Autoimmune Addison's Disease Research Articles

8393 Low Polygenic Risk Score For Autoimmune Addison’s Disease Identifies Misdiagnosed Cases of Monogenic Primary Adrenal Insufficiency

Abstract Disclosure: M. Aranda Guillen: None. I. Botusan: None. V. Fernando: None. E. Røyrvik: None. A. Bøe Wolff: None. S. Johansson: None. E.S. Husebye: None. S. Bensing: None. O. Kampe: None. D. Eriksson: None. Background: Primary adrenal insufficiency (PAI) is sometimes misdiagnosed as autoimmune Addison's disease (AAD), affecting clinical management and genetic counselling. We tested a polygenic risk score (PRS) for AAD (PRS14AAD) as a tool to reevaluate disease etiology and identify patients misdiagnosed with AAD. Methods: We calculated the PRS14AAD in a cohort of patients diagnosed with AAD but lacking 21-hydroxylase autoantibodies (n=124). Patients with low genetic susceptibility to AAD were selected for whole-genome sequencing to detect potential monogenic causes (n=35). Results: Among the 35 patients, monogenic PAI was diagnosed in 5 (14%) and suspected in 3 additional cases (9%). Three out of the 5 patients diagnosed with monogenic PAI developed the disease in adulthood, indicating late-onset monogenic disease associated with hypomorphic genetic variants. Conclusion: A PRS for AAD can help identify potential monogenic cases, regardless of the age at diagnosis. Early identification of the underlying cause of PAI enables accurate management and correct genetic counselling. Presentation: 6/2/2024

The multiple faces of autoimmune Addison's disease in children.

Primary adrenal insufficiency (PAI) is a rare medical condition, characterized by a deficiency in adrenal hormones. Although rare, PAI is a life-threatening disease requiring prompt recognition and treatment. However, symptoms of PAI are often non-specific and diagnosis can be challenging, causing frequent diagnostic delays. In adults, autoimmunity is the most common cause of PAI in industrialized countries, whereas in children, the most frequent etiology is represented by congenital defects of steroidogenesis and, in particular, by congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. A few recent case series from different countries have reported that autoimmunity is the second most common etiology of PAI in the pediatric age group. However, data on autoimmune PAI in children are still scant and the exact epidemiology, clinical manifestations, and long-term outcomes of this condition have yet to be defined. The scope of this review is to summarize the current knowledge on the etiology, presentation, and treatment of autoimmune PAI in childhood and to increase physicians' awareness of the signs that should raise an early suspicion of this condition.

Late-onset Schmidt's Syndrome Presenting with Severe Hyponatremia: A Case Report.

Schmidt's syndrome (SS) is a subtype of polyglandular autoimmune syndrome type-2 combining autoimmune thyroiditis (AIT) and autoimmune Addison's disease (aAD). It occurs most frequently in young adult females, and aAD is the most common initial manifestation [1]. We present a rare case of SS with late-onset aAD and severe hyponatremia as the first sign. A 73-year-old woman presented to the emergency department (ED) with a 10-day history of vomiting, diarrhea, and altered mental status. Her past medical history was remarkable for AIT and hypokinetic cardiomyopathy. Moreover, she had recently undergone a 2-week course of corticosteroid therapy for vertiginous symptoms, reporting subjective well-being. In ED, she appeared confused and hypotensive. Blood tests revealed a sodium level of 99 mEq/l with normal potassium. Initial treatment with saline infusions were started, followed by ex juvantibus intravenous hydrocortisone awaiting hormone results, which proved consistent with primary adrenal insufficiency (ACTH 1314 pg/ml, cortisol 4.72 ug/dL). Replacement therapy with both hydrocortisone and fludrocortisone was then implemented, with substantial clinical improvement and normalization of sodium levels. However, the patient later developed right heart failure and hypokalemia, which were likely caused by overreplacement and resolved after adjusting the treatment regimen. The final diagnosis of aAD was confirmed by positive adrenal autoantibodies. aAD should be suspected in each case of severe hyponatremia [2], especially in patients with AIT independent of age. Furthermore, caution is needed in managing high-dose glucocorticoids along with fludrocortisone in elderly patients with cardiac disease to limit the risk of excessive mineralocorticoid activity and heart failure [3].

