Management of immune-related adverse events in endocrine organs induced by immune checkpoint inhibitors: clinical guidelines of the Japan Endocrine Society.

Immune checkpoint inhibitors (ICIs) have become a promising treatment for advanced malignancies. However, these drugs can induce immune-related adverse events (irAEs) in several organs, including skin, gastrointestinal tract, liver, muscle, nerve, and endocrine organs. Endocrine irAEs comprise hypopituitarism, primary adrenal insufficiency, thyroid dysfunction, hypoparathyroidism, and type 1 diabetes mellitus. These conditions have the potential to lead to life-threatening consequences, such as adrenal crisis, thyroid storm, severe hypocalcemia, and diabetic ketoacidosis. It is therefore important that both endocrinologists and oncologists understand the clinical features of each endocrine irAE to manage them appropriately. This opinion paper provides the guidelines of the Japan Endocrine Society and in part the Japan Diabetes Society for the management of endocrine irAEs induced by ICIs.

Adolescent Inhalant Abuse Results in Adrenal Dysfunction and a Hypermetabolic Phenotype with Persistent Growth Impairments.

BACKGROUND/AIMS: Abuse of toluene products (e.g., glue-sniffing) primarily occurs during adolescence and has been associated with appetite suppression and weight impairments. However, the metabolic phenotype arising from adolescent inhalant abuse has never been fully characterised, and its persistence during abstinence and underlying mechanisms remain unknown. METHODS: Adolescent male Wistar rats (post-natal day 27) were exposed to inhaled toluene (10,000 ppm) (n = 32) or air (n = 48) for 1 h/day, 3 days/week for 4 weeks, followed by 4 weeks of abstinence. Twenty air rats were pair-fed to the toluene group, to differentiate the direct effects of toluene from under-nutrition. Food intake, weight, and growth were monitored. Metabolic hormones were measured after exposure and abstinence periods. Energy expenditure was measured using indirect calorimetry. Adrenal function was assessed using adrenal histology and hormone testing. RESULTS: Inhalant abuse suppressed appetite and increased energy expenditure. Reduced weight gain and growth were observed in both the toluene and pair-fed groups. Compared to the pair-fed group, and despite normalisation of food intake, the suppression of weight and growth for toluene-exposed rats persisted during abstinence. After exposure, toluene-exposed rats had low fasting blood glucose and insulin compared to the air and pair-fed groups. Consistent with adrenal insufficiency, adrenal hypertrophy and increased basal adrenocorticotropic hormone were observed in the toluene-exposed rats, despite normal basal corticosterone levels. CONCLUSIONS: Inhalant abuse results in negative energy balance, persistent growth impairment, and endocrine changes suggestive of adrenal insufficiency. We conclude that adrenal insufficiency contributes to the negative energy balance phenotype, potentially presenting a significant additional health risk for inhalant users.

Update on the Systemic Risks of Superpotent Topical Steroids.

INTRODUCTION: The potential for systemic effects due to percutaneous absorption of superpotent topical steroids has been a longstanding concern. The Food and Drug Administration currently recommends limiting the use of superpotent topical steroids to 50g per week for 2 or 4 consecutive weeks depending on the formulation, which is mostly based on the exact duration with which phase 3 clinical trials were allowed to be conducted per the FDA. This article reviews all published clinical incidence of adrenal adverse effects in the medical literature, specifically Cushing's syndrome (CS) and pathologic adrenal suppression (PAAS), to try to ascertain a more realistic limit for the safe use of superpotent topical steroids as it pertains to its potential systemic effects.

METHODS: Literature search was conducted using PubMed. Only cases of CS and PAAS secondary to the use of Class I superpotent topical steroids were included. Pediatric cases and full articles unavailable in English were excluded.

RESULTS: There were a total of 14 cases of CS and 5 cases of subsequent PAAS found in the current literature.

