Adrenal Failure Research Articles

COVID-19 infection: from stress-related cortisol levels to adrenal glands infarction.

Cortisol is a key element in acute stress including a severe infection. However, in coronavirus-associated disease, 20% of subjects experience hypocortisolemia due to direct or immune damage of pituitary and adrenal glands. One extreme form of adrenal insufficiency is found in 2∕3 of cases with viral and post-viral adrenal infarction (AI) (with∕without adrenal hemorrhage) that is mostly associated with a severe coronavirus disease 2019 (COVID-19) infection; it requires prompt glucocorticoid intervention. Some reports are incidental findings at computed tomography (CT)∕magnetic resonance imaging (MRI) scans for non-adrenal complications like pulmonary spreading and others are seen on post-mortem analysis. This is a review of PubMed-accessible, English papers focusing on AI in addition to the infection, between March 1, 2020 and November 1, 2021. Exclusion criteria were acute adrenal insufficiency without the histopathological (HP) and∕or imaging report of adrenal enlargement, necrosis, etc., respective adrenal failure due to pituitary causes, or non-COVID-19-related adrenal events. We identified a total of 84 patients (different levels of statistical evidence), as follows: a retrospective study on 51 individuals, two post-mortem studies comprising nine, respectively 12 patients, a case series of five subjects, seven single-case reports. HP aspects include necrosis associated with ischemia, cortical lipid degeneration (+/- focal adrenalitis), and infarcts at the level of adrenal cortex, blood clot into vessels, acute fibrinoid necrosis in arterioles and capsules, as well as subendothelial vacuolization. Collateral potential contributors to adrenal damage are thrombotic events, coagulation anomalies, antiphospholipid syndrome, endothelial dysfunction, severe COVID-19 infection with multiorgan failure, etc. Clinical picture is variable from acute primary adrenal insufficiency to asymptomatic or mild evolution, even a retrospective diagnostic; it may be a part of long COVID-19 syndrome; glucocorticoid therapy for non-adrenal considerations might mask cortisol deficient status due to AI∕hemorrhage. Despite its rarity, the COVID-19-associated AI/hemorrhage represents a challenging new chapter, a condition that is essential to be recognized due to its gravity since prompt intervention with glucocorticoid replacement is lifesaving.

The role for long-term use of dehydroepiandrosterone in adrenal insufficiency.

Dehydroepiandrosterone (DHEA) is an androgen produced by the zona reticularis of the adrenal gland. Patients with adrenal insufficiency will have a deficiency of DHEA. Unlike glucocorticoid and mineralocorticoid replacement, DHEA supplementation is not considered essential for life and is therefore not routinely replaced in adrenal failure. DHEA deficiency is associated with morbidity, including adverse impacts on metabolic function, quality of life and sexuality in multiple studies. The role for replacement, however, remains unclear. The benefits of DHEA supplementation have been definitively demonstrated in a number of historical studies of patients with primary and secondary adrenal insufficiency. Beneficial impacts on quality of life, body composition, bone health and metabolic markers have been demonstrated. However, published data are inconsistent; controversies persist around the exact role of DHEA replacement and around which patient cohorts are most likely to benefit. There is also a paucity of recent randomized controlled trials in the medical literature to inform on optimal dose and duration of DHEA replacement in adrenal failure. Here, we review the evidence for DHEA supplementation in patients with adrenal insufficiency. We highlight knowledge gaps in the medical literature and areas that should be prioritized for future research endeavours.

Customized autoantibodies (autoAbs) profiling to predict and monitor immune-related adverse events (irAEs) in patients receiving immune checkpoint inhibitors (ICI).

