Diagnosis Of Relative Adrenal Insufficiency Research Articles

Endocrinology for the hepatologist.

Endocrinology for the hepatologist.

HYPOCORTISOLISM IN A PATIENT WITH COVID-19: A CASE REPORT AND DISCUSSION ON MANAGEMENT

TOPIC: Critical Care TYPE: Medical Student/Resident Case Reports INTRODUCTION: Long COVID- 19 or post-acute COVID -19 syndrome is now recognized as a range of symptoms that can last weeks or months after first being infected with COVID-19 or SARS -CoV 2 virus. It can appear weeks after infection irrespective of the severity of the illness1. It can affect most, if not all, body systems including heart, lung, kidney, skin, and brain functions. Here we present a case with Covid-19 infection with hyporcortisolism presenting as dyspnea and fatigue as the dominant long Covid-19 symptom. CASE PRESENTATION: A 55-year-old female with a past medical history of hyperthyroidism on propranolol, was diagnosed with mild COVID -19 infection, advised to treat with self-isolation. She revisited ER 6 weeks later with persistent dyspnea, fatigue, and poor ability to focus and concentrate. She was given a trial of the direct oral anticoagulant for 4 weeks with no change in her symptoms. The subsequent workup done;head-computer tomography scan (CTS) was negative for subarachnoid hemorrhage and cerebral venous thrombosis. The Lungs CTS did not reveal any pulmonary fibrosis. The 6-minute walk test was impaired at 79%. The Pulmonary Function test did not show any significant obstruction or restriction. The Cardiopulmonary Exercise Test overall was suggestive of deconditioning. The laboratory work included creatine kinase, Aldolase, vitamin B12, Folic acid, C-reactive protein, Vitamin D, Antinuclear antibody Thyroid Function test all were unremarkable. The AM cortisol level came back as less than 2. The patient was started on oral prednisone for a diagnosis of relative adrenal insufficiency. All her symptoms improved within 2 weeks of treatment and resolved after 4 -6 weeks, she was tapered down and finally weaned off prednisone. DISCUSSION: The proposed mechanism of COVID-19 induced relative adrenal insufficiency is likely hypophysitis.2 The principal target for the virus entry is the angiotensin-converting Enzyme 2 (ACE-2) receptor which is found on pneumocytes, arterial and venous endothelial cells of many organs including adrenal glands and hypothalamic and pituitary tissues2. Furthermore, SARS- Cov2 virus has amino acid sequences which are similar to the host's ACTH, so antibodies made against the virus destroys the host ACTH and consequently may cause contribute to cortisol insufficiency.2,3 CONCLUSIONS: Post COVID-19 infection has a multifaceted manifestation. Hypocortisolism can persist in patients with post COVID-19 and should be sought for if the symptoms are suggestive. The treatment is simple and effective. REFERENCE #1: Naserghandi, S.F. Allameh and R. Saffarpour. All about COVID-19 in brief. New Microbes New Infect. 2020 May;35: 100678. Published online 2020 Apr 13. doi: 10.1016/j.nmni.2020.100678 PMID: 32292590. REFERENCE #2: Pal, R. COVID-19, hypothalamo-pituitary-adrenal axis and clinical implications. Endocrine 68, 251–252 (2020). https://doi.org/10.1007/s12020-020-02325-1. REFERENCE #3: R. Wheatland, Molecular mimicry of ACTH in SARS—implications for corticosteroid treatment and prophylaxis. Med. Hypoth. 63, 855–862 (2004) PMID: 15488660. DISCLOSURES: No relevant relationships by Parinaz Ayat, source=Web Response No relevant relationships by Aaliya Burza, source=Web Response No relevant relationships by Charlyn Habeeb, source=Web Response

STUDY OF ADRENAL INSUFFICIENCY IN SEVERE FALCIPARUM MALARIA WITH SHOCK KEY WORDS: Falciparum Malaria, Shock, Adrenal