DISCUSSION: From our review of these cases, if the amount used per week is within FDA guidelines, it appears that patients needed to use superpotent topical steroids for far greater than 2 or 4 weeks to develop CS or PAAS. CS did not necessarily predict occurrence of PAAS, but in all cases CS appeared to be a prerequisite for developing PAAS. All cases of CS and all but one case of PAAS were reversible. If excessive amount of greater than 50g per week is avoided, it appears that superpotent topical steroids may be safe to use consecutively for months, perhaps even years, without causing systemic effects.

J Drugs Dermatol. 2017;16(7):643-648.

[Bilateral adrenal hemorrhage (BAH): cannabis and vascular involvement]. / Hémorragie surrénalienne bilaterale (HSB): cannabis et atteintes vasculaires.

We report the case of a 39-year-old man with bilateral adrenal haemorrhage. The diagnosis is rarely primarily made with imaging alone. Our patient had a previous history of a stroke six years prior to this episode. We evoke the possibility that long-term daily cannabis use could be the underlying cause of the patient's vascular pathologies. After thorough review of existing literature, this link was found to be probable. Cannabis is the most consumed recreational drug in the world, and this tendency is ever-increasing. Serious complications other than psychiatric resulting from consumption are reported with increasing frequency. Neurological, cerebrovascular, cardiovascular and respiratory complications have been observed. It is thus important to remain vigilant when patients are hospitalised notably through the emergency department, in order to obtain a complete anamnesis, optimise screening, and to adapt the treatment of these patients.

Pituitary and adrenal disorders induced by immune checkpoint inhibitors.

Over the past decade, the development of ICI (immune checkpoint inhibitors) has constituted a revolution in the treatment of many cancers, but with a specific toxicity profile including endocrine IRAEs (immune-related adverse events). As the indications for these molecules are constantly increasing due to their efficacy, it is important that endocrinologists and oncologists know how to detect, manage and monitor this type of toxicity. Many guidelines and recommendations have been proposed in the last few years for the management of endocrinopathies. French guidelines on immunotherapy-related endocrine IRAEs were published in 2018, with a specific algorithm for hypophysitis and primary adrenal insufficiency (PAI), based on clinical suspicion followed by biochemical and imaging evaluation, and are still relevant today. Here we present the general pathophysiological mechanisms of these toxicities, and discuss the incidence, diagnosis, treatment, progression, management and monitoring of pituitary and adrenal disorders in patients treated by immunotherapy, with emphasis on hypophysitis, which is much more frequent than PAI with this type of molecule. We also highlight several key points, such as the need for emergency treatment by hydrocortisone with the possibility of continuing immunotherapy in these endocrinopathies, and the long-term persistence of corticotropin or adrenal deficiency in most cases, requiring specific "hydrocortisone education". These points should be kept in mind by oncologists and endocrinologists who treat and monitor patients treated by immunotherapy.

Bilateral adrenal hemorrhage: the unrecognized cause of hemodynamic collapse associated with heparin-induced thrombocytopenia.

