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Journal of Internal Medicine Feb 2018Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical...
BACKGROUND
Early detection of autoimmune Addison's disease (AAD) is important as delay in diagnosis may result in a life-threatening adrenal crisis and death. The classical clinical picture of untreated AAD is well-described, but methodical investigations are scarce.
OBJECTIVE
Perform a retrospective audit of patient records with the aim of identifying biochemical markers for early diagnosis of AAD.
MATERIAL AND METHODS
A multicentre retrospective study including 272 patients diagnosed with AAD at hospitals in Norway and Sweden during 1978-2016. Scrutiny of medical records provided patient data and laboratory values.
RESULTS
Low sodium occurred in 207 of 247 (84%), but only one-third had elevated potassium. Other common nonendocrine tests were largely normal. TSH was elevated in 79 of 153 patients, and hypoglycaemia was found in 10%. Thirty-three per cent were diagnosed subsequent to adrenal crisis, in whom electrolyte disturbances were significantly more pronounced (P < 0.001). Serum cortisol was consistently decreased (median 62 nmol L [1-668]) and significantly lower in individuals with adrenal crisis (38 nmol L [2-442]) than in those without (81 nmol L [1-668], P < 0.001).
CONCLUSION
The most consistent biochemical finding of untreated AAD was low sodium independent of the degree of glucocorticoid deficiency. Half of the patients had elevated TSH levels. Only a minority presented with marked hyperkalaemia or other nonhormonal abnormalities. Thus, unexplained low sodium and/or elevated TSH should prompt consideration of an undiagnosed AAD, and on clinical suspicion bring about assay of cortisol and ACTH. Presence of 21-hydroxylase autoantibodies confirms autoimmune aetiology. Anticipating additional abnormalities in routine blood tests may delay diagnosis.
Topics: Addison Disease; Adolescent; Adult; Aged; Biomarkers; Blood Glucose; Child; Child, Preschool; Early Diagnosis; Female; Humans; Hydrocortisone; Hyperkalemia; Hypoglycemia; Hyponatremia; Male; Middle Aged; Potassium; Retrospective Studies; Sodium; Thyrotropin; Young Adult
PubMed: 29098731
DOI: 10.1111/joim.12699 -
Internal Medicine (Tokyo, Japan) 2016We herein describe a second Japanese case of sarcoidosis presenting Addison's disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory...
We herein describe a second Japanese case of sarcoidosis presenting Addison's disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory findings, including bilateral hilar lymphadenopathy and elevated levels of serum angiotensin-converting enzyme and lysozyme, as well as the presence of noncaseating epithelioid granulomas. The patient also exhibited general fatigue, pigmentation, weight loss, hypotension and hyponatremia, suggestive of chronic adrenocortical insufficiency. An endocrine examination confirmed primary adrenocortical insufficiency. This case suggests the direct involvement of sarcoid granuloma in the adrenal glands.
Topics: Addison Disease; Adrenal Glands; Diagnosis, Differential; Fatigue; Granuloma; Humans; Hyponatremia; Lymphatic Diseases; Male; Middle Aged; Peptidyl-Dipeptidase A; Sarcoidosis
PubMed: 27150885
DOI: 10.2169/internalmedicine.55.5392 -
The Journal of Clinical Endocrinology... Apr 2020In autoimmune Addison's disease (AAD), exogenous glucocorticoid (GC) therapy is an imperfect substitute for physiological GC secretion. Patients on long-term steroid...
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.
UNLABELLED
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.
Topics: Addison Disease; Adrenal Glands; Adrenocorticotropic Hormone; Adult; Biomarkers; Cosyntropin; Drug Therapy, Combination; Female; Follow-Up Studies; Hormones; Humans; Hydrocortisone; Immunologic Factors; Male; Middle Aged; Quality of Life; Rituximab; Young Adult
PubMed: 31863094
DOI: 10.1210/clinem/dgz287 -
BMJ Case Reports Aug 2021
Topics: Addison Disease; Diagnosis, Differential; Humans; Hyperpigmentation
PubMed: 34404673
DOI: 10.1136/bcr-2021-245610 -
Folia Medica Cracoviensia 2021There is increasing evidence that several autoimmune diseases, as well as their activity, are associated with vitamin D (VD) deficiency. Our study aimed to evaluate the...
INTRODUCTION
There is increasing evidence that several autoimmune diseases, as well as their activity, are associated with vitamin D (VD) deficiency. Our study aimed to evaluate the prevalence of VD insufficiency in patients with Addison's disease (AD), as well as to evaluate associations between VD concentrations and various clinical and laboratory parameters of the disease.
MATERIALS AND METHODS
We retrospectively analyzed medical records of 31 adult patients diagnosed with autoimmune Addison's disease, in whom serum VD was measured. We assessed correlations between serum VD and various clinical and laboratory parameters. R e s u l t s: 90.3% of AD patients had inadequate VD concentrations (<30 ng/mL), and 19.3% of them were found to be severely VD deficient (<10 ng/mL). Among assessed laboratory variables, only serum calcium concentrations significantly correlated with VD status (r = 0.53, p = 0.006). The mean serum VD concentration was significantly lower in patients with severe fatigue (15.17 ± 8.41 vs 26.83 ± 12.29 ng/mL, p = 0.011) and limited exercise capacity (12.38 ± 6.9 vs 21.63 ± 10.87 ng/mL, p = 0.016). C o n c l u s i o n s: This study demonstrates a high prevalence of VD deficiency in AD patients, as well as the association between low VD concentrations with symptoms such as severe fatigue or limited exercise capacity. Further studies are needed to clarify if impaired VD status is a risk factor in the pathogenesis of AD and to assess if VD supplementation improves the quality of life of AD patients.