Malaria remains a serious health problem in South East Asian Region (SEAR) with nearly 290 million people are estimated to be at high risk.India accounts for 77% of the regional total malarial cases.Most of deaths in malaria are due to severe falciparum malaria. Odisha is a unique state in the eastern region of India, which contributes 4% of the population and counting up to >40% of total falciparum malaria cases of India. Malaria is one of the most important public health disease in Odisha. In spite of such an important disease, there are many areas on severe falciparum malarias where research work is scanty. One among of them is detection of relative adrenal insufficiency in severe falciparum malaria. As there is limited work about the relative adrenal insufficiency in severe falciparum malaria with shock and its relation to mortality. This study has been undertaken with the following aims and objectives, firstly detection of relative adrenal insufficiency in severe falciparum malaria with shock and secondly to establish the relation of mortality with or without adrenal insufficiency in severe falciparum malaria.The present study has established that relative adrenal insufficiency is an important cause contributing to shock and increased mortality. Thus addition of corticosteroid saves life and must be used in the relative adrenal insufficiency. However the firm diagnosis of relative adrenal insufficiency depends upon estimation of basal serum cortisol level & post ACTH serum cortisol level. As corticosteroid reduces the mortality rate, it should be empirically used in critically ill severe falciparum malaria cases with shock.

Including Relative Adrenal Insufficiency in Definition and Classification of Acute-on-Chronic Liver Failure

Relative adrenal insufficiency (RAI) is defined by insufficient production of cortisol relative to organ demand. RAI is observed frequently in hospitalized patients with cirrhosis, but there is disagreement over the clinical effects of RAI in these patients. We evaluated the prevalence and the clinical effects of RAI in hospitalized patients with cirrhosis. We performed a prospective study of 160 patients admitted to a hospital in Italy for acute decompensation of cirrhosis from May 2011 through September 2016. Patients were followed up until death, liver transplantation, or a maximum of 90 days. Serum and salivary levels of cortisol were measured before and after a 1-hour Short Synacthen Test. A diagnosis of RAI was given to patients with an increase in serum cortisol of less than 9 μg/dL, after Synacthen administration, in patients with baseline serum levels of cortisol less than 35 μg/dL. We collected blood samples before the Synacthen test and analyzed them for blood cell counts, liver and renal function, levels of C-reactive protein, and lipid profiles (total cholesterol, high-density lipoprotein cholesterol, apolipoprotein-A1). A diagnosis of RAI was made for 78 patients (49%). Age (odds ratio [OR], 0.95; P= .030), number of leukocytes (OR, 3.10; P= .006), and levels of high-density lipoprotein cholesterol (OR, 0.30; P= .039) were associated independently with RAI. Patients with RAI had a significantly higher risk of developing bacterial infections (hazard ratio [HR], 1.60; P= .038), sepsis (HR, 2.95; P= .001), septic shock (HR, 4.94; P= .038), new organ failures (HR, 2.45; P= .014), and acute-on-chronic liver failure (HR, 2.27; P= .037) than patients without RAI. RAI was associated independently with death within 90 days of diagnosis (subdistribution HR, 4.83; P= .001). Patients with RAI and mild renal dysfunction or hepatic encephalopathy had no significant difference in cumulative incidence of 28-day mortality vs patients with acute-on-chronic liver failure grade 1 (25% vs 22%). We found RAI to occur in almost half of patients admitted to a hospital for acute decompensation of cirrhosis. RAI was associated with a deficit of substrates for steroidogenesis and an increase in markers of inflammation. Patients with RAI have a high risk of developing sepsis, septic shock, organ failure, and death within 90 days. RAI has similar prognostic value to nonrenal organ failures.

Neonatal adrenal insufficiency: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report.