OBJECTIVE: Heparin-induced thrombocytopenia is a common adverse effect of treatment with heparin resulting in paradoxical thromboses. An immunoglobulin G class "heparin-induced thrombocytopenia antibody" attaches to a heparin-platelet factor 4 protein complex. The antibody then binds to the FcγIIa receptor on the surface of a platelet, resulting in activation, consumption, and thrombocytopenia in the clinical syndrome of heparin-induced thrombocytopenia. In contradistinction to other drug-induced thrombocytopenias that lead to a risk of hemorrhage, the state of thrombocytopenia in heparin-induced thrombocytopenia leads to an acquired hypercoagulability syndrome. Bilateral adrenal hemorrhage associated with heparin-induced thrombocytopenia has become an increasingly documented association. The adrenal gland has a vascular construction that lends itself to venous thrombus in the setting of heparin-induced thrombocytopenia and subsequent arterial hemorrhage. A literature search revealed 17 reported cases of bilateral adrenal hemorrhage in the setting of heparin-induced thrombocytopenia uniformly presenting with complete hemodynamic collapse. DATA SOURCES: An Ovid MEDLINE search of the English-language medical literature was conducted, identifying articles describing cases of bilateral adrenal hemorrhage in the setting of heparin-induced thrombocytopenia. STUDY SELECTION: All cases with this association were included in the review. DATA EXTRACTION AND DATA SYNTHESIS: A total of 14 articles were identified, describing 17 individual case reports of bilateral adrenal hemorrhage associated with heparin-induced thrombocytopenia. All cases confirmed known characteristics of heparin-induced thrombocytopenia and uniformly revealed hypotension due to adrenal insufficiency. There were five deaths, resulting in an overall mortality rate of 27.8%, and 100% mortality in the three cases where adrenal insufficiency went unrecognized. CONCLUSIONS: The secondary complication of adrenal vein thrombosis leading to bilateral adrenal hemorrhage remains insufficiently recognized and undertreated. The nonspecific presentation of adrenal hemorrhage and insufficiency as a complication of heparin-induced thrombocytopenia, coupled with the catastrophic clinical course of untreated adrenal collapse, requires a high index of suspicion to achieve rapid diagnosis and provide life-saving therapy.

Hypothalamic-pituitary-adrenal axis suppression in asthmatic children on inhaled and nasal corticosteroids: is the early-morning serum adrenocorticotropic hormone (ACTH) a useful screening test?

BACKGROUND: Hypothalamic-pituitary-adrenal axis suppression (HPAS) in asthmatic children treated with inhaled corticosteroids (ICS), with or without nasal steroids (NS), may be more common than previously thought. Only dynamic testing will identify children at risk of adrenal crisis. It is impractical to test all asthmatic children for HPAS with a gold standard adrenal function test, i.e. the metyrapone or insulin tolerance test. OBJECTIVE: To determine which clinical or biochemical parameter is the most useful screening test for HPAS in asthmatic children. METHODS: Twenty-six asthmatic children, 5-18 yr old, on ICS ± NS, not treated with oral or topical steroids in the preceding year were recruited. Height, weight, height velocity, weight velocity and a change in systolic blood pressure from the recumbent to the standing position (ΔSBP) were recorded. Early-morning urine for urinary free cortisol (UFC) and urinary cortisol metabolites (UCM) was collected. UFC was analysed by both a chemiluminescent assay and gas chromatography/mass spectrometry (GC-MS). Morning serum cortisol and adrenocorticotropic hormone (ACTH) levels were measured. The overnight metyrapone test was performed if the fasting morning serum cortisol was >83 nmol/l. HPAS was diagnosed if the ACTH failed to rise >100 pg/ml after metyrapone. Spearman correlation coefficients (r) were calculated between the post-metyrapone ACTH and each variable. A receiver-operating characteristics (ROC) curve was drawn for the most promising test, and the diagnostic performance was calculated. RESULTS: All clinical and biochemical parameters investigated were weakly and non-significantly correlated with the post-metyrapone ACTH, except for the morning serum ACTH (r = 0.68; p <0.001). The best discrimination between those who have and those who do not have HPAS is a morning serum ACTH level of 11.7 pg/ml. This corresponds to a sensitivity of 0.89 (0.57-0.98), a specificity of 0.77 (0.53-0.90), a positive predictive value of 0.67 (0.39-0.87), a negative predictive value of 0.93 (0.69-0.99), an accuracy of 0.81 (0.61-0.94), a positive likelihood ratio of 3.78 (1.68-9.49) and a negative likelihood ratio of 0.15 (0.03-0.60). CONCLUSIONS: The morning serum ACTH level was found to be the most useful screening test to detect HPAS in this sample of children receiving ICS ± NS. A larger study should be undertaken to refine the diagnostic precision of the morning serum ACTH level.

Prevention of CCl(4)-induced oxidative damage in adrenal gland by Digera muricata extract in rat.

