Tertiary Adrenal Insufficiency Research Articles

Does secondary adrenal insufficiency require supplementation prior to oral surgery procedures? An update

Adrenal insufficiency (AI) is linked to a rare medical emergency, acute AI, or adrenal crisis (AC), which can occur following stressful events, like infection or surgery. A commonly overlooked form of secondary AI occurs when individuals take exogenous glucocorticoids for extended periods of time, resulting in hypoactivity of the adrenal glands. Many patients take glucocorticoids to treat conditions like asthma, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, or dermatitis. These patients may be prone to secondary AI, which may go undetected, increasing their risk of facing a medical emergency. Our aim is to review the literature on current guidelines for corticosteroid supplementation for patients at risk of AC; and assess the risk of developing AI in patients taking exogenous glucocorticoids and whether the current supplementation guidelines require modifications. Current recommendations from the Addison’s disease self-help group and Miller suggest steroid supplementation for dental procedures only for patients with primary AI. However, they do not recommend supplementation for patients with secondary or tertiary adrenal insufficiency. The drawbacks of short-term supplementation of glucocorticoids in patients at risk of secondary AI, for stressful dental procedures is negligible. Adverse effects of glucocorticoid use are typically seen after prolonged usage. Thus, steroid supplementation before dental procedures should be considered, customized based on identified risk factors and the stress associated with the procedure, as a pragmatic and preemptive approach to reduce the risk of AC. Moreover, this review highlights the need for updated guidance on supplementing patients at risk of secondary AI

Tertiary adrenal insufficiency in a patient with familial Mediterranean fever: Association or coincidence?

Tertiary adrenal insufficiency in a patient with familial Mediterranean fever: Association or coincidence?

The diagnosis of adrenal insufficiency and its implications in primary care

Adrenal insufficiency can be clinically challenging to diagnose, due to relatively low incidence rates in the European population. It is a condition requiring active consideration to achieve diagnosis. The main pathologies discussed here are primary adrenal insufficiency (PAI) and tertiary adrenal insufficiency. PAI is also commonly termed Addison’s disease. Secondary adrenal insufficiency is not considered in detail in this article. The article will address the underlying pathophysiology, presentation and investigation of adrenal insufficiency. It will also consider iatrogenic adrenal insufficiency and management of adrenal insufficiency in the primary care setting.

Clinical Approach to Adrenal Insufficiency

Adrenal insufficiency refers to inadequate production of glucocorticoids, mineralocorticoids, or both by the adrenal glands. This may result from dysfunction or complete destruction of the adrenal cortex (primary adrenal insufficiency), inadequate adrenocorticotropic hormone production by the pituitary (secondary adrenal insufficiency), or inadequate corticotropin-releasing hormone production by the hypothalamus (tertiary adrenal insufficiency). Diagnosis of adrenal insufficiency requires a high index of suspicion because of its nonspecific signs and symptoms. It is associated with a high morbidity and low quality of life even in patients on treatment. When it presents as adrenal crisis it has a high mortality. Glucocorticoid replacement is the mainstay of management, and this may be combined with mineralocorticoids in the case of primary adrenal insufficiency. Health care personnel must be reminded of this condition, to improve rates of early diagnosis and improve outcomes in management. In this review, we also look at the management of adrenal insufficiency in special populations and the potential role of newer long-acting steroids in the management of adrenal insufficiency is briefly discussed.

Alkindi Sprinkle for Pediatric Patients With Primary Adrenocortical Insufficiency: A Narrative Review.

Adrenocortical insufficiency, also known as adrenal insufficiency (AI), is an endocrine disorder characterized by inadequate production of adrenal hormones, including glucocorticoids and mineralocorticoids (MCs). The condition can be categorized as primary, secondary, or tertiary AI, depending on the location of the defect. Classical symptoms of AI include weakness, fatigue, abdominal pain, tachycardia, hypotension, electrolyte imbalances, and hyperpigmentation. In children, the most common cause of AI is classical congenital adrenal hyperplasia, which results from a deficiency in the 21-hydroxylase enzyme. The 21-hydroxylase enzyme produces all steroids, such as cortisol and aldosterone. AI management primarily involves hormone replacement therapy, typically with oral hydrocortisone and MC supplementation. However, the administration of hydrocortisone to pediatric patients presents challenges related to the lack of available dose-appropriate formulations. Historically, crushed or split adult tablets were used for the pediatric treatment of AI, although this poses an increased risk of under- or overtreatment. Inadequate dosing in the pediatric population can adversely affect growth, development, and metabolic health. Alkindi Sprinkle is a pediatric-specific hydrocortisone oral granule preparation that manages cortisol levels to help facilitate accurate therapeutic dosing. Alkindi offers several advantages, including accurate dosing, taste masking, and ease of administration. The present investigation describes AI, the management of AI, and the treatment of pediatric AI using Alkindi Sprinkle, including clinical efficacy.