Polygenic risk score for autoimmune Addison's disease combined with whole-genome sequencing identifies patients with undiagnosed monogenic primary adrenal insufficiency

Polygenic risk score for autoimmune Addison's disease combined with whole-genome sequencing identifies patients with undiagnosed monogenic primary adrenal insufficiency

Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study

ObjectiveThis study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. MethodsWe performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. ResultsOur findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08–1.27), psoriasis (OR 1.10; 95 % CI 1.04–1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23–1.63), pernicious anemia (OR 1.23; 95 % CI 1.12–1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11–1.26), alopecia areata (OR 1.22; 95 % CI 1.10–1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12–1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. ConclusionsWe substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities.

Excessive pickle consumption: beware of adrenal crisis

Adrenal insufficiency (AI) is one of the most life-threatening disorders resulting from adrenal cortex dysfunction. Symptoms and signs of AI are often nonspecific, and the diagnosis can be missed and lead to the development of AI with severe hypotension and hypovolemic shock.We report the case of a 13-year-old child admitted for cardiac arrest following severe hypovolemic shock. The patient initially presented with isolated mild abdominal pain and vomiting together with unexplained hyponatremia. He was discharged after an initial short hospitalization with rehydration but with persistent hyponatremia. After discharge, he had persistent refractory vomiting, finally leading to severe dehydration and extreme asthenia. He was admitted to pediatric intensive care after prolonged hypovolemic cardiac arrest with severe anoxic encephalopathy leading to brain death. After re-interviewing, the child's parents reported that he had experienced polydipsia, a pronounced taste for salt with excessive consumption of pickles lasting for months, and a darkened skin since their last vacation 6 months earlier. A diagnosis of autoimmune Addison's disease was made.Primary AI is a rare life-threatening disease that can lead to hypovolemic shock. The clinical symptoms and laboratory findings are nonspecific, and the diagnosis should be suspected in the presence of unexplained collapse, hypotension, vomiting, or diarrhea, especially in the case of hyponatremia.

Rare copy number variation in autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

Hypoglycaemia in adrenal insufficiency.

Adrenal insufficiency encompasses a group of congenital and acquired disorders that lead to inadequate steroid production by the adrenal glands, mainly glucocorticoids, mineralocorticoids and androgens. These may be associated with other hormone deficiencies. Adrenal insufficiency may be primary, affecting the adrenal gland's ability to produce cortisol directly; secondary, affecting the pituitary gland's ability to produce adrenocorticotrophic hormone (ACTH); or tertiary, affecting corticotrophin-releasing hormone (CRH) production at the level of the hypothalamus. Congenital causes of adrenal insufficiency include the subtypes of Congenital Adrenal Hyperplasia, Adrenal Hypoplasia, genetic causes of Isolated ACTH deficiency or Combined Pituitary Hormone Deficiencies, usually caused by mutations in essential transcription factors. The most commonly inherited primary cause of adrenal insufficiency is Congenital Adrenal Hyperplasia due to 21-hydroxylase deficiency; with the classical form affecting 1 in 10,000 to 15,000 cases per year. Acquired causes of adrenal insufficiency can be subtyped into autoimmune (Addison's Disease), traumatic (including haemorrhage or infarction), infective (e.g. Tuberculosis), infiltrative (e.g. neuroblastoma) and iatrogenic. Iatrogenic acquired causes include the use of prolonged exogenous steroids and post-surgical causes, such as the excision of a hypothalamic-pituitary tumour or adrenalectomy. Clinical features of adrenal insufficiency vary with age and with aetiology. They are often non-specific and may sometimes become apparent only in times of illness. Features range from those related to hypoglycaemia such as drowsiness, collapse, jitteriness, hypothermia and seizures. Features may also include signs of hypotension such as significant electrolyte imbalances and shock. Recognition of hypoglycaemia as a symptom of adrenal insufficiency is important to prevent treatable causes of sudden deaths. Cortisol has a key role in glucose homeostasis, particularly in the counter-regulatory mechanisms to prevent hypoglycaemia in times of biological stress. Affected neonates particularly appear susceptible to the compromise of these counter-regulatory mechanisms but it is recognised that affected older children and adults remain at risk of hypoglycaemia. In this review, we summarise the pathogenesis of hypoglycaemia in the context of adrenal insufficiency. We further explore the clinical features of hypoglycaemia based on different age groups and the burden of the disease, focusing on hypoglycaemic-related events in the various aetiologies of adrenal insufficiency. Finally, we sum up strategies from published literature for improved recognition and early prevention of hypoglycaemia in adrenal insufficiency, such as the use of continuous glucose monitoring or modifying glucocorticoid replacement.