Digera muricata (L.) Mart. is a weed and commonly found in waste places, road sides and in maize fields during the summer season. It possesses antioxidant capacity and is locally used for various disorders such as inflammation, urination, as refrigerant, aperient and in sexual anomalies. In this study antioxidant potential of Digera muricata methanol extract (DMME) and n-hexane extract (DMHE) was evaluated against CCl(4)-induced oxidative stress in adrenal gland of Sprague-Dawley male rats. 42 rats were equally divided into 7 groups of 6 rats in each. Group I remained untreated, while Group II treated with vehicles. Group III received only CCl(4) (1 ml/kg b.w., 10% in olive oil) once a week for 16 weeks. Group IV and VI received DMME and DMHE at a dose of 200 mg/kg b.w. along with CCl(4). Animals of Group V and VII administered with DMME and DMHE alone at a dose of 200 mg/kg b.w. once a week for 16 weeks. Lipid peroxidation significantly increased while activities of antioxidant enzymes (CAT, SOD, GST, GSR and GSH-Px) were reduced in adrenal gland samples by the administration of CCl(4). Glutathione (GSH) concentration was significantly decreased whereas DNA fragmentation% and AgNORs count was increased in adrenal gland by CCl(4) administration. Treatment of rat by both the extracts (DMME, DMHE) and CCl(4) increased the glutathione level and activities of antioxidant enzymes while reduced the lipid peroxidation, DNA fragmentation percent and AgNORs count in adrenal gland. These results indicate that Digera muricata extract is able to ameliorate oxidative stress in adrenal gland induced by CCl(4) in rat.

Spontaneous heparin-induced thrombocytopaenia with adrenal haemorrhage following orthopaedic surgery: a case report and literature review.

A 68-year-old woman was admitted to the hospital for elective total knee arthroplasty in both knees without preceding heparin exposure. She developed adrenal haemorrhage and thrombocytopaenia on postoperative day 12, followed by right leg arterial occlusion and multiple venous intra-abdominal sites thrombosis. After given unfractionated heparin to treat arterial occlusion, platelet count was gradually declined. Spontaneous heparin-induced thrombocytopaenia was diagnosed by heparin-induced platelet activation test with light transmission aggregometry. The patient was successfully treated with fondaparinux and intravenous immunoglobulin. Apixaban was given after recovery of platelet count. Resolution of both thrombus along aorta and adrenal haemorrhage were shown by CT of whole abdomen after 2 months of treatment. Our case demonstrates that this serious complication is important but seldom recognised early.

[Adrenal hemorrhage acutised by adrenocorticotropin hormone]. / Hématomes surrénaliens potentialisés par le Synacthène (HSS).

OBJECTIVE: Many spontaneous adrenal hematomas have been observed in patients being treated by Synacthène. The purpose of this study is to define how to take those patients in charge on a short-, mid- and long-term. PATIENTS AND METHODS: From January 2000 to December 2008, five patients (four males and one female), mean age 47, were taken in charge in our service for spontaneous adrenal hematomas. All those patients had been treated with Synacthène for a mid-sciatic pain for 72 hours. We associated a clinical, endocrine and radiologic staging to treat those patients. RESULTS: Four patients underwent a watchful waiting, only one patient needed surgery. No adrenal tumor was ever found during the mean two years follow-up (one to four). Two patients suffered of the condition of the antiphospholipid syndrome. CONCLUSION: Spontaneous adrenal hematomas are a most uncommon pathology. The clinical attitude has thus to be defined clearly. The patient must be under close clinical evaluation. Biological and morphological parameters have to be often repeated. An adrenal tumor has to be excluded by the evaluation, as that tumor could be secreting or could not be secreting. Antiphospholipid syndrome must also be excluded.

Immune checkpoint inhibitors and endocrine side effects, a narrative review.