2528 Background: Using a customized microarray, we previously reported that patients (pts) who develop irAEs grade (G)≥2 and those who do not, have different median fluorescent intensity (MFI) levels of specific autoAbs at baseline (pre-ICI). Leveraging a larger dataset, we evaluated whether overall baseline autoAbs elevation and early increases in autoAbs after ICI can predict irAEs as well as if steroid treatment can reduce autoAbs. Methods: Plasma was obtained from pts receiving ICI in two clinical trials (MET4-IO, NCT03686202 and INSPIRE, NCT02644369) and from healthy controls (hc). Collection time points in MET4-IO and INSPIRE studies included: baseline, 3-4 weeks (w), 6-8 w, 24 w and at the end of treatment and baseline and 6 w respectively. Arrays with 162 autoAg customized for frequent irAEs were incubated with plasma and probed with Abs to detect IgG and IgM reactivity. AutoAbs with MFI >500 per individual were compared between hc and pts with and without irAEs G≥2 by the Student-t test. Results: Samples from 114 pts and 14 hc were analyzed (pts characteristics are summarized in the Table). G≥2 irAEs included: hypothyroidism (13), pneumonitis (10), colitis (7), hepatitis (4), skin toxicity (7), infusion reaction (2), pancreatitis (2), meningitis (1), hypophysitis (1), corneal ulcer (1), high creatinine (1), myocarditis (1), myositis (1), diabetes (1), mucositis (1), myasthenia (1) and adrenal failure (1). Hc had less autoAbs with MFI >500 as compared to pts at baseline (median 32 vs 62 p<0.001). IgG with MFI >500 were higher at baseline in pts who developed G≥2 irAEs vs those without G≥2 irAEs (median 39 vs 33, p=0.03). In 23 pts with plasma collected at the time of irAEs, we observed a significant increase of autoAbs with MFI>500 from baseline (median 84 vs 77 p= 0.009). Paired samples at the time of irAEs and after steroids were available for 9/23 pts, showing lower autoAbs after steroid treatment (54 vs 79 p=0.006). No differences in autoAbs with MFI>500 pre and post ICI were seen in pts without G≥2 irAEs (baseline vs first post ICI collection median 58 vs 60, p=0.13). Conclusions: We observed a higher number of IgG with MFI >500 at baseline and a greater increase after ICI administration in individuals with irAEs compared to those without irAEs. Steroid treatment resulted in a decrease in autoAbs. A prospective study is ongoing to validate the potential role of autoAbs for risk stratification and monitoring of irAEs. [Table: see text]

An altered state of consciousness while using anticoagulants and the incidental discovery of a pituitary lesion: considering pituitary apoplexy.

SummaryPituitary apoplexy (PA) is a medical emergency with complex diagnosis and management. In this study, we describe a case of PA in a 63-year-old male treated with oral anticoagulant therapy for atrial fibrillation. In the patient, PA manifested itself with asthenia and severe headache not responsive to common analgesics. Despite the finding of a pituitary mass through CT, and in anticipation of the endocrinological evaluation and pituitary MRI, the patient’s clinical condition worsened with an escalation of headache and asthenia associated with deterioration of the visual field and impairment of consciousness level. The emergency assessments revealed an adrenal failure, whereas MRI showed a haemorrhagic pituitary macroadenoma with compression of the optic chiasm. Intravenous fluids repletion and high-dose hydrocortisone were started with a rapid improvement of the patient’s health and visual field abnormalities. Hydrocortisone was gradually reduced to a replacement dose. During the follow-up, panhypopituitarism was documented, and replacement therapies with l-thyroxine and testosterone were introduced. Three months later, a pituitary MRI showed a 50% reduction in the pituitary adenoma volume.Learning pointsPituitary apoplexy (PA) is a medical emergency that can result in haemodynamic instability and abnormalities in the level of consciousness.The management of PA requires a multidisciplinary team that includes endocrinologists, ophthalmologists, neuro-radiologists, and neuro-surgeons.Pituitary MRI with gadolinium is the diagnostic gold standard for PA.PA therapy aims to improve general conditions and treat compression symptoms, especially visual field abnormalities.Adrenocorticotrophic hormone deficiency is a common and severe complication of PA. Thus, all patients with PA must be promptly treated with injective synthetic glucocorticoids (e.g. hydrocortisone 100 mg) and i.v. saline.PA must be taken into consideration in case of sudden headache in patients with a pituitary macroadenoma, especially if other risk factors are recognized.

