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The Addison Disease, or primary adrenal insufficiency, is an insidious disease and rare, which may present high morbimortality levels when the diagnosis is unknown and the treatment doesn’t start at the right time. There is multiple symptoms, highlighting arterial hypotension, skin hyperpigmentation, hyponatremia and hyperkalemia. When left untreated, it can evolve with adrenal crisis and cardiovascular collapse. The Addison Disease diagnosis is clinical and through the laboratorial discoveries, as high adrenocorticotropic hormone (ACTH) levels and low cortisol plasmatic concentrations. The treatment depends on the cause and requires multidisciplinary approach, but overall can be done with glucocorticoids replacement and, occasionally, other hormones. This article describes an Addison Disease case diagnosed in Primary Health Assistance, an uncommon situation, due to the beginning nonspecific disease symptoms, which is not considered. Key-words: Addison Disease; Primary Adrenal Insufficiency; Case Report; Primary Health Assistance. Resumen La enfermedad de Addison, o insuficiencia suprarrenal primaria, es una enfermedad insidiosa y rara que puede presentar altas tasas de morbi-mortalidad cuando su diagnóstico no es reconocido y su tratamiento no se inicia prematuramente. Presenta síntomas variados, entre ellos se destaca hipotensión arterial, hiperpigmentación cutánea, hiponatremia e hiperpotasemia. Cuando no se trata, puede evolucionar una crisis adrenal y colapso cardiovascular. El diagnóstico de la enfermedad de Addison se hace clínicamente y a través de los hallazgos, en exámenes de laboratorio, de concentraciones elevadas de la hormona adrenocorticotrófica (ACTH) y de bajas concentraciones de cortisol en el plasma. El tratamiento depende de la causa y requiere un enfoque multidisciplinario, pero en general se hace con reemplazo de glucocorticoides y, en ocasiones, otras hormonas. Este artículo describe un caso de Enfermedad de Addison diagnosticada en la Atención Primaria de Salud, situación que no es común, ya que la enfermedad presenta síntomas clínicos bastante inespecíficos, principalmente en sus etapas iniciales, y a menudo no es un diagnóstico considerado. Palabras Clave: Enfermedad de Addison; Insuficiencia Adrenal Primaria; Relato de Caso; Atención Primaria de Salud A doença de Addison, ou insuficiência adrenal primária, é uma doença insidiosa e rara, que pode apresentar altas taxas de morbi-mortalidade quando o seu diagnóstico não é reconhecido e o seu tratamento não é iniciado precocemente. Apresenta sintomas variados, entre eles destacando-se hipotensão arterial, hiperpigmentação cutânea, hiponatremia e hipercalemia. Quando não tratada, pode evoluir com crise adrenal e colapso cardiovascular. O diagnóstico da doença de Addison é feito clinicamente e através dos achados, em exames laboratoriais, de concentrações elevadas do hormônio adrenocorticotrófico (ACTH) e de baixas concentrações de cortisol no plasma. O tratamento depende da causa e requer abordagem multidisciplinar, mas em geral se faz com reposição de glicocorticoides e, ocasionalmente, demais hormônios. Este artigo descreve um caso de Doença de Addison diagnosticada na Atenção Primária à saúde, situação esta que não é comum, já que a doença apresenta sintomas clínicos bastante inespecíficos, principalmente em seus estágios iniciais, e frequentemente não é um diagnóstico considerado. Palavras Chave: Doença de Addison; Insuficiência Adrenal Primária; Relato de caso; Atenção primária à saúde. &nbsp

We report here a woman in her 70s presenting with adrenal insufficiency secondary to a primary adrenal lymphoma. The patient had a previous history of aphthous ulcers on dexamethasone and was referred to endocrinology with symptoms of fatigue and orthostasis. Subsequent Cosyntropin stimulation showed primary adrenal insufficiency and adrenal CT demonstrated large infiltrative masses. Adrenal biopsy confirmed the diagnosis of primary adrenal lymphoma of the B-cell type. This case demonstrates the importance of including lymphoma in the differential diagnosis of adrenal insufficiency, particularly in the elderly population and in the setting of negative 21-hydroxlyase antibody results.

Just Anorexia?

Background Primary adrenal insufficiency in children has non-specific and extensive clinical features, so the diagnosis of its etiology is complex and challenging. Although congenital adrenal hyperplasia is the most common cause, more and more other genetic causes have been identified. GNAS mutation is easily overlooked as a rare cause of primary adrenal insufficiency. Here we firstly report a neonatal case of primary adrenal insufficiency caused by GNAS mutation. Case presentation A boy was diagnosed with congenital hypothyroidism 10 days post-partum and treated immediately. He also had persistent hyperkalaemia and hyponatraemia with elevated adrenocorticotropic hormone. At 70 days after birth, he was transferred to our hospital on suspicion of congenital adrenal hyperplasia. Physical examination found no other abnormalities except for growth retardation. Laboratory examination revealed increased aldosterone and normal cortisol, 17-hydroxyprogesterone, and androstenedione levels. Abnormally elevated parathyroid hormone was accompanied by normal blood calcium. Genetic assessment found a de novo, heterozygous c.432 + 1G > A variant in GNAS. Conclusions We report this case to highlight that GNAS mutation is an unusual cause of primary adrenal insufficiency. The combination of primary hypothyroidism and /or pseudohypoparathyroidism will provide diagnostic clues to this condition.