It is difficult to make a diagnosis of adrenal insufficiency in the newborn, because the clinical findings are not specific and the normal serum cortisol level is far lower compared to children and adults. However, dehydratation, hyperpigmentation, hypoglycemia, hyponatremia, hyperkalemia and metabolic acidosis should suggest the diagnosis of adrenal insufficiency. Hypotension which does not respond to vasopressors should especially be considered a warning. If the adrenocorticotropin hormone level measured simultaneously with a low serum cortisol level is 2-fold higher than the upper normal limit of the reference range, a diagnosis of primary adrenal insufficiency is definite. Even if the serum cortisol level is normal, a diagnosis of relative adrenal insufficiency can be made with clinical findings, if the patient is under heavy stress. The serum cortisol level should be measured using the method of ‘high pressure liquid chromatography’ or ‘LC mass spectrometry’. Adrenal steroid biosynthesis can be evaluated more specifically and sensitively with ‘steroid profiling’. Rennin and aldosterone levels may be measured in addition to serum electrolytes for the diagnosis of mineralocorticoid insufficiency. Adrenocorticotropic hormone stimulation test may be used to confirm the diagnosis and elucidate the etiology. In suspicious cases, treatment can be initiated without waiting for the adrenocorticotropic hormone stimulation test. In schock which does not respond to vasopressors, intravenous hydrocortisone at a dose of 50-100 mg/m2 or a glucocorticoid drug at an equivalent dose should be initiated. In maintanence treatment, the physiological secretion rate of hydrocortisone is 6 mg/m2/day (15 mg/m2/day in the newborn). The replacement dose should be adjusted with clinical follow-up and by monitoring growth rate, weight gain and blood pressure. Fludrocortisone (0,1 mg tablet) is given for mineralocorticoid treatment (2x0,5-1 tablets). A higher dose may be needed in the neonatal period and in patients with aldosterone resistance. If hyponatremia persists, oral NACl may be added to treatment. In the long-term follow-up, patients should carry an identification card and the glucocorticoid dose should be increased 3-10-fold in cases of stress.

Defining normal adrenal function testing in the intensive care unit setting: A canine study*

To determine whether intensive care medicine therapies and testing influence hypothalamic-pituitary-adrenal test results. It is routine in intensive care medicine to measure hypothalamic-pituitary-adrenal function, commonly utilizing the adrenocorticotropic hormone stimulation test to diagnose absolute or relative adrenal insufficiency. Prospective, 96-hr animal study. Research laboratory. Twenty-four healthy canines. Animals were randomized into two groups--awake and unrestrained or treated with intensive care medicine therapies, including sedation, intubation, and mechanical ventilation. Animals were further randomized to receive dexamethasone (or placebo) or undergo either a total of four or seven adrenocorticotropic hormone stimulation tests over 96 hrs. Sedation, intubation, and mechanical ventilation transiently increased both basal and postadrenocorticotropic hormone total and free cortisol concentrations >2-fold as compared with baseline for the first 24 hrs (p < or = .05 for both). Performance of seven stimulation tests increased both basal and postadrenocorticotropic hormone total and free cortisol concentrations from baseline by >1.5-fold for the duration of the 96-hr study (p < or = .05). Neither sedation, intubation, and mechanical ventilation nor the performance of more stimulation tests affected delta cortisol measurements (total or free cortisol, p = NS). In contrast, dexamethasone suppressed basal total cortisol concentrations by >2-fold (p < or = .005) at all time points and transiently increased delta total cortisol by approximately 35% during the first 24 hrs of the study (p < or = .05). Total and free cortisol measurements--whether pre- or post- adrenocorticotropic hormone or as a calculated delta--were altered by intensive care therapies or frequent adrenocorticotropic hormone stimulation testing with one exception. Delta free cortisol was the only hypothalamic-pituitary-adrenal measurement unaffected by sedation, intubation, and mechanical ventilation, completion of more adrenocorticotropic hormone stimulation tests, or dexamethasone therapy. These findings support the need to determine normal ranges for hypothalamic-pituitary-adrenal testing in subjects receiving intensive care medicine before establishing laboratory criteria for the diagnosis of relative adrenal insufficiency.