A man with Erb’s disease

A man, currently aged 72, developed a spastic paraparesis without sensory abnormalities progressing to wheel-chair dependence and late urinary incontinence over 14 years. Apart from a history of type 2 diabetes mellitus, he was otherwise well. Extensive blood and CSF investigations including screening for HIV, HTLV1, syphilis, and Lyme disease were normal or negative. There was no evidence of neuropathy or denervation on EMG. MRI showed mild non-specific white matter signal change in both cerebral hemi- spheres. A provisional diagnosis of primary lateral sclerosis (PLS) was revised with the finding of elevated Very Long Chain Fatty Acids (VLCFAs). Genetic testing revealed a novel missense variant c.1771C>Gp. (Arg591Gly) in exon 7 of the ABCD1 gene. Mutation in ABCD1 transporter leads to accumulation of VLCFAs in the peroxisomes and cytosol which is toxic, causing oxidative stress and demyelination in the CNS and PNS. Literature review did not reveal reports of AMN mimicking PLS. Our patient highlights the importance of screening VLCFAs (abnormal in ~99% of men with AMN) in suspected PLS, a diagnosis of exclusion. Diagnosis of ALD/AMN allows genetic counselling, screening for adrenal failure, and access to stem cell therapy for children with asymptomatic cerebral onset ALD.sara.leddy1@nhs.net

IDF21-0185 Prevalence of autoimmune diseases in young patients with type 1 diabetes

Background: Autoimmunity and viral infections are the main etiopathological factors implicated in the pathogenesis of T1DM on the background of genetic predisposition. Type 1 diabetes mellitus (T1DM) is associated with various autoimmune disorders like celiac disease, thyroid disorder, adrenal failure, etc. However, how common is this association in Indian children is not clearly known. Aim: This cross-sectional study was planned to investigate the prevalence of autoimmune disorders like autoimmune thyroid disorders, celiac disease, and other autoimmune disorders in T1DM. Method: In this cross-sectional study, patients requiring insulin and ketosis-prone diabetic and with history of diabetic ketoacidosis/undetectable fasting C-peptide levels were included. Beside demographic and clinical data, detailed biochemistry evaluations were performed. Celiac disease was diagnosed as per the ESPGHAN diagnostic criteria. ACTH stimulation test was done to confirm the adrenal insufficiency in patients with basal serum cortisol <5 μg/dL. Thyroid function test (TSH) and anti-TPO antibody were assessed in all patients. Screening for other autoimmune disorders was done only when clinically indicated or symptoms or family history was suggestive of presence of such disorder. Results: Among 200 patients enrolled, 65% were males and mean age was 12.37 ± 3.34 years. Mean age at diagnosis of T1DM was 10.1 ± 3.58 years and duration of diabetes was 3.52 ± 3.21 years. The prevalence of antibodies positive against autoimmune diseases was anti-tTG IgA (21%), anti-TPO (34%), anti-CCP ab (1.5%), and ANA (0.8%). Significantly higher proportion of females had raised anti-TPO antibodies than males (48.1% vs. 26.4%, P = 0.005). Celiac disease was most common association (25.4%) followed by hypothyroidism (13.8%) and Grave's disease (3.2%). Significantly higher proportion of females had hypothyroidism than males (26.1% vs. 8.6%, respectively, P = 0.006). Prevalence of raised anti-tTG and anti-TPO did not differ significantly by the age (P = 0.841 and P = 0.067) or duration of T1DM (P = 0.493 and P = 0.399). Discussion: In this part of country, celiac disease, hypothyroidism, and Graves's disease are common associations in children with T1DM. This study also emphasizes the importance of total IgA estimation and duodenal biopsy in IgA anti-tTG-negative patients having strong suspicion of celiac disease on the basis of history. This study reinforces a call to improve the quality of healthcare services, including implementation of universal screening for thyroid dysfunction and celiac disease in children with T1DM.

Impact of pre-operative Metyrapone therapy on post-operative Steroid dependence in patients undergoing Adrenalectomy for Cushing’s Syndrome