Immune checkpoint inhibitors (ICPIs) are novel drugs in the field of oncology however carry the risk of immune-related dermatologic, gastrointestinal, and endocrine side effects which can be fatal. These new innovative immunoregulatory drugs have intertwined the fields of oncology and endocrinology. CTLA-4 and PD-1 are co-inhibitory receptors on T cells that turn the T cell 'off' when binding to receptors on APCs. Tumor cells can also carry receptors for CTLA- and PD-1. By rendering T cells inactive, tumor cells can evade immune attack. Antibodies that bind to CTLA-4 and PD-1 lead to T cell activation and destruction of both tumor and normal host cells. ICPIs have been used in a variety of malignancies including melanoma, kidney cancer, and non-small cell lung cancer. A unique underrecognized side effect of the autoimmune response is hypophysitis leading to central adrenal insufficiency which can be fatal. Additional immune-related adverse events (irAEs) include hypothyroidism, hyperthyroidism, diabetes, and hypoparathyroidism.

[Bilateral adrenal hemorrhage under apixaban in primary antiphospholipid syndrome]. / Nécrose hémorragique bilatérale des surrénales sous apixaban : penser au syndrome des antiphospholipides ?

INTRODUCTION: Adrenal hemorrhage is a classical but rare complication of antiphospholipid syndrome, revealing diagnosis in one third of the cases. Anti-vitamin K therapy is the standard treatment but direct oral anticoagulants are discussed as an alternative. In the latest recommendations, it is advised not to use direct oral anticoagulants in the setting of antiphospholipid syndrome. CASE REPORT: We present a case of bilateral adrenal hemorrhage revealing primary antiphospholipid syndrome with triple positive antibody profile, in a 47-year-old man treated by apixaban for previous venous thromboembolism. CONCLUSION: To our knowledge, it is the first case of adrenal hemorrhage occurring during apixaban treatment in a patient with antiphospholipid syndrome. This case illustrates the inefficacy of direct oral anticoagulants to prevent thrombotic events in antiphospholipid syndrome, in accordance with the latest recommendations.

Attention-Deficit/Hyperactivity Disorder, Its Pharmacotherapy, and Adrenal Gland Dysfunction: A Nationwide Population-Based Study in Taiwan.

This study aims to examine the co-occurrence rate of attention deficit hyperactivity disorder (ADHD) and adrenal gland disorders, as well as whether pharmacotherapy may affect ADHD patients' risk of developing adrenal gland disorder. One group of patients newly diagnosed with ADHD (n = 75,247) and one group of age- and gender-matching controls (n = 75,247) were chosen from Taiwan's National Health Insurance database during the period of January 1999 to December 2011. Both patients and controls were monitored through December 31, 2011, in order to identify the occurrence of adrenal gland disorders (ICD-9-CM code 255.X). We also explored the potential effect of methylphenidate (MPH) and atomoxetine (ATX) treatments on the risk of developing adrenal gland disorders. We found that ADHD patients showed a significantly increased probability of developing an adrenal gland disorder compared to the control group (0.2% of ADHD vs. 0.1% of controls). However, neither MPH nor ATX treatment significantly influenced the patients' risk of developing adrenal gland dysfunction. We propose that patients with ADHD had greater comorbid rates with adrenal gland dysfunction than the control subjects. Nevertheless, undergoing treatment with MPH or ATX did not significantly influence the risk of developing adrenal gland dysfunction among ADHD patients.

Neonate Death Due to Marijuana Toxicity to the Liver and Adrenals.

BACKGROUND Marijuana is the considered the most widely available and used drug across the world. Up to this time, there have been no reports of human death directly caused by acute marijuana toxicity in adults, fetuses, or newborn neonates. CASE REPORT We report a death of an 11-day-old white female neonate due to acute marijuana toxicity. She died of extensive necrosis and hemorrhage of the liver and adrenals due to maternal use of marijuana. CONCLUSIONS This case is unique in that other possible causes of death can be eliminated. With growing use of marijuana by pregnant women and increases in newborn drug screening of umbilical cord homogenate, more cases of neonatal death due to acute marijuana toxicity could be discovered.