Increased Resting-State Functional Connectivity in Patients With Autoimmune Addison Disease.

Individuals with autoimmune Addison disease (AAD) take replacement medication for the lack of adrenal-derived glucocorticoid (GC) and mineralocorticoid hormones from diagnosis. The brain is highly sensitive to these hormones, but the consequence of having AAD for brain health has not been widely addressed. The present study compared resting-state functional connectivity (rs-fc) of the brain between individuals with AAD and healthy controls. Fifty-seven patients with AAD (33 female) and 69 healthy controls (39 female), aged 19 to 43 years were scanned with 3-T magnetic resonance imaging (MRI). Independent component and subsequent dual regression analyses revealed that individuals with AAD had stronger rs-fc compared to controls in 3 networks: the bilateral orbitofrontal cortex (OFC), the left medial visual and left posterior default mode network. A higher GC replacement dose was associated with stronger rs-fc in a small part of the left OFC in patients. We did not find any clear associations between rs-fc and executive functions or mental fatigue. Our results suggest that having AAD affects the baseline functional organization of the brain and that current treatment strategies of AAD may be one risk factor.

Altered biomarkers for cardiovascular disease and inflammation in autoimmune Addison's disease - a cross-sectional study.

Increased prevalence of cardiovascular disease has been reported in autoimmune Addison's disease (AAD), but pathomechanisms are poorly understood. Cross-sectional study. We compared serum levels of 177 cardiovascular and inflammatory biomarkers in 43 patients with AAD at >18-h glucocorticoid withdrawal and 43 matched controls, overall and stratified for sex. Biomarker levels were correlated with the frequency of adrenal crises and quality of life (QoL) by AddiQoL-30. Finally, we investigated changes in biomarker levels following 250 µg tetracosactide injection in patients without residual adrenocortical function (RAF) to explore glucocorticoid-independent effects of high ACTH. Nineteen biomarkers significantly differed between patients with AAD and controls; all but 1 (ST1A1) were higher in AAD. Eight biomarkers were significantly higher in female patients compared with controls (IL6, MCP1, GAL9, SPON2, DR4, RAGE, TNFRSF9, and PGF), but none differed between male patients and controls. Levels of RAGE correlated with the frequency of adrenal crises (r = 0.415, P = .006) and AddiQoL-30 scores (r = -0.347, P = .028) but not after correction for multiple testing. PDL2 and leptin significantly declined 60 min after injection of ACTH in AAD without RAF (-0.15 normalized protein expression [NPX], P = .0001, and -0.25 NPX, P = .0003, respectively). We show that cardiovascular and inflammatory biomarkers are altered in AAD compared with controls, particularly in women. RAGE might be a marker of disease severity in AAD, associated with more adrenal crises and reduced QoL. High ACTH reduced PDL2 and leptin levels in a glucocorticoid-independent manner but the overall effect on biomarker profiles was small.