Abstract Introduction Prolonged elevated cortisol in Cushing’s Syndrome can lead to adrenal insufficiency post-adrenalectomy. Metyrapone is licensed to suppress endogenous cortisol production pre-operatively for symptom relief. The aim of this study was to investigate whether pre-treatment of patients with metyrapone led to reduced adrenal insufficiency, hence reduced steroid dependence post-op. Methods Cases were identified from UKRETS submissions between 2008–2020, with Electronic Patient Records used for data collection. Patients with adrenocortical carcinoma (ACC) and/or lost to follow-up were excluded. The remaining cases were divided into those treated with metyrapone pre-operatively and those not. Results were analysed via IBM SPSS Statistics software. Results Of 59 patients, those lost to follow up (n=6) and those with ACC (n=4) were excluded leaving 49 cases. Metyrapone patients (n=29) had a median of 3 symptoms of cortisol excess (0–9) compared to 2 symptoms (0–5) in non-metyrapone (n=20) (p=0.061). 82.8% (n=24) of metyrapone patients and 65% (n=13) of non-metyrapone patients were successfully weaned off steroids post-op, with the remaining patients still steroid dependent. Cox proportional hazards regression showed metyrapone did not impact steroid dependence (p=0.230). Metyrapone treatment increased the likelihood of adrenal recovery whereas increasing symptom burden reduced the likelihood (hazard ratio 0.271 and -0.143 respectively), however these findings were not significant (p=0.445 and p=0.117 respectively). Conclusion We found metyrapone had no significant impact on rate of adrenal failure. A larger series may more accurately determine whether metyrapone pre-operatively confers a higher likelihood of adrenal recovery and determine whether high symptom burden pre-operatively increases risk of steroid dependence post-operatively.

ADRENOLEUKODYTROPHY IN MOROCCAN CHILD: CASE REPORT

A boy of 10 years was admitted in our hospital for recurrent generalized seizures, spastic tetraparesis.A gradual impairment of vision and abnormal behaviors noticed for last 3 years. His family history find an uncle (motherÂ’s brother) deceaded at the age of 6 years without a stated diagnosis, examination finding revealed generalized hyperpimentation more marked on lips and finger nails.Neurogical examination find spastic tetraparesis, deep tendon reflexes were brisk and pupils were roud and reacting to light.Fundoscopic examination note bilateral primary optic atrophy, his cardiovascular, respiratory and abdominal systems were clinically normal. All routine investigations revealed normal finding exception biochemical features (very high ACTH level, Low basal cortisol), of primary adrenal failure. MRI of the head showed bilateral white matter abnormalities in parieto-occipital regions. The diagnosis of adrenoleukodystrophy was strongly suggested from the medical history, biochemical and radiological findings of brain. The purpose of our report case is to highlight this rare disease to all, because its progress can be delayed with early diagnosis and itÂ’s incidence can be reduced by genetic counseling.

Parturient with Endocrine Disorders in the Intensive Care Unit.

Almost every endocrine axis is influenced by pregnancy. The diagnosis in acute cases is challenging as the classical symptoms are often masked. Thyroid storm is found in only 1–2% of hyperthyroid parturients (0.1–0.4% of all pregnancies). Burch and Wartofsky scoring system is useful for the identification of thyroid storms. Myxedema coma is an extremely rare complication of overt hypothyroidism with a 20% mortality rate. Diabetic ketoacidosis usually reported in the second and third trimesters carries a risk of fetal loss in 10–25% of cases. The size of the tumor rises in 2.7% of microprolactinomas and 22.9% of macroprolactinomas during pregnancy. Adrenal insufficiency in pregnancy is usually caused by primary adrenal failure, which is mostly autoimmune in origin. Pheochromocytoma may present as preeclampsia during pregnancy. Unrecognized pheochromocytoma is associated with a maternal mortality rate of 50%. Shared decision-making and close coordination between critical care, anesthesiology, obstetrics, and endocrinology can help in assuring good maternal and fetal outcomes.How to cite this articleSingh AK, Sarkar S, Khanna P. Parturient with Endocrine Disorders in the Intensive Care Unit. Indian J Crit Care Med 2021;25(Suppl 3):S255–S260.

Current Approach for Diagnosis and Treatment of Adrenal Tuberculosis-Our Experience and Review of Literature.