Objective. The study was aimed to assess the effect of hydrocortisone (HC) replacement therapy on bone mineral density (BMD) and bone turnover markers in patients with primary adrenal insufficiency (PAI). Methods. A cross-sectional study was conducted in 37 PAI patients treated with HC. BMD and selected bone turnover markers (β-crosslaps and osteocalcin) were measured. A stepwise binary logistic regression model was applied to determine the independent variables associated with low BMD. Results. Osteoporosis was noted in 14.3% and osteopenia in 34.3% of cases. These patients were older (p=0.01) and received higher daily HC dose compared to patients with normal BMD (p=0.01). BMD values in the lumbar spine and the femoral neck were negatively correlated with daily HC dose (r=–0.36, p=0.03 and r=–0.34, p=0.05, respectively). Plasma osteocalcin was negatively correlated with disease duration (r=–0.38, p=0.02) and cumulative HC dose (r=–0.43, p Conclusions. Impaired bone mineralization in patients with PAI is correlated with HC dose. A daily HC dose ≥12 mg/m2/day was associated with an increased risk of osteopenia and osteoporosis in these patients.

IntroductionHypoaldosteronism can be congenital or acquired, isolated or part of primary adrenal insufficiency, and caused by an aldosterone deficit, resistance, or a combination of both. Reduced mineralocorticoid action can induce a decrease in urine K+ and H+ excretion and an increase in urine Na+ excretion, leading to hyperkalemia, and/or hyponatremia, often combined with metabolic acidosis. We aimed to characterize the clinical manifestations of hypoaldosteronism, and their associated factors.MethodsRetrospective analysis of 112 episodes of hypoaldosteronism diagnosed in 86 adult patients from 2012-2019 by the Endocrinology and Nutrition Department of a tertiary hospital. The frequency of hyperkalemia, hypovolemic hyponatremia (HH) and metabolic acidosis (MA), and their associated factors were evaluated.ResultsPatients had a median age of 77 [65 – 84], 55.4% were male. 94.6% cases showed hyperkalemia, 54.5% HH, and 60.3% MA. The mean serum K+ of all cases was 5.4 ± 0.5 mmol/L, Na+: 132.1 ± 6.3 mmol/L, HCO3: 22.6 ± 3.3 mmol/L. Hypoaldosteronism was isolated in the majority of cases: only 6/112 (5%) had primary adrenal insufficiency. Hypovolemia was associated with hyponatremia and a more florid clinical presentation. HH was associated with a combined presence of aldosterone-lowering and mineralocorticoid resistance factors. MA was associated with the presence of mineralocorticoid resistance factors.ConclusionsHypoaldosteronism in adult endocrinological clinical practice is primarily isolated, and acquired. It predisposes not only to the development of hyperkalemia and MA, but also to that of HH. Hypoaldosteronism must be considered in the differential diagnosis of HH with urinary sodium wasting.

Adrenoleukodystrophy (ALD) is an X-linked, metabolic disorder caused by deficiency of peroxisomal ALD protein resulting in accumulation of very-long chain fatty acids (VLCFA), primarily in the adrenal cortex and central nervous system. Approximately 35-40% of boys with ALD develop cerebral ALD (CALD), which causes rapidly progressive cerebral demyelination, loss of neurologic function, and death. Approximately 70-80% of boys with ALD have impaired adrenal function prior to the onset of neurologic symptoms. We present a boy who had recurrent episodes of hypoglycaemia from age two years and was diagnosed with adrenal insufficiency without adrenal antibodies at age 5.5 years. Following initial normal VLCFA levels, subsequent VLCFA analysis demonstrated elevated C26 fatty acids consistent with peroxisomal dysfunction and suggestive of ALD, which was confirmed via molecular genetic analysis of the ABCD1 gene. Brain imaging at age 7 suggested cerebral involvement and the child underwent successful allogeneic hematopoietic stem cell transplantation. At last assessment (11.5 years old), he was performing as expected for age. This case highlights the importance of pursuing a diagnosis when clinical suspicion remains, and the significance of VLCFA analysis for patients with adrenal insufficiency without adrenal antibodies in securing an ALD diagnosis. Subsequent brain imaging surveillance can detect early, pre-symptomatic cerebral disease, allowing for timely treatment and successful arrest of cerebral disease progression.

Background Primary adrenal insufficiency (PAI) is life-threatening, and a definitive aetiological diagnosis is essential for management and prognostication. We conducted this study to investigate the genetic aetiologies of PAI in South China and explore their clinical features. Methods Seventy children were enrolled in this cross-sectional study. Clinical information was collected, and combined genetic tests were performed according to the children’s manifestations. Statistical analysis was performed among the different groups. In silico or in vitro experiments were applied to determine the pathogenicity of novel variants. Results Among the 70 children, 84.3% (59/70) were diagnosed with congenital adrenal hyperplasia (CAH), and 21-hydroxylase deficiency (21-OHD) was genetically confirmed in 91.5% of these cases. Salt wasting (SW), simple virilization (SV), and non-classic (NC) CAH accounted for 66.1% (39/59), 30.5% (18/59), and 3.4% (2/59) of the cases, respectively. The 17-hydroxyprogesterone (17-OHP) and testosterone (TES) levels were significantly higher in children with SW than with SV. The 17-OHP and cortisol levels in female SW patients were significantly higher than those in males. The 17-OHP, cortisol, dehydroepiandrosterone (DHEAS) and TES levels in female SW patients were significantly higher than those in female SV patients. Additionally, 72.7% (8/11) of uncharacterized PAI patients had positive genetic findings. Among all the patients, two novel variants in the CYP21A2 gene (c.833dupT and c.651 + 2T > G) were found. A microdeletion (Xp21.2–21.3) and five novel variants, including 2 in the NR0B1 gene (c.323–324CG > GA and c.1231_1234delCTCA), 2 in the AAAS gene (c.399 + 1G > A and c.250delT) and 1 in the NNT gene (c.2274delT), were detected. The novel variant c.399 + 1G > A in the AAAS gene was further confirmed to lead to exon 4 skipping during mRNA transcription and produce a truncated ALADIN protein. Conclusions We found ethnicity-based differences in the CYP21A2 gene variant spectrum among different study populations. Female 21-OHD patients tended to have higher 17-OHP and TES levels, which warrants caution in relation to the effects of virilization. Novel gene variants detected in the CYP21A2, NR0B1, AAAS and NNT genes expanded the genetic spectrum of PAI, however, further improvement of genetic testing tools beyond our protocol are still needed to uncover the complete aetiology of PAI in children.