FRI258 A Diagnostic Journey To Autoimmune Polyendocrine Syndrome Type 2

Abstract Disclosure: S. Amankwah: None. H.K. Driscoll: None. C. Muojieje: None. M. Sanati: None. Background: Approximately 50-65% of patients with autoimmune adrenal insufficiency have one or more autoimmune endocrine disorders. This case demonstrates the importance of considering autoimmune polyendocrine syndrome (APS) when a patient presents with more than one autoimmune endocrine disorder. Case: A 29-year-old woman with history of idiopathic intracranial hypertension, hypothyroidism on levothyroxine 50 mcg daily, endometriosis, and chronic migraines complained of fatigue, word finding difficulty, misspeaking of words, and staring spells. An MRI of the brain w+wo IV contrast revealed hypo-enhancing appearance of the pituitary gland. The patient was referred to endocrinology by neurology. Hormonal work up was performed checking for prolactin, ACTH, morning cortisol, TSH, Free T4, FSH, LH, IGF-1 and a serum chemistry panel. Thyroid antibodies were also ordered to help understand the etiology of her hypothyroidism. Pituitary hormones were normal except elevated TSH and borderline low serum cortisol. Subsequently a co-syntropin stimulation test resulted in inadequate cortisol rise. ACTH level measured inappropriately low normal. The patient then started steroid replacement therapy. Thereafter, 21-hydroxylase antibodies, serum renin and aldosterone were checked to screen for Addison Disease. Her 21-hydroxylase antibody was positive, aldosterone level low, and renin elevated pointing to autoimmune adrenalitis etiology. Her thyroid antibodies were also positive indicating autoimmune thyroid disease. Considering these results, the condition of APS came into question. Hence, the patient was screened for type 1 diabetes mellitus which was positive for glutamic acid decarboxylase 65 antibody but negative for insulin and pancreatic islet cell antibodies. Her hemoglobin A1c was 5.0%. Due to her history of gluten intolerance, she was screened for celiac disease which was negative for t-Transglutaminase antibody. The patient’s fatigue improved on steroid replacement therapy. She became euthyroid after increasing her levothyroxine dose to 75 mcg daily, and repeated MRI a year later did not show pituitary abnormalities. Discussion: APS type 2 is a polygenic inherited disorder associated with HLA-DR3 and DR4 that affects adult females more than males. The syndrome is characterized by type 1 diabetes mellitus, autoimmune thyroid disease and Addison disease. Associated nonendocrine autoimmune syndromes include celiac disease, pernicious anemia, and atrophic gastritis. These characteristics overlap with APS type 1 except for autoimmune thyroid disease that presents with type 2. It should be noted that thyroxine therapy can precipitate a life-threatening Addison crisis in a patient with untreated adrenal insufficiency and hypothyroidism. Therefore, it is necessary to evaluate adrenal function in all hypothyroid patients in whom APS is suspected. Presentation: Friday, June 16, 2023

Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease.

Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the HLA region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the two genes, and therefore we asked if genetic variation of the CYP21 genes is associated with AAD. Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P together with HLA alleles in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase, and in 1,393 healthy controls. With 95% of individuals carrying two functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (p = 5 x 10-44) together with associations of additional nucleotide variants in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (p = 9 x 10-63), which in combination with the DRB1*04:04-DQB1*03:02 haplotype imposed the greatest risk of AAD. We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.

Resting-state functional connectivity in Autoimmune Addison's Disease

Patients with autoimmune Addison’s disease (AAD) are unable to produce glucocorticoids (GCs), mineralocorticoids (MCs) and androgens from the adrenal cortex and therefore require life-long treatment with GCs and MCs. Due to the sensitivity of the brain to cortisol and androgens, brain function might be affected in patients, as the replacement regime cannot mimic the natural rhythmicity of hormonal secretion. Alterations in brain function might predispose to cognitive or mood disturbances. The present study investigated resting-state functional connectivity (rs-fc) in patients with AAD. Resting-state fMRI data was collected from 57 (33 females) patients with AAD and 69 (39 females) control participants, aged 19-43 years. Resting-state brain networks were identified with independent component analysis (FSL MELODIC). Dual-regression analysis was applied to test for group differences in rs-fc in these networks. Within the patient group we tested the association between rs-fc and glucocorticoid replacement dose in mg/m2/day. Significant clusters were identified with threshold free cluster enhancement and considered to be significant at p<0.05. Patients with AAD had increased fc in the bilateral medial orbitofrontal cortex compared to controls. A higher glucocorticoid replacement dose was associated with stronger functional connectivity in several networks in the prefrontal cortex in patients. AAD seems to be associated with stronger fc at rest in an area known to contain a high density of GC receptors. Further research is needed to investigate if this increased activity is part of an adaptive mechanism or if it predisposes to disturbances in mood and executive functioning.

Plasma-Metanephrines in Patients with Autoimmune Addison's Disease with and without Residual Adrenocortical Function.