Addison's disease was first described by Thomas Addison in 1855. He demonstrated the destruction of bilateral adrenal gland by tuberculosis (TB) in six patients. Since then, the incidence of TB has declined in the Western world, but in developing countries, it is still the most common cause of adrenal insufficiency. Because of the introduction of antituberculous chemotherapy, the incidence of adrenal TB has been declined in the past decades. The most common symptoms are nonspecific; therefore, diagnosis is often delayed, and patients may first present with a life-threatening adrenal crisis. The most commonly identified organism for adrenal failure in adrenal TB is Mycobacterium tuberculosis infection. Adrenal TB involves bilateral adrenal glands more frequently than unilateral glands. Computed tomography (CT) scan and magnetic resonance imaging (MRI) are useful investigations to differentiate between tuberculous Addison's disease and the other causes of adrenal insufficiency. In CT scans or MRI, features of adrenal TB are bilateral adrenal enlargement and peripheral rim enhancement with or without calcifications. Antituberculous drugs, biochemical monitoring of adrenal function, and steroid therapy are essential for the management of adrenal TB and adrenal insufficiency. Here, we describe a case of adrenal TB with abscess formation followed by a review of the current literature of adrenal TB for better diagnosis and management of this condition.

Disorders of Sex Development of Adrenal Origin.

Disorders of Sex Development (DSD) are anomalies occurring in the process of fetal sexual differentiation that result in a discordance between the chromosomal sex and the sex of the gonads and/or the internal and/or external genitalia. Congenital disorders affecting adrenal function may be associated with DSD in both 46,XX and 46,XY individuals, but the pathogenic mechanisms differ. While in 46,XX cases, the adrenal steroidogenic disorder is responsible for the genital anomalies, in 46,XY patients DSD results from the associated testicular dysfunction. Primary adrenal insufficiency, characterized by a reduction in cortisol secretion and overproduction of ACTH, is the rule. In addition, patients may exhibit aldosterone deficiency leading to salt-wasting crises that may be life-threatening. The trophic effect of ACTH provokes congenital adrenal hyperplasia (CAH). Adrenal steroidogenic defects leading to 46,XX DSD are 21-hydroxylase deficiency, by far the most prevalent, and 11β-hydroxylase deficiency. Lipoid Congenital Adrenal Hyperplasia due to StAR defects, and cytochrome P450scc and P450c17 deficiencies cause DSD in 46,XY newborns. Mutations in SF1 may also result in combined adrenal and testicular failure leading to DSD in 46,XY individuals. Finally, impaired activities of 3βHSD2 or POR may lead to DSD in both 46,XX and 46,XY individuals. The pathophysiology, clinical presentation and management of the above-mentioned disorders are critically reviewed, with a special focus on the latest biomarkers and therapeutic development.

Hard bilateral syphilitic testes with vasculitis: a case report and literature review

BackgroundWe report the case of a patient with syphilitic testicular gumma and vasculitis with adrenal failure due to chronic steroid use.Case presentationA 63-year-old male presented with hard right eye swelling and very firm bilateral testes on palpation, which he had for 2 years. Testicular tumor markers were negative; syphilis test was positive. Radiological examination suggested aortitis and bilateral testicular malignancy. The patient received ampicillin for the infection and prednisolone for vasculitis. Left orchidectomy was performed to confirm the presence of testicular tumor; histological examinations revealed granulomatous orchitis. The prednisolone doses were adjusted because of relapses and adverse effects of steroid use. Unfortunately, the patient died in the intensive care unit because of uncontrolled blood pressure and pneumonia.ConclusionsThis is a rare case of syphilis with testicular involvement and vasculitis. This report shows the importance of broadening the differential diagnoses of testicular firmness.

Disorders of Sex Development.

Disorders of Sex Development.

A Novel Intronic Splice—Site Mutation of the CYP11A1 Gene Linked to Adrenal Insufficiency with 46,XY Disorder of Sex Development

A novel CYP11A1: c.1236 + 5G > A was identified, expanding the mutation spectrum of the congenital adrenal insufficiency with 46,XY sex reversal. In a now 17-year-old girl delivered full-term (G2P2, parents unrelated), adrenal failure was diagnosed in the first year of life based on clinical picture of acute adrenal crisis with vomiting, dehydration, weight loss, hypotension, and electrolyte disturbances. At the time, hormonal tests revealed primary adrenocortical insufficiency and steroid profiles showed lack of products of steroidogenesis, and since then the patient has been treated with substitution doses of hydrocortisone and fludrocortisone. At the age of 14, considering the absence of puberty symptoms, extended diagnostic tests revealed elevated LH levels (26.5 mIU/mL) with pre-puberty FSH levels (4.9 mIU/mL), low estradiol (28 pmol/L), testosterone (<2.5 ng/mL), and extremely high levels of ACTH (4961 pg/mL). A cytogenetic study revealed a 46 XY karyotype. A molecular examination confirmed the missense mutation and a novel splice-site mutation of CYP11A1 gene. Compound heterozygosity for the CYP11A1 gene with a known pathogenic variant in one allele and a novel splice site mutation in the second allele is most probably responsible for congenital adrenal insufficiency with 46,XY sex reversal. We discuss the necessity of cytogenetic test in the case of early onset of adrenal failure in the absence of steroidogenesis metabolites in the steroid profile.