Adrenal crisis is a life-threatening manifestation of acute adrenal insufficiency. One of the most important underlying causes is Addison disease (primary adrenal insufficiency).A 42-year-old White woman with a medical history of Addison disease on chronic steroid therapy was admitted to the emergency department due to sustained episodes of cardiopulmonary arrest. Upon admission, she was hypotensive and hypoglycemic. Despite resuscitation attempts, she developed multiorgan failure and eventually died. At autopsy, no definitive adrenal gland tissue was grossly identified, but histology detected atrophy of adrenal glands with patchy chronic inflammation. Evidence of acute pneumonia was seen. The cause of death was determined to be complications of adrenal/Addisonian crisis.A review of the literature showed only a few autopsy studies regarding deaths due to adrenal crisis. Forensic pathologists should include adrenal crisis in their differential diagnosis. Adequate medical history and pertinent autopsy findings can corroborate deaths due to adrenal crisis, but exhaustive biochemical analyses are mandatory to support the diagnosis further.

Context Primary ovarian insufficiency (POI) is defined by menopause before 40 years of age. POI prevalence is higher among women with autoimmune Addison’s disease (AAD) than in the general population, but their clinical characteristics are insufficiently studied. Objective To assess the prevalence of POI in a large cohort of women with AAD and describe clinical, immunological, and genetic characteristics. Methods An observational population-based cohort study of the Norwegian National Addison Registry. The Norwegian Prescription Database was used to assess prescription of menopausal hormone replacement therapy (HRT). A total of 461 women with AAD were studied. The primary outcome measure was prevalence of POI. Secondary outcomes were clinical characteristics, autoantibodies, and genome-wide single nucleotide polymorphism variation. Results The prevalence of POI was 10.2% (47/461) and one-third developed POI before 30 years of age. POI preceded or coincided with AAD diagnosis in more than half of the women. The prevalence of concomitant autoimmune diseases was 72%, and AAD women with POI had more autoantibodies than AAD women without (≥2 autoantibodies in 78% vs 25%). Autoantibodies against side-chain cleavage enzyme (SCC) had the highest accuracy with a negative predictive value for POI of 96%. HRT use was high compared to the age adjusted normal population (11.3 % vs 0.7%). Conclusion One in 10 women with AAD have POI. Autoantibodies against SCC are the most specific marker for autoimmune POI. We recommend testing women with AAD

Objective While vitamin D regulates immune cells, little is known about it in autoimmune Addison’s disease (AAD). We investigated the vitamin D status in AAD patients from five European populations to assess its deficiency. In addition, we studied two case-control cohorts for vitamin D metabolism and pathway genes. Design Cross-sectional study. Methods A total of 1028 patients with AAD from Germany (n = 239), Italy (n = 328), Norway (n = 378), UK (n = 44) and Poland (n = 39) and 679 controls from Germany (n = 301) and Norway (n = 378) were studied for 25(OH)D3 (primary objective). Secondary objectives (1,25(OH)2D3 and pathway genes) were examined in case-controls from Germany and Norway correlating 25(OH)D3 and single nucleotide polymorphisms within genes encoding the vitamin D receptor (VDR), 1-α-hydroxylase (CYP27B1), 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1) and vitamin D binding protein (GC/DBP). Results Vitamin D deficiency (25(OH)D3 10–20 ng/mL) was highly prevalent in AAD patients (34–57%), 5–22% were severely deficient (30 ng/mL). Lower 25(OH)D3 and 1,25(OH)2D3 levels were observed both in Norwegian and German AAD (P = 0.03/0.003 and P = 1 × 10-5/< 1 × 10-7, respectively) the former was associated with CYP2R1 (rs1553006) genotype G. Whereas controls achieved sufficient median 25(OH)D3 in summers (21.4 to 21.9 ng/mL), AAD patients remained largely deficient (18.0 to 21.2 ng/mL) and synthesize less 1,25(OH)2D3. Conclusion Vitamin D deficiency and insufficiency are highly prevalent in AAD patients. The vitamin D status of AAD may be influenced by genetic factors and suggests individual vitamin D requirements throughout the year.