Residual adrenocortical function, RAF, has recently been demonstrated in one-third of patients with autoimmune Addison's disease (AAD). Here, we set out to explore any influence of RAF on the levels of plasma metanephrines and any changes following stimulation with cosyntropin. We included 50 patients with verified RAF and 20 patients without RAF who served as controls upon cosyntropin stimulation testing. The patients had abstained from glucocorticoid and fludrocortisone replacement > 18 and 24 h, respectively, prior to morning blood sampling. The samples were obtained before and 30 and 60 min after cosyntropin stimulation and analyzed for serum cortisol, plasma metanephrine (MN), and normetanephrine (NMN) by liquid-chromatography tandem-mass pectrometry (LC-MS/MS). Among the 70 patients with AAD, MN was detectable in 33%, 25%, and 26% at baseline, 30 min, and 60 min after cosyntropin stimulation, respectively. Patients with RAF were more likely to have detectable MN at baseline (p = 0.035) and at the time of 60 min (p = 0.048) compared to patients without RAF. There was a positive correlation between detectable MN and the level of cortisol at all time points (p = 0.02, p = 0.04, p < 0.001). No difference was noted for NMN levels, which remained within the normal reference ranges. Even very small amounts of endogenous cortisol production affect MN levels in patients with AAD.

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.

Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p<2e-16), and 1.2 SD higher in the young patients compared with the old (p=3e-4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Self-management and hospitalization in 615 Swedish patients with Addison's disease during the COVID-19 pandemic - a retrospective study.

Autoimmune Addison's disease (AAD) entails a chronic adrenal insufficiency and is associated with an increased risk of severe infections. It is, however, unknown how patients with AAD were affected by the coronavirus disease 2019 (COVID-19) pandemic of 2020-2021. The aim of this study was to investigate the incidence of COVID-19 in patients with AAD in Sweden, the self-adjustment of medications during the disease, impact on social aspects and treatment during hospitalization. Additionally, we investigated if there were any possible risk factors for infection and hospitalization. Questionnaires were sent out from April to October 2021 to 813 adult patients with AAD in the Swedish Addison registry. The questionnaires included 55 questions inquiring about COVID-19 sickness, hospital care, medications, and co-morbidities, focusing on the pre-vaccine phase. Among the 615 included patients with AAD, COVID-19 was reported by 17% of which 8.5% required hospital care. Glucocorticoid treatment in hospitalized patients varied. For outpatients 85% increased their glucocorticoid dosage during sickness. Older age (p=0.002) and hypertension (p=0.014) were associated with an increased risk of hospital care while younger age (p<0.001) and less worry about infection (p=0.030) correlated with a higher risk of COVID-19. In the largest study to date examining AAD during the COVID-19 pandemic, we observed that although one fifth of the cohort contracted COVID-19 few patients required hospital care. A majority of the patients applied general recommended sick-rules despite reporting limited communication with healthcare during the pandemic.

Replication of association at the LPP and UBASH3A loci in a UK autoimmune Addison's disease cohort.

Autoimmune Addison's disease (AAD) arises from a complex interplay between multiple genetic susceptibility polymorphisms and environmental factors. The first genome wide association study (GWAS) with patients from Scandinavian Addison's registries has identified association signals at four novel loci in the genes LPP, SH2B3, SIGLEC5, and UBASH3A. To verify these novel risk loci, we performed a case-control association study in our independent cohort of 420 patients with AAD from the across the UK. We report significant association of alleles of the LPP and UBASH3A genes [odds ratio (95% confidence intervals), 1.46 (1.21-1.75)and 1.40 (1.16-1.68), respectively] with AAD in our UK cohort. In addition, we report nominal association of AAD with SH2B3 [OR 1.18 (1.02-1.35)]. We confirm that variants at the LPP and UBASH3A loci confer susceptibility to AAD in a UK population. Further studies with larger patient cohorts are required to robustly confirm the association of SH2B3 and SIGLEC5/SPACA6 alleles.

A Rare Case of Autoimmune Addison's Disease in a Patient with Previously Diagnosed Primary Hyperaldosteronism.

A Rare Case of Autoimmune Addison's Disease in a Patient with Previously Diagnosed Primary Hyperaldosteronism.