A Camouflaged Case of Disseminated Tuberculosis Presenting as Adrenal Crisis

Lymphohematogenous spread of mycobacterium tuberculosis to multiple organs presents a complex diagnostic challenge to any physician. A holistic and vigilant approach is required in the quest to diagnose disseminated tuberculosis causing adrenal failure. Although tuberculosis can affect various endocrine glands of the body yet adrenal remains the most common.[1] It is also the fifth most common site for extra-pulmonary tuberculosis.[2] The incidence of tuberculous Addison’s disease has lowered courtesy of anti-tubercular medications accounting for only 7-20% of cases.[1] Here we showcase a rare incidence where a 39 years old gentleman with no constitutional symptoms and no known co-morbidities presenting with neck pain went into adrenal crisis and eventually was found to be due to disseminated tuberculosis which affected his lungs, adrenal glands, cervical spine, and brain.

In Vitro Splicing Assay Proves the Pathogenicity of Intronic Variants in MRAP

Introduction: Familial glucocorticoid deficiency (FGD) is characterised by isolated glucocorticoid deficiency in a patient who retains normal mineralocorticoid production. FGD causing mutations in the MC2R accessory protein, MRAP, are often splice-site or nonsense mutations resulting in a truncated protein. Many of these mutations occur at the canonical donor splice-site of intron 3, where it has been shown previously that c.106 + 2_3dupTA, for example, results in skipping of the first coding exon with unknown consequences at the protein level. Patients and methods: DNA was isolated from three consanguineous individuals diagnosed with early onset FGD (0 - 13 months) with high ACTH and/or low cortisol levels and underwent whole exome sequencing. The proband in family 1 (P1) presented at 13 months and had a hyperpigmented sibling who died in neonatal period due to adrenal failure. Patient 2 (P2), who also had a family history of adrenal insufficiency, was noted to be hyperpigmented at birth with markedly raised ACTH, patient 3 (P3) was noted to have diffuse hyperpigmentation in the early neonatal period and on formal testing at 16m was found to have low serum cortisol. Variants were confirmed using Sanger sequencing and predicted splice-site mutations were investigated using an in vitro splicing assay. Results: Homozygous mutations in MRAP were identified in all three cases which were heterozygous in their parents. Previously described mutations, c.106 + 1delG (chr21:33671388delG; rs1476574441; CD050155) in P1 and c.106 + 2dupT (Chr21: 33671390_91insT; rs761576317; CI118288) in P2 at the canonical donor splice-site of intron 3, were identified, with the former predicted to destroy the splice site and the latter to weaken it. These mutations in vitro resulted in the complete skipping of exon 3, which contains the translational start site, and presumably result in no protein product. A novel homozygous mutation in intron 4, c.206 + 5G>T; (chr21:33679055G>T rs1064796398) was identified in P3, but was not predicted to alter splicing. In vitro, this mutation negates the canonical donor splice site and creates two different alternative sites, both resulting in frameshifts and predicted early termination of the protein (p.Val44fs*50, p.Pro72fs*90). Conclusion: All mutations reported here are predicted to produce no protein, either because the start site is excluded (for c.106 + 1delG and c.106 + 2dupT) or because the transcripts are likely to undergo nonsense mediated decay (for c.206 + 5G>T), resulting in the early onset FGD seen in the patients. Splice prediction protocols, although effective for variants within 2bp of exon/intron boundaries may not predict the true outcome of a base change whereas the splice assay conclusively revealed the effect of all three variants allowing us to assign pathogenicity to them.