Background: Craniopharyngiomas are benign tumors of embryologic origin located in the sellar region. Patients have both neurological and endocrinological symptoms. Symptoms may be subtle in the early clinical course, which leads to delayed diagnosis. This study evaluated the clinical and endocrinological manifestations of childhood-onset craniopharyngioma. Methods: We retrospectively reviewed medical records of 45 children diagnosed as having craniopharyngioma between 1995 and 2019. We collected data on clinical symptoms and signs, height, weight, biochemical and hormone data, images, operation records, and pathology reports. A three-graded classification system was applied to define the degree of hypothalamic damage (HD). We analyzed clinical and endocrinological manifestations among patients with and without obesity, with short and normal stature, and with differing degrees of HD. Results: Clinical endocrinologic manifestations included adrenocortical insufficiency (42%), central hypothyroidism (37%), short stature (31%), obesity (20%), weight

Objective: Primary adrenal insufficiency (PAI) is a rare but potentially life-threatening condition. In childhood, PAI is usually caused by monogenic diseases. Although congenital adrenal hyperplasia (CAH) is the most common cause of childhood PAI, numerous non-CAH genetic causes have also been identified. Methods: Patients aged 0-18 years and diagnosed with PAI between 1998 and 2019 in a tertiary care hospital were retrospectively evaluated. After the etiologic distribution was determined, non-CAH PAI patients were evaluated in detail. Results: Seventy-three PAI patients were identified. The most common etiology was CAH (69.9%, n=51). Non-CAH etiologies accounted for 30.1% (n=22) and included adrenoleukodystrophy (ALD; n=8), familial glucocorticoid deficiency (n=3), Triple A syndrome (n=5), autoimmune adrenalitis (n=1), adrenal hypoplasia congenital (n=1), IMAGe syndrome (n=1), and other unknown etiologies (n=3). The median age at the time of AI diagnosis for non-CAH etiologies was 3.52 (0.03-15.17) years. The most frequent symptoms/clinical findings at onset were hyperpigmentation of skin (81.8%), symptoms of hypoglycemia (40.9%), and weakness/fatigue (31.8%). Hypoglycemia (50.0%), hyponatremia (36.4%) and hyperkalemia (22.7%) were prominent biochemical findings. Diagnosis of specific etiologies were proven genetically in 13 of 22 patients. A novel p.Q301* hemizygous frameshift mutation of the DAX1 gene was identified in one patient. Conclusion: Etiology was determined in 86.3% of children with non-CAH PAI through specific clinical and laboratory findings with/without molecular analysis of candidate genes. ALD was the most common etiology. Currently, advanced molecular analysis can be utilized to establish a specific genetic diagnosis for PAI in patients who have no specific diagnostic features.

Over the last 10 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.

Background The most common cause of primary adrenal failure (Addison’s disease) in the Western world is autoimmunity characterized by autoantibodies against the steroidogenic enzyme 21-hydroxylase (CYP21A2, 21OH). Detection of 21OH-autoantibodies is currently used for aetiological diagnosis, but how levels of 21OH-autoantibodies vary over time is not known. Setting Samples from the national Norwegian Addison’s Registry and Biobank established in 1996 (n = 711). Multi-parameter modelling of the course of 21OH-autoantibody indices over time. Results 21OH-autoantibody positivity is remarkably stable, and >90% of the patients are still positive 30 years after diagnosis. Even though the antibody levels decline with disease duration, it is only rarely that this downturn reaches negativity. 21OH-autoantibody indices are affected by age at diagnosis, sex, type of Addison’s disease (isolated vs autoimmune polyendocrine syndrome type I or II) and HLA genotype. Conclusion 21OH-autoantibodies are reliable and robust markers for autoimmune Addison’s disease, linked to HLA risk genotype. However, a negative test in patients with long disease duration does not exclude autoimmune aetiology.

In 1877 Harriet Staunton died in Penge, Kent, and four members of her family were convicted of her murder by malicious starvation. The defence attempted to show that she had died from tuberculous meningitis, but reappraisal of the evidence leads to the conclusion that she died from tuberculous Addison’s disease and that the defendants were wrongly convicted.

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.

Objective Replacement therapy in primary adrenal insufficiency (PAI) with corticosteroids modulates sodium homeostasis. Serum sodium is, however, prone to osmotic shifts induced by several additional factors besides corticosteroids and does not always reliably reflect treatment quality. Non-osmotic tissue storage can be visualized by sodium MRI (23Na-MRI) and might better reflect corticosteroid activity. Design Longitudinal study of 8 patients with newly diagnosed PAI and cross-sectional study in 22 patients with chronic PAI is reported here. Comparison was made with matched healthy controls. Methods Using a 23Na-MRI protocol on a 3T scanner, relative sodium signal intensities (rSSI) to signal intensities of the reference vial with 100 mmol/L of sodium were determined in the muscle and skin of the lower calf. Results In newly diagnosed patients, tissue rSSI (median, range) were reduced and significantly increased after treatment initiation reaching levels similar to healthy controls (muscle: from 0.15 (0.08, 0.18) to 0.18 (0.14, 0.27), P = 0.02; skin: from 0.12 (0.09, 0.18) to 0.18 (0.14, 0.28), P P Conclusion 23Na-MRI provides an additional insight into sodium homeostasis, and thus the quality of replacement therapy in PAI, as tissue sodium significantly changes once therapy is initiated. The increased tissue sodium in patients with chronic PAI might be an indication of over-replacement.