A Retrospective Study on Weaning Glucocorticoids and Recovery of the Hypothalamic-Pituitary-Adrenal Axis.

Glucocorticoids suppress the hypothalamic-pituitary-adrenal (HPA) axis, resulting in tertiary adrenal insufficiency (AI). When weaning patients off glucocorticoids there is no consensus on whether to maintain patients on prednisolone or convert to hydrocortisone. To investigate HPA axis recovery in patients on long-term prednisolone and assess outcome after hydrocortisone conversion. This was a retrospective cohort study at an outpatient endocrine steroid clinic. Patients were on long-term prednisolone and referred for HPA axis testing between 2015 and 2022. The main outcomes measured were (1) HPA axis recovery rate in patients on prednisolone demonstrated by a normal adrenocorticotrophic hormone (ACTH) stimulation test (AST) and (2) HPA axis recovery rate subanalysis of dose-matched patients with confirmed tertiary AI on prednisolone or hydrocortisone were measured. In total, 206 patients on prednisolone were tested for tertiary AI. Of these, 176 remained on prednisolone while 30 were converted to hydrocortisone. The overall HPA axis recovery rate for patients on prednisolone after interval testing was 137/206 (66.5%). The HPA axis recovery rate in dose-matched prednisolone and hydrocortisone conversion groups was 7/10 (70%) and 2/13 (15%) (P = .008), respectively. There was no difference in mean (SD) age (67.1 [12.2] vs 63.4 [11.1] years; P = .464) and baseline cortisol (5.3 [4.2] vs 4.6 [3.1] µg/dL; P = .648) and median [interquartile, IQR] glucocorticoid duration (1213 [1114] vs 2316 [4808] days; P = .693) and baseline ACTH (20.5 [29.0] vs 16.3 [14.8] ng/L; P = .905) between dose-matched prednisolone and hydrocortisone groups. Follow-up duration in the prednisolone group was significantly lower (median [IQR] 348 [975] vs 667 [884] days; P = .012). Patients with glucocorticoid-induced AI maintained on once-daily prednisolone can recover HPA axis function when weaning. There is no apparent advantage to recover HPA axis function in converting to multiple-dosing hydrocortisone.

Defining the basal serum cortisol cut-off for weaning patients off glucocorticoids in suspected tertiary adrenal insufficiency

Defining the basal serum cortisol cut-off for weaning patients off glucocorticoids in suspected tertiary adrenal insufficiency

Retrospective study of steroid weaning in tertiary adrenal insufficiency comparing prednisolone and hydrocortisone

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Understanding tertiary adrenal insufficiency

Understanding tertiary adrenal insufficiency

A Prospective Analysis of the Metyrapone Short Test Using Targeted and Untargeted Metabolomics

Introduction: The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. Methods: 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 μg/L) and a pathological (11-deoxycortisol <70 μg/L) response group. Clinical follow-up examination was performed for validation. Ultraperformance liquid chromatography tandem mass spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. Results: At baseline, lower levels of cortisone (42 vs. 50 nmol/L, p = 0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/L, p = 0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 μg/L, p < 0.001) and ACTH (49 vs. 113 pg/mL, p < 0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p < 0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/L showed a high diagnostic performance (sensitivity 100%, specificity 96%). Conclusion: The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

Corticosteroid Suppression in Patients Receiving Inhaled Glucocorticoids: Time to Reassess Risk?