Bypassing the Adrenals: A Rare Case of Adrenal Insufficiency Following Bariatric Surgery

Background: Adrenal insufficiency (AI) is a life-threatening disorder that is generally caused by primary adrenal failure or by hypothalamic-pituitary impairment of the corticotropic axis. Patients often present with fatigue, hypotension, anorexia, and weight loss. There are few reported cases of AI following bariatric surgery; a type of procedure designed to cause weight loss and anorexia - two of the cardinal symptoms of AI. Establishing a diagnosis of AI in patients who have undergone bariatric surgery can be challenging due to symptom overlap, but it is of critical importance given that an acute stressor has the potential to precipitate adrenal crisis with risk of death. Clinical Case: A 42-year-old woman presented 15-months after sleeve gastrectomy with biliopancreatic diversion and duodenal switch with nausea, vomiting, decreased oral intake, weight loss, weakness and fatigue. Her symptoms were severe, requiring admission to the hospital and were initially thought to be a result of her bariatric surgery. Initial intake exam and labs were notable for mild hypotension, persistent hypoglycemia with hemoglobin A1c <3.4%. Further evaluation revealed a low AM cortisol (5.5 μg/dL) and diagnosis of AI was confirmed by a failed cosyntropin stimulation test with cortisol levels of 7.0 μg/dL and 10.6 μg/dL 30- and 60-minutes after cosyntropin administration, respectively. Her diagnosis remained confounded by the presence of concomitant micronutrient deficiencies including copper, zinc, vitamin D and vitamin B6. Furthermore, she was found to have low insulin and c-peptide levels of 1 μU/mL and 0.4 ng/ml, respectively, despite persistent hypoglycemia. The patient was treated with enteral nutrition via nasojejunal feeds and glucocorticoid replacement therapy with daily oral hydrocortisone and fludrocortisone. Each of her symptoms improved after initiation of steroid replacement therapy and she was discharged home. Conclusion: Clinicians should keep a high degree of suspicion for adrenal insufficiency in patients who have undergone bariatric surgery due to the degree of symptom overlap in this population.

An Case of Poems Syndrome With Primary Adrenal Insufficiency

POEMS syndrome is rare multi-system disorder characterised by a paraneoplastic plasma cell disorder. The acronym POEMS stands for Polyneuropathy, Organomegaly, Endocrinopathy, M protein, and Skin changes. The underlying mechanisms are poorly understood, but chronic overproduction of pro-inflammatory cytokines have an integral role in the disorder. Diagnosis of POEMS is difficult owing to the variety of clinical manifestations. Mandatory diagnostic criteria are (a) one major criterion of either polyneuropathy or monoclonal gammopathy, in association with (b) one minor criterion including, but not limited to, organomegaly, endocrinopathy or skin changes. Endocrinopathies have been identified in 67–84% of patients with POEMS [1]. While hypogonadism and hypothyroidism are relatively common, primary adrenal failure is rarely reported. We present a 54-year-old woman who was found to have a raised hemoglobin, hematocrit and thrombocytosis on routine blood testing. She was concomitantly investigated for a rapidly-ascending, bilateral peripheral motor and sensory neuropathy. Diagnosis of POEMS was made and she underwent chemotherapy with Lenalidomide and high dose dexamethasone in 2015. Since then, she has not received endogenous glucocorticoids. She had an unplanned admission in April 2020 with a likely viral illness and was found to be glucocorticoid deplete. A 250-mcg short synacthen test demonstrated an inadequate response in cortisol, from 4.31 µg/dl to 6.13 µg/dl, with a raised adrenocorticotrophic hormone (ACTH) level of 66 mU/L. Adrenal antibodies were not detected. CT scan of the abdomen reported no adrenal gland abnormalities. The patient denied symptoms of mineralocorticoid deficiency, with no postural blood pressure (BP) drop - sitting BP 123/69 mmHg and standing BP 131/74 mmHg. Serum electrolytes were normal (renin and aldosterone levels are pending) and androgen screen was within normal limits. Thyroid stimulating hormone (TSH) was 8.07 mIU/L, free thyroxine (fT4) levels 0.93 ng/dL, and thyroid receptor and thyroid peroxidase antibodies were both negative. The patient is now established on Hydrocortisone therapy: 10mg (morning), 5mg (lunchtime). In summary, we present a 54-year-old woman with POEMS syndrome with subacute primary adrenal failure, characterised by glucocorticoid deficiency and ACTH excess. Although rare, it is important for all clinicians to be aware of POEMS syndrome as a potential diagnosis if the diagnostic criteria described above are filled, and for Endocrinologists to be aware that POEMS endocrinopathies can occur in any gland, including the adrenal glands.1.Gandhi, G.Y., et al., Endocrinopathy in POEMS syndrome: the Mayo Clinic experience. Mayo Clin Proc, 2007. 82(7): p. 836–42.