Transient adrenal insufficiency in the premature newborn

Relative adrenal insufficiency is a controversial phenomenon described in adults and children with critical illness, especially septic shock. In the past 2 decades, relative adrenal insufficiency has also been reported in the critically ill premature as well as term newborn. The present study will review the initial and more recent studies addressing adrenal insufficiency in the premature infant. Studies suggest that 'relative adrenal insufficiency' is a contributing factor to hemodynamic instability in the sick preterm newborn. Many ill preterm newborns have inappropriately low serum cortisol concentrations and respond to steroid administration. Adrenal insufficiency is transient and likely reflects normal adrenal physiology at younger gestational ages. There is no general consensus on its diagnosis, effective minimum dose for treatment and duration of treatment. More large scale, multicenter, randomized, double-blind studies are needed to make the diagnosis of relative adrenal insufficiency and to determine the indication, dose, complications and outcome of glucocorticoid therapy.

Insuficiência adrenal relativa no choque séptico: comparação da resposta ao tratamento com hidrocortisona em pacientes diagnosticados através de dosagem única do cortisol plasmático versus teste da corticotropina

The incidence of relative adrenal insufficiency (RAI) in patients with septic shock is high and has a significant impact on survival. The purpose of this study was to determine whether a random cortisol concentration < 25 mg/dL was as good as a low dose (1 mg) corticotrophin stimulation test in the diagnosis of RAI in patients with septic shock as assessed by the hemodynamic response to hydrocortisone. Patients were randomized to a single cortisol determination or to a low dose corticotrophin stimulation test. After blood collection to cortisol determinations, hydrocortisone (100 mg every 8 hrs) was administered for all patients in the first 36 hours. RAI was defined by a random cortisol concentration < 25 mg/dL or a D cortisol concentration < 9 mg/dL in the corticotrophin test. Sixty patients (G1 = 30; G2 = 30) were included in the analysis and were comparable regarding to demographic data, nosologies and disease severity. The time to norepinephrin withdrawal in group 1 patients with RAI diagnostic criteria was not different from the patients with cortisol > 25 mg/dL. In group 2 patients with D cortisol < 9 mg/dL had a shorter time of norepinephrin infusion (3 days) compared to patients with D cortisol > 9 (6 days). This study suggests that 1 mg corticotrophin test is better than a random cortisol determination < 25 mg/dL to the diagnosis of relative adrenal insufficiency in septic shock patients.

Hypothalamo-pituitary-adrenal axis activity after intracranial catastrophies: what is enough?

This commentary on a paper by Bendel and colleagues in the previous issue of Critical Care describes the difficulty in assessing the sufficiency of adrenal responses to endogenous, stress-induced adrenocorticotropic hormone (ACTH) release by the pituitary or to exogenous ACTH administration in the critically ill patient in general, and after subarachnoid hemorrhage in particular. It is argued that comparisons with responses under circumstances of equal stress as well as assessments of severity of disease are necessary to judge the sufficiency of cortisol responses to endogenous and exogenous ACTH before treatment is considered. There are no universally applicable cutoff values for cortisol levels – and increases in cortisol levels with increasing levels of ACTH – for the diagnosis of relative adrenal insufficiency (or as it is now commonly termed, critical illnes-related corticosteroid insufficiency) following, for example, subarachnoid hemorrhage or other intracranial catastrophes. The paper by Bendel and colleagues is critically discussed in view of these concepts.