Insilico prediction and functional analysis of nonsynonymous SNPs in human CTLA4 gene

The CTLA4 receptor is an immune checkpoint involved in the downregulation of T cells. Polymorphisms in this gene have been found to be associated with different diseases like rheumatoid arthritis, autosomal dominant immune dysregulation syndrome, juvenile idiopathic arthritis and autoimmune Addison's disease. Therefore, the identification of polymorphisms that have an effect on the structure and function of CTLA4 gene is important. Here we identified the most damaging missense or non-synonymous SNPs (nsSNPs) that might be crucial for the structure and function of CTLA4 using different bioinformatics tools. These in silico tools included SIFT, PROVEAN, PhD-SNP, PolyPhen-2 followed by MutPred2, I-Mutant 2.0 and ConSurf. The protein structures were predicted using Phyre2 and I-TASSER, while the gene–gene interactions were predicted by GeneMANIA and STRING. Our study identified three damaging missense SNPs rs1553657429, rs1559591863 and rs778534474 in coding region of CTLA4 gene. Among these SNPs the rs1553657429 showed a loss of potential phosphorylation site and was found to be highly conserved. The prediction of gene–gene interaction showed the interaction of CTlA4 with other genes and its importance in different pathways. This investigation of damaging nsSNPs can be considered in future while studying CTLA4 related diseases and can be of great importance in precision medicine.

PSAT037 The Unlikely Suspect - A New Diagnosis of Autoimmune Addison's Disease in an 80-year old Lady

Abstract Introduction Hyponatremia is a common cause of hospitalization in older adults. Addison's disease (AD), an uncommon cause of hyponatremia, is primary adrenal insufficiency (AI) caused by autoimmune adrenalitis, infections, adrenal hemorrhage, or infiltration. Autoimmune adrenalitis is an uncommon cause of AD after age 60 years. We report an 80 year old patient with hyponatremia who was ultimately diagnosed with autoimmune AD. Case report An 80 year-old lady with steroid-controlled asthma, presented to the ER with weakness, imbalance, nausea and vomiting two weeks after a urinary tract infection. Her blood pressure was 96/64 mm Hg with otherwise normal vital signs and unremarkable general examination. Laboratory evaluation revealed hyponatremia (Na 120 mmol/L), hyperkalemia (K 5.7 mmol/L) and acute kidney injury (creatinine 1.2 mg/dl, GFR 43 ml/min/m). Hyperkalemia resolved with intravenous fluids, insulin and dextrose therapy (K 4.7 mmol/L). However, hyponatremia persisted (Na 120-123 mmol/L) despite fluid restriction, normal saline, and salt tablets. Additionally, patient remained hypotensive with blood pressure between 90/40-120/60 mm Hg. Due to concern for AI from prior steroid use, morning cortisol was measured and was low (4.63 mcg/dl). Concurrent ACTH level was elevated (252 pg/ml, range 7.2-63.3 pg/ml). Cosyntropin stimulation test done during hospitalization was abnormal (4.5 mcg/d→6.7 mcg/dl→8 mcg/dl) confirming AD. At outpatient consultation with endocrinology, patient reported nausea and vomiting for 18 months prior to hospitalization, 50 lbs weight loss, weakness, short-term memory loss, and dizziness attributed to vertigo. Symptoms worsened a month prior to patient's hospitalization. Repeat cosyntropin stimulation test remained abnormal (8.5 mcg/dl→9.6 mcg/dl→10 mcg/dl). CAT scan of the abdomen with adrenal protocol was unremarkable for adrenal masses, hemorrhage, infiltration, or metastasis. Surprisingly, 21-hydroxylase antibody testing was positive confirming autoimmune AD. The patient has been on hydrocortisone 15 mg in AM + 5 mg in PM and fludrocortisone 0.1 mg daily for one year now with improvement in symptoms. Discussion Medications, poor diet, and diabetes are common causes of hyponatremia in the elderly. AD, an uncommon cause of hyponatremia, should be considered in a hospitalized hyponatremic elderly patient. Non-specificity of AD symptoms makes the diagnosis in this age group difficult, often causing delay in appropriate management. Autoimmune AD is characterized by the presence of 21-hydroxylase antibodies. Data on autoimmune AD incidence in the elderly is limited due to rarity. Our patient's autoimmune AD was likely masked due to steroid use for asthma. During COVID-19 pandemic, masking, and social distancing decreased the patient's steroid needs and unmasked AD after the UTI. Our case highlights the importance of considering autoimmune AD as a cause of AI even in the elderly. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.