The aim of the study was to assess the effect of glucocorticoid replacement therapy in patients with Addison´s disease on bone mineral density (BMD), parameters of calcium - phosphate (Ca-P) metabolism as well as on bone turneover markers.The study group consisted of 46 patients with Addison´s disease (12men, 17 pre- and 17 postmenopausal women, the control group consisted of 44 healthy individuals (8 men, 16 prepre- and 16 postmenopausal women). Ca-P metabolism parameters, bone turnover markers and adrenal hormones were examined in all groups. BMD was measured by dual-energy X-ray absorptiometry in the lumbar spine (BMD lumb) and forearm (BMDfore).We did not confirm an increased prevalence of osteoporosis and osteopenia in patients with Addison´s disease. BMD values did not correlate with hydrocortisone (HCT) doses, HCT doses calculated on body weight and body surface area as well as with duration of substitution treatment. Patients with daily HCT dosesgt; 25 mg had significantly lower BMD in lumbar spine compared with patients with daily HCT doses 25 mg. In study group we observed decreased levels of adrenal androgens, in women also estradiol. Decreased level of serum calcium and increased level of osteocalcin, bone alkaline phosphatase, 25- hydroxyvitamin D were present in women with Addison´s disease. RANKL/OPG ratio was higher in patients with Addison´s disease compared with controls.Glucocorticoid replacement therapy is not a significant risk factor for development of osteoporosis in patients with Addison disease, because this therapy only physiologically replaces endogenous cortisol deficiency. An increased RANKL / OPG ratio may indicate a relative lack of OPG. It is possible that female patients, despite adequate substitution, have an increased bone turnover and a relatively higher risk of decrease in BMD. Potential risks are higher doses of glucocorticoid replacement therapy (HCTgt; 25 mg daily) and a typical steroid constellation (decreased adrenocortical androgens DHEA and DHEAS and in women also estradiol).

Review the literature concerning adrenal insufficiency (AI) and adrenal crisis (AC) in adolescents and young adults.Searches of PubMed identifying relevant reports up to March 2022.AI is rare disorder that requires lifelong glucocorticoid replacement therapy and is associated with substantial morbidity and occasional mortality among adolescents and young adults. Aetiologies in this age group are more commonly congenital, with acquired causes, resulting from tumours in the hypothalamic-pituitary area and autoimmune adrenalitis among others, increasing with age. All patients with AI are at risk of AC, which have an estimated incidence of 6 to 8 ACs/100 patient years. Prevention of ACs includes use of educational interventions to achieve competency in dose escalation and parenteral glucocorticoid administration during times of physiological stress, such as an intercurrent infection. While the incidence of AI/AC in young children and adults has been documented, there are few studies focussed on the AC occurrence in adolescents and young adults with AI. This is despite the range of developmental, psychosocial, and structural changes that can interfere with chronic disease management during this important period of growth and development.In this review, we examine the current state of knowledge of AC epidemiology in emerging adults; examine the causes of ACs in this age group; and suggest areas for further investigation that are aimed at reducing the incidence and health impact of ACs in these patients.

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.

OBJECTIVE To determine the clinical presentation of Addison's disease in order to increase the awareness of presentation in Pakistani children. STUDY DESIGN Observational study. PLACE AND DURATION OF STUDY Department of Diabetes and Endocrinology, National Institute of Child Health, Karachi, Pakistan, from 2015 to 2019. METHODOLOGY Sixty-three children of Addison's disease were enrolled in the study, who have visited and facilitated from the services of National Institute of Child Health from urban and rural region of the Sindh province. Diagnosis were made through biochemical analysis and detailed examination of acute and chronic symptoms. Study was initiated after taking the approval from Institutional Review Board. Moreover, written informed consents were also taken from each of the study participant. RESULTS There were 36 boys and 27 girls with a mean age at diagnosis of 3.92 and 4.96 years, respectively. Twelve patients were presented with an adrenal crisis following an acute illness. All of them had hyponatraemia; however, 10 had a hyperkalaemia and 8 had been reported with hypoglycaemia. Increased skin pigmentation was observed in 45 children with other identifiable features including weight loss, lethargy, and poor response in activities. Moreover 15 of them were identified with associated disorder (autoimmune polyendocrinopattay syndrome (APS), Allgrove or triple A syndrome, and adrenoleukodystrophy). Conclusion: Typical and atypical presentations of Addison's disease in children of Pakistani population are defined in this study which may assist in better management of Addison's patients. Key Words: Adrenal crisis, Hyponatremia, Hyperkalemia, APS, Allgrove, Adrenoleukodystrophy.

Background Perioperative glucocorticoid supplementation has been suggested as a potentially effective precaution against perioperative adrenal crisis in patients on long-term glucocorticoid medication. Methods This retrospective cohort study used a national inpatient database in Japan. We included patients who underwent general surgery and those who received long-term glucocorticoid medication before surgery. A one-to-one propensity score-matched analysis was performed to compare patients who received 100 mg hydrocortisone during surgery with those who received no supplementation. The primary outcome was use of vasopressor agents on the day of surgery. The secondary outcomes included bleeding, perioperative infection, wound dehiscence, postoperative length of stay, and in-hospital mortality. Results Among the 807 propensity score-matched pairs, there was no significant difference in use of vasopressor agents between patients with and without glucocorticoid supplementation (24.5% vs. 21.9%; P = 0.22) and no significant differences in any secondary outcomes. Conclusions Perioperative glucocorticoid supplementation was not associated with decreased morbidity or mortality.