It is estimated that 350 million people worldwide are affected by asthma (1) and, as such, any associated complications of treatment have the potential for a significant impact on global public health. The recent study by Kachroo et al in Nature Medicine is a valuable addition to the literature in relation to adrenal suppression in patients receiving inhaled glucocorticoid (GC) therapy. The authors applied corticosteroid metabolomic profiling to address the question of adrenal suppression using several different large datasets and methodologies. They identified significant suppression in serum corticosteroids (and their precursors/metabolites) associated with adrenocorticotropin (ACTH)-dependent steroidogenesis in participants with asthma compared with controls and assessed the association with inhaled corticosteroid (ICS) exposure (2). Tertiary adrenal insufficiency (TAI) occurs due to suppression of the hypothalamic–pituitary–adrenal (HPA) axis by exogenous GC exposure and is reported in association with all GC preparations (3). As both oral and inhaled GC therapy form an important component of asthma management (1), patients with asthma are undoubtedly at risk of TAI. However, the prevalence and potential consequences of TAI in this cohort remain uncertain due to the many challenges in determining the full impact of GC exposure on adrenal function in asthma, which include the wide spectrum of cumulative GC exposure between patients, differences in potency between various ICS preparations, and the potential discrepancy between the prescribed ICS dose and the dose received by the patient because of suboptimal adherence to ICS medication and incorrect inhaler technique (4).

Safer care for patients with adrenal insufficiency: weighing the evidence, balancing risks and acknowledging uncertainties

The National Patient Safety Alert supporting early recognition and treatment of adrenal crisis is a vital new component of care for adults affected by primary adrenal insufficiency. Benefits for patients with secondary and tertiary adrenal insufficiency need to be weighed alongside other considerations such as security of the diagnosis, relative likelihood of adrenal crisis and potential for anxiety and distress from assigning 'physical dependency' in relation to glucocorticoid therapy. All clinicians must be vigilant for and responsive to managing risks of adrenal crisis in at-risk patients, while avoiding diagnostic anchoring in the context of acute illness. More research is required to help define who is at greatest risk of adverse outcomes (including avoidance of therapeutic glucocorticoid therapy for fear of adrenal insufficiency) and a cross-specialty approach is advocated.

The Prevalence of Tertiary Adrenal Insufficiency in Patients Receiving Topical Glucocorticoid Treatment for Oral Lichen Planus

Abstract Objective: Glucocorticoid (GC) treatment suppress the hypothalamic-pituitary-adrenal axis, which may lead to tertiary adrenal insufficiency. This study aimed to investigate the prevalence of tertiary adrenal insufficiency among patients with oral lichen planus treated with topical GC (clobetasol propionate) in the oral cavity, a standard treatment option for this condition. Methods: In this cross-sectional study, we included 24 patients with oral lichen planus receiving long-term (&amp;gt; 6 weeks) clobetasol propionate treatment. Adrenal function was assessed by measuring serum cortisol between 8–9 AM, after a withdrawal of treatment for 48 hours. For patients with serum cortisol concentrations below 280 nmol/L (10 µg/dL), a 250 µg corticotropin stimulation test was performed. Results: Twenty patients had normal serum cortisol concentrations (range 280–621 nmol/L), whereas four patients had low serum cortisol concentrations (13, 45, 63, and 229 nmol/L, respectively). A corticotropin stimulation test revealed partial adrenal insufficiency in two patients (serum cortisol peak level 350 nmol/L and 360 nmol/L) and severe adrenal insufficiency in another two patients (serum cortisol peak level 150 nmol/L and 210 nmol/L). Conclusion: In this small study, approximately 20% of patients receiving chronic topical GCs treatment for oral lichen planus had tertiary adrenal insufficiency. It is essential to be aware of this potential risk and to inform patients about the need for GC stress-doses during an intercurrent illness episode.

Adrenal insufficiency.

Adrenal insufficiency (AI) is a condition characterized by an absolute or relative deficiency of adrenal cortisol production. Primary AI (PAI) is rare and is caused by direct adrenal failure. Secondary AI (SAI) is more frequent and is caused by diseases affecting the pituitary, whereas in tertiary AI (TAI), the hypothalamus is affected. The most prevalent form is TAI owing to exogenous glucocorticoid use. Symptoms of AI are non-specific, often overlooked or misdiagnosed, and are related to the lack of cortisol, adrenal androgen precursors and aldosterone (especially in PAI). Diagnosis is based on measurement of the adrenal corticosteroid hormones, their regulatory peptide hormones and stimulation tests. The goal of therapy is to establish a hormone replacement regimen that closely mimics the physiological diurnal cortisol secretion pattern, tailored to the patient's daily needs. This Primer provides insights into the epidemiology, mechanisms and management of AI during pregnancy as well as challenges of long-term management. In addition, the importance of identifying life-threatening adrenal emergencies (acute AI and adrenal crisis) is highlighted and strategies for prevention, which include patient education, glucocorticoid emergency cards and injection kits, are described.