Genome-Wide Association Study Links Autoimmune Addison’s Disease to Break of Central Tolerance

Abstract Autoimmune Addison’s disease is the predominant cause of primary adrenal failure, and is highly heritable. The genetic background has remained poorly understood due to the low prevalence and complex inheritance of the disease. We performed a genome-wide association study, which identified nine independent risk loci (P &amp;lt; 5 × 10–8). In addition to novel and previous risk loci involved in lymphocyte functionality, we further associated autoimmune Addison’s disease with two independent protein-coding alterations in the gene Autoimmune Regulator (AIRE). The most striking is the amino-acid substitution p.R471C (rs74203920, OR = 3.4 (2.7–4.3), P = 9.0 × 10–25), which introduces an additional cysteine residue in the zinc-finger motif of the PHD2 domain of AIRE. This unbiased elucidation of the genetic contribution to development of autoimmune Addison’s disease points to the importance of central immunological tolerance, and explains 35–41 percent of heritability.

Severe Virilization in a Girl With the Homozygous G200SNicotinamide Nucleotide Transhydrogenase Mutation Is Surprisingly Caused by Rare Bilateral Para-Overian Adrenal Rest Tumors

Background: Patients with NNT (Nicotinamide Nucleotide Transhydrogenase) gene mutations, a rare cause of glucocorticoid and mineralocorticoid deficiency require hormone replacement therapy. Adrenal Rest Tumor (ART) in females is very rare (<20 cases world-wide) and was reported only in noncompliant patients with congenital adrenal hyperplasia having extremely elevated ACTH levels. This study characterizes the clinical characteristics, the pathophysiology and the molecular ontogeny of a unique ART in a female with adrenal failure due to the G200S mutation in NNT. Clinical presentation and Method: A 15-year-old girl, with homozygous G200S NNT-mutation that caused adrenal insufficiency reappeared to follow-up after several years with severe virilization and elevated serum testosterone (28.3 nmol/l) and ACTH (> 1500 pmol/l) levels. Pelvic MRI and Ultrasound demonstrated one sided para-ovarian round tumor with pathological vascularization. Laparoscopic exploration revealed bilateral para-ovarian mesosalpinx masses involving the serosa of the Fallopian tube (3 and 1 cm in diameter); the testosterone level normalized within one day after removal of those masses (0.2 nmol/l). Results: Histopathology demonstrated a pattern of adrenal rest tissue with strong intracellular positive staining for adrenal markers such as SF-1, calretinin, MART1, inhibin and the pituitary corticotroph marker-ACTH. The staining for ovarian characteristic markers such as PAX 8 was negative. Studying mRNA extracted from the tissue by RT-PCR revealed the presence of CYP17A1, CYP21A2 and MC2R (ACTH receptor) cDNA confirming typical adrenocortical transcriptional pattern in the tissue. cDNA of POMC was not detected suggesting that in spite of dense ACTH staining the tissue is not classically originated from pituitary corticotrophs. Methylome studies to further characterise the tissue are underway. Conclusion: This study exemplifies severe virilization that resulted from a unique and rare type of ART in ovarian related tissue that was caused by incompliance to treatment in a patient with NNT gene mutation. Given the ubiquitous expression of NNT and its reported pathophysiology as free radicals scavenger in all adrenocortical layers, it is surprising to have high ACTH induced severe virilization in spite of severe NNT dysfunction and adrenal insufficiency. This study may indicate timely testosterone screening in females with NNT mutation and when increased they should probably be laparoscopically surveyed for ART even when not detected by imaging. How NNT mutation damages mineralo and glucocorticoid secreting cells while androgen secreting cells are rescued is a theme for further studies.