Purpose Polyglandular autoimmune syndromes (PAS) are complex, heterogeneous disorders in which various autoimmune diseases can occur, affecting both endocrine and non-endocrine organs. In this meta-analysis, the prevalence of associated autoimmune disorders was investigated in PAS II and III. Methods A comprehensive search in MEDLINE and Embase databases identified 479 studies with the keywords of PAS II and PAS III. 18 records containing a total of 1312 patients fulfilled our inclusion criteria (original studies reporting at least 10 cases and containing the combination of other autoimmune disorders) and were selected for further analysis. A meta-analysis of prevalence was performed using the random-effects model with the calculation of 95% confidence intervals (CI). Results of each meta-analysis were displayed graphically using forest plots. Results Distinction between PAS II and PAS III was made in 842 cases, of which 177 and 665 were PAS II and III (21.1 vs 78.9%), respectively. The prevalence of Hashimoto’s thyroiditis was significantly higher than that of Graves’s disease (39% [95% CI 17–65%] vs. 4% [95% CI 0–10%], respectively; p = 0.001). In PAS II, Addison’s disease (AD) coexisted with AITDs, T1DM or the combination of these conditions in 65, 18 and 10% of cases, respectively. In addition, one other endocrine and five non-endocrine organ-specific autoimmune disorders were reported. In PAS III, two other autoimmune endocrinopathies, six non-endocrine organ-specific, and four systemic autoimmune disorders were found in combination with AITDs. Conclusions AITDs, T1DM and AD are the most common combinations in PAS, thus screening for these conditions seems to be reasonable.

Concurrent type 1 diabetes (T1D) and Addison’s disease (AD) is a rare combination of diseases and, in approximately one third of these patients, it is also combined with an autoimmune thyroid disease. Recently, it was shown that patients with both T1D and AD have a higher risk of premature death compared to patients with T1D alone, the most common causes of death being due to diabetic complications and cardiovascular disease. These patients receiving replacement therapies with both insulin and glucocorticoids face an increased risk of hypo- and hyperglycemia and diabetic ketoacidosis and have a higher risk of adrenal crisis than patients with AD alone. Treatment challenges include the opposing effects of insulin and glucocorticoids on glucose homeostasis and the need to balance and synchronize these two treatments. The rarity of this disease combination may explain the paucity of data on outcome and specific treatment strategies in this patient group. Based on this review, we suggest management strategies for their insulin and glucocorticoid replacement therapies and indicate future areas of research.

Objective Autoimmune conditions tend to cluster in subjects with Addison’s disease (AD) and probably also among their relatives. The aim of the study was to estimate the frequency of the endocrine gland-specific autoantibodies in first-degree relatives of patients with AD. Methods Autoantibodies were investigated in 113 family members using RIA and ELISA assays. The control group comprised 143 age-matched volunteers. Results Autoimmune diseases were diagnosed in 38.1% relatives. Hashimoto’s thyroiditis was found in 20.3%, Graves’ disease in 8.0%, vitiligo and type 1 diabetes in 3.5%, whereas AD, rheumatoid arthritis and atrophic gastritis with pernicious anaemia in 2.7% each. All studied antibodies except for islet antigen-2 (P = 0.085) were significantly more frequent in AD relatives than in controls (P P = 0.014; OR: 3.16; 95% CI: 1.23–8.12). Circulating autoantibodies were found more frequently in the relatives of affected males (P = 0.008; OR: 3.31; 95% CI: 1.33–8.23), and in family members of patients with polyendocrine autoimmunity (P = 0.009; OR: 3.55; 95% CI: 1.31–9.57). Conclusions This study provides evidence of increased susceptibility for the endocrine autoimmunity, especially thyroid disease, in close relatives of patients with AD. Relatives of the male AD patients and of those with autoimmune polyendocrine syndrome are at particular risk and should undergo periodic screening for autoimmune endocrine disorders.

Autoimmune polyglandular syndromes are combinations of various endocrine and nonendocrine autoimmune diseases, as well as the presence of elevated organ-specific antibody titers. We present a clinical case of a 41-year-old pregnant patient with type 2 autoimmune polyglandular syndrome, combining Addison’s disease, Hashimoto’s thyroiditis and hypogonadism. The pregnancy was achieved after the use of assisted reproductive technology. During the pregnancy the patient was strictly monitored. Glucocorticoid and mineralocor­ticoid replacement therapy was adjusted according to the electrolyte profile and general condition of the patient. Management during pregnancy was difficult due to fluctuations in electrolyte levels, thyroid hormones and orthostatic manifestations. Prior to delivery adrenal crisis occurred, but the condition was successfully managed. No complications were reported for the mother and the newborn.

Background Addison's disease is an uncommon condition encountered during pregnancy; however, pregnant patients with Addison's disease are at higher risk for multiple pregnancy related complications. Treatment during pregnancy involves steroid replacement therapy. Case report A 34-year-old previously healthy G2P1001 presented with lethargy, skin hyperpigmentation, polyuria, and salt craving. Laboratory evaluation showed hyperkalemia, hyponatremia, elevated ACTH, and low cortisol. The patient terminated the pregnancy due to her symptoms. She was then placed on a regimen of hydrocortisone and fludrocortisone, leading to symptom resolution. On second presentation as a G5P1031, her Addison's disease was managed with hydrocortisone and fludrocortisone. When Addison's symptoms recurred, ACTH levels were checked to determine if her current medications could be optimized. She ultimately delivered a healthy male infant vaginally. For her third presentation as a G6P2032, her pregnancy was managed in a similar manner to the previous pregnancy. Conclusion There is currently minimal cohesive literature on the management of Addison's disease during pregnancy. Patients can be managed successfully by monitoring for recurrence of Addison's symptoms and adjusting medication dosing as needed.