Evaluating tertiary adrenal insufficiency in rheumatology patients on long-term systemic glucocorticoid treatment.

Patients with rheumatic diseases are often treated with prolonged, high-dose systemic glucocorticoids which can cause hypothalamic-pituitary-adrenal (HPA) axis suppression and development of tertiary adrenal insufficiency. Adrenal insufficiency carries the risk of serious, potentially life-threatening adrenal crisis. Our study evaluated the prevalence, characteristics and recovery of patients with underlying rheumatology conditions who had received prolonged glucocorticoid treatment. Retrospective, cross-sectional study. We evaluated 238 patients seen in outpatient rheumatology clinic, managed in accordance with current nationally and internationally accepted clinical guidelines. Data collected included patient demographics, historical steroid data, 09.00h cortisol/short synacthen test (SST) results and follow-up data on those with repeat assessments. Overall, 65% of our cohort had a 09.00h cortisol <350nmol/L. On SST, 43% of patients demonstrated evidence of possible tertiary adrenal insufficiency. Prednisolone equivalent dose at time of SST was significantly higher in the group who failed SST vs. those who passed; mean of 5.57mg vs. 3.59mg (p=.005). 09.00h cortisol result correlated with 30-min cortisol on SST (R2 =.20, p=.002). 0-min cortisol on SST correlated more strongly with 30-min cortisol than 09.00h cortisol (R2 =.59, p-value<.001). Patients with 0-min cortisol >350nmol/L, all passed their SST. Patients who remained on prednisolone were more likely to recover (71%) vs. those switched to hydrocortisone (27%), P=.02. Peak steroid dose was predictive of recovery; significantly lower in those who recovered (mean of 22.3mg vs. 33.8mg, P=.03). Steroid duration was not found to be a predictor of recovery [recovery (64.2months) vs. non-recovery (55.6months), P=.58]. There was no correlation found to outcome on SST with age, sex, peak steroid dose, steroid duration, underlying rheumatological condition, additional exogenous steroid use or serum sodium. Forty three percent of our patients demonstrated sub-optimal adrenal function on SST. Steroid dose at the time of SST was the only significant predictive risk factor for tertiary adrenal insufficiency. 09.00h cortisol demonstrated good correlation with outcome on SST and could represent a valid screening test to reduce need for SST if 09.00h >350nmol/L. Further prospective data are required to further characterize risk factors, predictive features of recovery and establish optimal management strategy of steroids (prednisolone vs hydrocortisone) to encourage adrenal recovery.

Adrenal Insufficiency Caused by Chronic Corticosteroid Use, Identified through Medication Therapy Management

OBJECTIVE: To report a case of adrenal insufficiency caused by chronic corticosteroid treatment.Summary: This case study describes a 71-year-old Caucasian woman diagnosed with secondary adrenal insufficiency (SAI). She had a long history of multiple medical problems that affected her quality of life. The pharmacist reviewed 18 years (2001-2018) of medical records, including her corticosteroid usage history. The patient had been receiving chronic medium-high dose inhaled corticosteroids for asthma, with intermittent oral prednisone for exacerbations. The pharmacist suspected a possible SAI or tertiary adrenal insufficiency (TAI) caused by hypothalamic pituitary adrenal axis suppression induced by chronic corticosteroid use. After discussions with the patient's primary care physician and a screening adrenal function test, the patient was referred to an endocrinologist, and the diagnosis was confirmed. Low-dose hydrocortisone (<30 mg daily) was prescribed; the patient had improvements in mood, skin hyperpigmentation, and asthma symptoms, which eliminated the routine visits to the emergency room/clinic during the winter season.CONCLUSION: The case illustrated the benefits of utilizing a pharmacist's expertise. A consultant pharmacist can identify an underdiagnosed and rare condition, corticosteroid-induced adrenal insufficiency, through comprehensive medication review in a community medication therapy management service setting.