Topics: Addison Disease; Adult; Humans; Laboratories; Quality of Life; Retrospective Studies; Vitamin D
PubMed: 34510165
DOI: 10.24425/fmc.2021.137224 -
Acta Medica Indonesiana Jan 2009
Topics: Addison Disease; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Adult; Antitubercular Agents; Humans; Hyperpigmentation; Male; Tuberculosis, Pulmonary
PubMed: 19258679
DOI: No ID Found -
BMC Genomics Nov 2020Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency....
BACKGROUND
Primary hypoadrenocorticism (or Addison's disease, AD) is an autoimmune disease that results in destruction of the adrenal cortex and consequent adrenal insufficiency. The disease has been described in purebred and mixed breed dogs, although some breeds, including the Bearded Collie, are at increased risk for AD. Candidate gene approaches have yielded few associations that appear to be breed-specific. A single other genome-wide association study reported no significant regions of association for AD in Standard Poodles. The present study aimed to identify genomic regions of association for canine AD in Bearded Collies.
RESULTS
Our study consists of the first genome-wide association analysis to identify a genome-wide significant region of association with canine AD (CFA18). Peaks of suggestive association were also noted on chromosomes 11, 16 and 29. Logistic regression analysis supported an additive effect of risk genotypes at these smaller effect loci on the probability of disease associated with carrying a risk genotype on CFA18. Potential candidate genes involved in adrenal steroidogenesis, regulation of immune responses and/or inflammation were identified within the associated regions of chromosomes 11 and 16. The gene-poor regions of chromosomes 18 and 29 may, however, harbor regulatory sequences that can modulate gene expression and contribute to disease susceptibility.
CONCLUSION
Our findings support the polygenic and complex nature of canine AD and identified a strongly associated locus on CFA18 that, when combined with three other smaller effect loci, was predictive of disease. The results offer progress in the identification of susceptibility loci for canine AD in the Bearded Collie. Further studies are needed to confirm association with the suggested candidate genes and identify actual causative mutations involved with AD susceptibility in this breed.
Topics: Addison Disease; Animals; Dog Diseases; Dogs; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Polymorphism, Single Nucleotide
PubMed: 33243158
DOI: 10.1186/s12864-020-07243-0 -
Internal Medicine (Tokyo, Japan) 2017We herein report a case of Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles...
We herein report a case of Addison's disease caused by tuberculosis characterized by atypical hyperpigmentation, noted as exacerbation of the pigmentation of freckles and the occurrence of new freckles, that was diagnosed in the presence of active pulmonary tuberculosis. The clinical condition of the patient was markedly ameliorated by the administration of hydrocortisone and anti-tuberculosis agents. When exacerbation of the pigmentation of the freckles and/or the occurrence of new freckles are noted, Addison's disease should be considered as part of the differential diagnosis. In addition, the presence of active tuberculosis needs to be assumed whenever we treat patients with Addison's disease caused by tuberculosis, despite its rarity.
Topics: Addison Disease; Diagnosis, Differential; Humans; Hyperpigmentation; Male; Middle Aged; Tuberculosis, Pulmonary
PubMed: 28717080
DOI: 10.2169/internalmedicine.56.7976 -
Frontiers in Immunology 2021CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison's disease (AAD)....
OBJECTIVES
CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison's disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH), restricted by HLA-A2, and EPLARLEL (21OH), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD.
METHODS
Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH.
RESULTS
We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated.
CONCLUSION
We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.
Topics: Addison Disease; CD8-Positive T-Lymphocytes; Epitopes, T-Lymphocyte; HLA-A2 Antigen; HLA-C Antigens; Humans; Immunodominant Epitopes; Steroid 21-Hydroxylase
PubMed: 34721410
DOI: 10.3389/fimmu.2021.742848 -
Clinical and Experimental Immunology Jan 2019Autoimmune Addison's disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease with 160 years of history. AAD is... (Review)
Review
Autoimmune Addison's disease (AAD), or primary adrenocortical insufficiency, is a classical organ-specific autoimmune disease with 160 years of history. AAD is remarkably homogeneous with one major dominant self-antigen, the cytochrome P450 21-hydroxylase enzyme, which is targeted by both autoantibodies and autoreactive T cells. Like most autoimmune diseases, AAD is thought to be caused by an unfortunate combination of genetic and environmental factors. While the number of genetic associations with AAD is increasing, almost nothing is known about environmental factors. A major environmental factor commonly proposed for autoimmune diseases, based partly on experimental and clinical data and partly on shared pathways between anti-viral immunity and autoimmunity, is viral infections. However, there are few reports associating viral infections to AAD, and it has proved difficult to establish which immunological processes that could link any viral infection with the initiation or progression of AAD. In this review, we will summarize the current knowledge on the underlying mechanisms of AAD and take a closer look on the potential involvement of viruses.
Topics: Addison Disease; Animals; Autoantibodies; Autoantigens; Autoimmunity; Gene-Environment Interaction; Humans; Steroid 21-Hydroxylase; T-Lymphocytes; Virus Diseases
PubMed: 30144040
DOI: 10.1111/cei.13207