The adrenal gland serve important roles in the modulation of the immune response, the adjustment of blood pressure, the stress reaction via glucocorticoids and the hydroelectrolytic balance via mineralocorticoids. Primary adrenal insufficiency, known as Addison disease, is characterized by a decrease in glucocorticoid secretion (cortisol) and, more rarely, by a hyposecretion of mineralocorticoids (aldosterone). The production of cortisol, which is a hormone that helps the body respond to stress, is regulated in the brain, the hypothalamus and the pituitary gland. The hypothalamus stimulates the pituitary gland to produce adrenocorticotropic hormone, which stimulates cortisol production from the adrenal gland. If left untreated, Addison disease has a high mortality rate. Corticotherapy used in the treatment of Addison disease is associated with a certain cardiovascular risk. The proatherogenic effect of corticoids is based on the chronic inflammatory response of the vascular wall to a series of events. The aim of the current case report was to review the pathophysiological mechanisms and interactions that may lead to the onset of acute coronary syndrome with ST elevation in a patient with Addison disease.

Background Despite adequate glucocorticoid (GC) and mineralocorticoid (MC) replacement therapy, patients suffering from primary adrenal insufficiency (AI) have an increased mortality, mainly due to cardiovascular diseases. Only little knowledge exists on the contribution of MC substitution to the cardiovascular risk. Therefore, this study investigates the impact of plasma renin concentration on parameters of micro- and macrovascular function. Methods 26 patients with primary AI [female = 18, age: 51 (28; 78) years; BMI: 24 (18; 40) kg/m2; disease duration: 18 (5; 36) years] were included in this cross-sectional analysis. Intima media thickness (IMT) and pulse wave velocity (PWV) were investigated to assess macrovascular remodeling and arterial stiffness. Microvascular function was estimated by post-occlusive reactive hyperemia using laser Doppler fluxmetry. Baseline perfusion, biological zero, peak perfusion, time to peak and recovery time were recorded. Patients were grouped according to their median plasma renin concentration of previous visits (Reninhigh vs Reninlow) and were compared to a group of healthy women [age: 44 (43; 46) years; BMI: 24.2 (21.8; 27.5)]. Results PWV was significantly higher in AI patients compared to controls [9.9 (5; 18.5) vs 7.3 (6.8; 7.7) m/s; p low time to peak perfusion was significantly longer [6.0 (3; 15) vs 3.5 (1.5; 11) s; p high and Reninlow. No impact of GC dose was observed. Conclusions Microvascular function is not impaired in patients with primary AI under adequate replacement therapy, although higher renin concentrations are associated with subclinical improvements. No relation between RAAS activity and macrovascular function is observed, while arterial stiffness might be increased in primary AI.

Primary adrenal insufficiency (Addison’s disease, AD) requires lifelong steroid substitution. Excess exogenous glucocorticoids promote abdominal obesity, insulin-glucose imbalance, and hypertension. Reliable markers of the adequate glucocorticoid replacement are lacking. Visfatin is a pro-inflammatory adipokine, with enzymatic activity of nicotinamide phosphoribosyltransferase. It enhances leukocyte function and synthesis of tumour necrosis factor α (TNFα) and interleukin-6 (IL-6). Serum visfatin is elevated in autoimmunity, but also in obesity, insulin resistance, and metabolic syndrome. This study was aimed to investigate whether serum visfatin could guide the glucocorticoid substitution in AD. Biochemical analyses were performed in 96 patients with AD (mean age 43.3±14.9 years) and 91 controls (43.5±12.5 years). Visfatin level was significantly elevated in patients with AD compared to controls (p