Glucocorticoid Tapering: a Literature Review

Glucocorticoids (GCs), a class of corticosteroids that widely used a variety of diseases, associated physiological processes in the body [1,2]. It has structurally and pharmacologically similar to the endogenous hormone cortisol with various beneficial functions like anti-inflammatory, immunosuppressive, anti-proliferative, and vasoconstrictive effects. As an anti-inflammatory and immunosuppressive effect, corticosteroids through a combination of both inhibition & upregulation of gene transcription [3-5]. Despite beneficial effects, they also have side effects that depend on the dose, type of steroid and length of treatments [6]. Short courses of high-dose GCs usually are safe and reasonably well-tolerated, but they do have numerous potential adverse effects [7]. Many of the severe complications occur in long-term use at doses greater than 20 mg of prednisone per day for three weeks or more causes tertiary adrenal insufficiency due to the HPA-axis (Hypothalamic Pituitary Adrenal Axis) suppression by endogenous GCs [8-10]. In this article, we’ll discuss how to manage GCs tapering and when is the right time to use GCs.

Managing patients with endocrine dysfunction during COVID-19: Review of literatures

Coronavirus disease (COVID-19), caused by the severe acute respiratory distress syndrome. Coronavirus 2 (SARS-CoV-2) is labeled as a global pandemic by the World Health Organization (WHO) on 12th March 2020, is sweeping across the world. There has been documented evidence from China that those patients who have endocrinological disorders face additional risks from COVID-19. Healthcare professionals consider people with diabetes are at higher risk of severe illness. As such people with diabetes are not more likely to get COVID-19 than the general population, but they experience severe symptoms, complications and worse outcome even death, once infected. Hence specific measures are advised for the diabetic patients. The same goes for people with autoimmune conditions that lead to adrenal insufficiency. There may be primary (Addison’s disease), secondary or tertiary adrenal insufficiency in some patients. They regulate the blood pressure, the immune response and body’s stress response. However, nearly 5% of the population takes long-term steroids for inflammatory conditions like bronchial asthma, inflammatory bowel diseases etc.; out of which many would have some degree of insufficient adrenal response in a crisis. As it relates to COVID-19, any such patient who has been on long term corticosteroid therapy; with a dry continuous cough, breathing difficulty and fever should immediately double their daily oral steroid dose and continue this regimen until the fever has subsided. It is recommended for people with adrenal insufficiency. Apart from that, they should seek immediate medical help to avoid complications. Keywords: COVID-19; diabetes; endocrinological disorders; SARS-CoV-2

Insuficiencia suprarrenal

Adrenal insufficiency (AI) is a low-incidence disorder with high comorbidity; it is the clinical manifestation of deficient production or action of glucocorticoids, with or without deficiency also in adrenal androgens and/or mineralocorticoids, resulting from disease intrinsic to the adrenal cortex (primary AI), pituitary impairment (secondary AI) or hypothalamic disease (tertiary AI). Symptomatology varies widely depending on impairment level and deficit acuteness. Nevertheless, diagnosis requires a high suspicion level, depending entirely on the demonstration that hormonal secretion is inappropriately low using hormonal tests. Treatment goal is glucocorticoid and hormonal replacement avoiding deleterious effects caused by an excessive dosage. Hydrocortisone and fludrocortisone are the glucocorticoid and mineralocorticoid of choice, respectively. Hormone replacement screening is mainly clinical. Patients should be informed of dose adjustments in intercurrent situations. In adrenal crisis treatment has to be initiated as sooner as possible (intravenous glucocorticoid and electrolyte replacement).

Critical Care Implications of Adrenal Disease States

Adrenal disease in the critically ill patient can present many challenges for the intensivist. Besides primary, secondary, and tertiary adrenal insufficiency, a state known as critical care–related corticosteroid insufficiency (CIRCI) has been described. Adrenal insufficiency can pose many issues to the critically ill patient as it can decrease the patient’s ability to respond to the stress that critical illness presents to the human body. Proper recognition and diagnosis of adrenal insufficiency in the critically ill patient can be extremely important in the treatment of these patients and could be a lifesaving intervention if CIRCI is discovered. A less commonly encountered issue of adrenal disease lies in the area of adrenal hormone excess caused by a pheochromocytoma or extra-adrenal paragangliomas. These tumors can release large amounts of endogenous catecholamines that cause significant patient morbidity and mortality if not recognized early and treated appropriately. Although adrenal insufficiency and adrenal excess are less commonly encountered problems in critically ill patients, the recognition and treatment of these disease states can prevent the morbidity and mortality of critically ill patients that suffer from these disease states. This review contains 5 figures, 5 tables, and 89 references. Key words: adrenal insufficiency, hypothalamic-pituitary axis, critical illness–related corticosteroid insufficiency, pheochromocytoma, steroid replacement therapy