dose (50–75 μg/daily) was stable in the follow-up in half patients. The MC activity of FC was dose-dependent: we observed a reduced but significant positive linear correlation between FC dose and sodium (
r
= 0.132) and negative linear correlation between FC and potassium (
r
= − 0.162) or renin (
r
= − 0.131, all
p
< 0.01). An overall reduction in the FC dose was observed at T2 in the group with longer follow-up (> 60 months,
p
< 0.05). Higher doses of FC were observed in patients with low-normal renin, especially in autoimmune PAI (86 vs 65 μg/daily,
p
< 0.05). On the contrary, reduced sodium and increased potassium levels were observed in patients with high renin at T2. The number of cardiovascular events (15 in the whole cohort) was similar in patients sorted by renin levels or FC dose.
Conclusions
Renin and electrolytes can indicate the MC activity of FC treatment: they should be routinely evaluated and used to titrate its dose that can be reduced in the long-term follow-up.
SUMMARY
Autoimmune polyglandular syndromes (APS) are conditions characterized by the association of two or more organ‐specific disorders. Type 2 APS is defined by the occurrence of Addison's disease ...with thyroid autoimmune disease and/or Type 1 diabetes mellitus. Clinically overt disorders are considered only the tip of the autoimmune iceberg, since latent forms are much more frequent. Historical, clinical, genetic, and immunological aspects of Type 2 APS are reviewed. Furthermore, data on 146 personal cases of Type 2 APS are also reported.
Purpose
Biallelic loss-of-function mutations of
AIRE
cause the autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome. However, single nucleotide mutations may cause a ...milder phenotype. In this paper, we describe an unusual and mild phenotype in a mother and her two children (son and daughter) who carry a rare heterozygous mutation of
AIRE
.
Methods and results
The son presented with alopecia and subclinical hypothyroidism due to Hashimoto’s Thyroiditis (HT); the daughter had alopecia, vaginal mycosis, stomach pains and subclinical hypothyroidism due to HT; and the mother had alopecia, vaginal mycosis and stomach pains. Organ- and non-organ-specific autoantibodies were evaluated as well as antibodies against interleukin-17A, -17F, -22 (IL-Abs) and interferon -α and -ω (IFN-Abs). The organ- and non-organ-specific autoantibodies screening was negative in the son, while the daughter was positive for liver–kidney microsomal antibodies (LKMAbs) and the mother was positive for glutamic acid decarboxylase antibodies (GADAbs). Daughter and mother were also positive for IFN-Abs. Analysis of the
AIRE
gene identified a rare heterozygous R203X mutation in all three family members.
Conclusions
We describe for a first time a family with heterozygous R203X
AIRE
mutation causing an APECED-like condition, as confirmed by presence of IFN-Abs. The unusual mild phenotype should be reassuring for the patients and assist in their clinical management.
Summary
Background
Among Western populations, the declining incidence of Helicobacter pylori infection coincides with a growing clinical impact of autoimmune gastritis.
Aims
To describe the ...histological phenotype of autoimmune gastritis, also to test the prognostic impact of OLGA staging in the autoimmune setting.
Methods
A single‐institutional series (spanning the years 2003–2011) of 562 consecutive patients (M:F ratio: 1:3.7; mean age = 57.6 ± 14.4 years) with serologically confirmed autoimmune gastritis underwent histology review and OLGA staging.
Results
Helicobacter pylori infection was ascertained histologically in 44/562 cases (7.8%). Forty six biopsy sets (8.2%) featured OLGA stages III–IV; they included all four cases of incidental epithelial neoplasia (three intraepithelial and one invasive; three of these four cases had concomitant H. pylori infection). There were 230 (40.9%) and 139 (24.7%) cases, respectively, of linear and micro‐nodular enterochromaffin‐like cell hyperplasia; 19 (3.4%) type I carcinoids were detected. The series included 116 patients who underwent repeated endoscopy/biopsy sampling (mean time elapsing between the two procedures = 54 months; range 24–108). Paired histology showed a significant (P = 0.009) trend towards a stage progression the stage increased in 25/116 cases (22%); it remained unchanged in 87/116 cases (75%).
Conclusions
In autoimmune gastritis, the cancer risk is restricted to high‐risk gastritis stages (III–IV), and is associated mainly with concomitant H. pylori infection. OLGA staging consistently depicts the time‐dependent organic progression of the autoimmune disease and provides key information for secondary gastric cancer prevention strategies.
Design:
The design of the study was to investigate the prevalence of the following: 1) premature ovarian failure (POF) in patients with autoimmune Addison's disease (AD); 2) steroid-producing cell ...antibodies (StCA) and steroidogenic enzymes (17α-hydroxylase autoantibodies and P450 side-chain cleavage enzyme autoantibodies) in patients with or without POF; and 3) the value of these autoantibodies to predict POF.
Patients:
The study included 258 women: 163 with autoimmune polyendocrine syndrome type 2 (APS-2), 49 with APS-1, 18 with APS-4, and 28 with isolated AD.
Methods:
StCA were measured by an immunofluorescence technique and 17α-hydroxylase autoantibodies and P450 side-chain cleavage enzyme autoantibodies by immunoprecipitation assays.
Results:
Fifty-two of 258 women with AD (20.2%) had POF. POF was diagnosed in 20 of 49 (40.8%) with APS-1, six of 18 (33.3%) with APS-4, 26 of 163 (16%) with APS-2, and none of 28 with isolated AD. In patients with APS-1 and APS-4, POF developed after AD, whereas it preceded AD in patients with APS-2. StCA were detected in 31 of 43 with POF (72%) and 51 of 198 without POF (25.7%). StCA were present in 22 of 38 with APS-1 (57.9%) (11 of 13 with POF); in five of 13 with APS-4 (38.5%) (three of four with POF); in 53 of 162 with APS-2 (32.7%) (17 of 26 with POF), and in one of 28 isolated AD patients (3.6%). Twelve of 13 patients with POF with a duration less than 5 yr (92.3%) and 18 of 25 with duration longer than 5 yr (72%) were StCA positive. Twenty-eight of 31 with POF (90.3%) were positive for at least one steroidogenic antibody. Forty-one women with AD less than 40 yr were followed up for a mean period of 9 yr. Eight of 21 women (38%) positive or seroconverted for steroidogenic autoantibodies developed POF at a mean age of 23 yr (six with APS-1, one with APS-2, and one with APS-4), and none of the 20 patients negative for steroidogenic autoantibodies developed POF.
Conclusions:
This study indicates that AD is frequently associated with POF and that steroidogenic antibodies are markers of patients with POF. Steroidogenic autoantibodies are predictive markers of POF in patients with AD.
PDF