A 13-year old miniature poodle presented with a 3-day episode of vomiting, anorexia, and lethargy. Lack of micturition had been noted for 2 days. Clinical examination indicated dehydration and a tense, painful abdomen. Laboratory parameters (severe azotaemia, hyperkalaemia, severe hyponatraemia, hypochloraemia, and hyperphosphataemia with glucosuria and proteinuria) were consistent with anuric acute kidney injury (AKI). Abdominal ultrasound revealed bilateral adrenal masses. ACTH stimulation test was diagnostic for Addison's disease. Computed tomography confirmed bilateral adrenal masses and indicated multifocal liver nodules. Additionally, infiltration of the caudal vena cava with partial luminal occlusion was demonstrated. Surgical removal of the adrenal masses with venous plasty intervention and stenting of the vessels deemed unrewarding in this patient in respect to progressed tumour growth with assumed metastatic spread. The dog was treated for Addison's disease and discharged with good overall condition. Eight weeks later, the dog was euthanized due to progressive caudal vena cava occlusion. Whilst hypoadrenocoticism typically affects young to middle aged dogs, in old dogs primary Addison's disease might be caused by neoplastic bilateral adrenal gland destruction. This is the first case report of hypovolaemia leading to AKI secondary to bilateral adrenal masses causing Addison's disease in a dog.Ein 13-jähriger Zwergpudel wurde aufgrund einer 3-tägigen Episode mit Erbrechen, Anorexie und Lethargie vorgestellt. Der letzte Urinabsatz war 2 Tage vor Vorstellung beobachtet worden. In der klinischen Untersuchung fielen eine Dehydratation und ein angespanntes, schmerzhaftes Abdomen auf. Anamnese, Harnblasengröße und Laborparameter (schwere Azotämie sowie Hyperkaliämie, Hyponatriämie, Hypochloridämie, Hyperphosphatämie, Glukosurie und Proteinurie) sprachen für eine akute anurische Nierenschädigung. Sonografisch ließen sich bilateral Nebennierenmassen darstellen. Mittels ACTH-Stimulationstest wurde ein Hypoadrenokortizismus nachgewiesen. Nach der Stabilisierung des Patienten erfolgte eine computertomografische Untersuchung des Abdomens, die bilaterale Nebennierenmassen mit Invasion in die Vena cava caudalis und Nierenarterien bestätigte und zudem multifokale Herde in der Leber zeigte. Die Invasion hatte bereits zu einer partiellen Verlegung des Lumens der genannten Gefäße geführt. In Anbetracht der Tumorausbreitung und der anzunehmenden Metastasierung erschien eine chirurgische Intervention als nicht erfolgversprechend. Der Patient wurde mit medikamentöser Therapie des Hypoadrenokortizismus bei gutem Allgemeinbefinden entlassen. Aufgrund eines progressiven tumorbedingten Verschlusses der Vena cava caudalis wurde der Patient 8 Wochen später euthanasiert. Wenngleich ein Hypoadrenokortizismus vornehmlich bei jüngeren und mittelalten Hunden auftritt, kann diese Erkrankung bei älteren Hunden die Folge eines bilateralen Nebennierentumors mit Zerstörung beider Nebennierenrinden sein. Dies ist der erste Fallbericht eines bilateralen Nebennierentumors, in dessen Folge eine Morbus-Addison-bedingte Hypovolämie zu einer akuten Nierenschädigung führte.

A Boy with Vomiting and Weight Loss An 11-year-old boy was evaluated at the hospital because of ongoing vomiting and weight loss. Endoscopic evaluation revealed erythema of the gastric antrum and m...

Oral (OP) and nail (NP) pigmentations may occur simultaneously in physiological or pathological conditions, and may be a sign of underlying syndromic conditions that necessitate further investigation and treatment. Interestingly, the nail unit and oral cavity show a clinical parallelism that may help the clinician to conduct a correct examination and reach a prompt diagnosis. Both OP and NP can manifest clinically with focal or diffuse involvement and are due to external factors (exogenous pigmentation, drug-induced pigmentation) or endogenous factors (racial pigmentation, post-inflammatory pigmentation, nevi, genetic conditions and other disorders). The most concerning differential diagnosis is melanoma. Here we report the pathogenetic basis of OP and NP, together with the description of similar clinical features. To the best of our knowledge this is the first paper to summarize and describe the causes of pigmentation of both the oral cavity and the nail unit.

SUMMARY Autoimmune polyglandular syndrome type 2 (APS 2) is defined by the presence of Addison’s disease (AD) associated with autoimmune thyroid disease and/or Type 1 diabetes mellitus (T1DM). It is a rare disease, affecting about 1.4-2 cases/100,000 inhabitants. Its less frequent clinical presentation is the combination of AD, Graves‘ disease, and T1DM. We present the case of a 42-year-old woman with a history of total thyroidectomy due to Graves’ disease, type 2 diabetes mellitus, and hypertension, who sought the ED due to asthenia, dizziness, nausea, and vomiting. She reported having stopped antihypertensive therapy due to hypotension and presented a glycemic record with frequent hypoglycemia. On physical examination, she had cutaneous hyperpigmentation. She had no leukocytosis, anemia, hypoglycemia, hyponatremia or hyperkalemia, and a negative PCR. Serum cortisol

Adrenoleukodystrophy (ALD) is an X-linked disorder caused by a hemizygous mutation of the ABCD1 gene. Patients with ALD show progressive central nervous system demyelination and primary adrenal insufficiency. In Japan, most reported ALD cases were childhood-onset, and only one case of an adult patient with Addison's disease form of ALD has ever been reported. Herein, we present a case of a 29-year-old man with Addison's disease form of ALD. The patient had anorexia, weight loss, and skin pigmentation from 18 years of age. At first visit, his weight had decreased by 12 kg from 57 kg when he was 15 years old. Endocrinological examination showed low serum cortisol (1.2 μg/dL) with high plasma ACTH (4,750 pg/mL), and abdominal computed tomography showed normal adrenal glands. Very-long-chain fatty acid (VLCFA) levels were elevated, and the ABCD1 mutation, p.Gly116Arg, was identified in hemizygous state. He had no significant neurological findings on physical examination and no white matter lesions on brain magnetic resonance imaging (MRI). He was diagnosed with ALD presenting as Addison's disease, and glucocorticoid replacement therapy was initiated. Four years after the diagnosis, he still did not show any neurological findings and any white matter lesions on brain MRI. Evaluating VLCFA levels for ALD diagnosis is important in young adult men with idiopathic primary adrenal insufficiency as well as in children. Early diagnosis enables more rational approaches including the early detection of neurological complications and might improve the prognosis of patients.

Nicotinamide nucleotide transhydrogenase (NNT) deficiency causes primary adrenal insufficiency (PAI) and possibly some extra-adrenal manifestations. A limited number of these patients were previously described. We present the clinical and genetic characteristics of three family members with a biallelic novel pathogenic variant in the