The Diagnosis of Relative Adrenal Insufficiency: The Long and Winding Road…

The Diagnosis of Relative Adrenal Insufficiency: The Long and Winding Road…

The Diagnosis of Relative Adrenal Insufficiency: The Long and Winding Road…

The Diagnosis of Relative Adrenal Insufficiency: The Long and Winding Road…

Variability of cortisol assays can confound the diagnosis of adrenal insufficiency in the critically ill population

To compare the total plasma cortisol values obtained from three widely used immunoassays and a high pressure liquid chromatography (HPLC) technique on samples obtained from patients with sepsis. Observational interventional in the general intensive care unit of a metropolitan hospital Patients admitted to the intensive care unit with a diagnosis of sepsis and fulfilling criteria of systemic inflammatory response syndrome. Standard short synacthen test performed with 250microg cosyntropin. Two of the three immunoassays returned results significantly higher than those obtained by HPLC: Immulite by 95% (95%CI 31-188%) and TDx by 79% (21-165%). The limits of agreement for all three immunoassays with HPLC ranged from -62% to 770%. In addition, by classifying the patients into responders and non-responders to ACTH by standard criteria there was concordance in all assays in only 44% of patients. Immunoassay estimation of total plasma cortisol in septic patients shows wide assay related variation that may have significant impact in the diagnosis of relative adrenal insufficiency.

Relative adrenal insufficiency in patients with septic shock; a close look to practice patterns

Purpose To assess patterns of practice in our institution specifically regarding corticosteroid deficiency diagnosis in patients with septic shock. Methods Consecutive adult patients with vasopressor-dependent septic shock admitted to the medical intensive care unit between January 2002 and September 2003 were studied. Relative adrenal insufficiency (RAI) was diagnosed by a random serum cortisol level ≤15 μg/dL or by a random cortisol level between 15 and 34 μg/dL and an increase in response to cosyntropin stimulation test (250 μg) ≤9 μg/dL. Results Ninety-two patients were included in the study. Mean (±SD) age was 59 ± 18 years. Overall mortality was 53%. Relative adrenal insufficiency was suspected in 44 (48%) patients and confirmed in 25 (57%). Maximal doses of vasopressors were comparable between groups but more patients in whom AI was suspected were on phenylephrine and/or vasopressin and more were treated with activated protein C ( P < .05). Diagnosis of RAI was confirmed by a low basal cortisol (<15 μg/dL) in 12 (48%) patients, whereas a diagnosis of RAI was made by a lack of response to the stimulation test in the rest. Conclusions Relative adrenal insufficiency was diagnosed in half of the patients investigated. Patients with presumed RAI were more likely to be on phenylephrine or vasopressin infusions and treated with activated protein C and had a longer intensive care unit stay but no difference in intensive care unit survival.

Cortisol Response in Relation to the Severity of Stress and Illness

The aim of the study was to compare the adrenal response, the course of the ACTH/cortisol ratio, as well as the variance and the diagnostic performance of different cutoffs after 1 and 250 microg ACTH stimulation in different stress situations. We investigated three groups with increasing stress levels: ambulatory controls (group A; n = 20), hospitalized medical patients (group B; n = 25), and patients undergoing coronary artery bypass grafting (group C; n = 29). All subjects underwent four consecutive ACTH stimulation tests and were randomized to either a 1- or 250-microg dose. Stimulated cortisol levels in group A were similar to basal cortisol levels under maximal stress (C3; P = 0.8). Peak cortisol concentrations were higher after 250 microg compared with 1 microg ACTH in group B (P = 0.006) and under maximal stress after extubation (group C3; P = 0.027), whereas there were no differences in group A. The ACTH/cortisol ratio was lower in surgical patients after extubation compared with unstressed conditions (P < or = 0.03) The within-subject variance was similar in ambulatory controls and medical patients and after both ACTH doses (all 17-36% of total variance). Cutoff dependent, the diagnosis of relative adrenal insufficiency would have been made in 0-58.3%, respectively. In moderate and major stress situations, cortisol concentrations in patients without hypothalamic-pituitary-adrenal disease were higher after stimulation with 250 microg compared with 1 mug ACTH. Data from our study give insight into the physiological adaptations of the hypothalamic-pituitary-adrenal axis to stress.

Corticosteroid Therapy in Patients with Severe Sepsis and Septic Shock

Corticosteroids have been considered for decades for the treatment of severe sepsis and septic shock, based on their pivotal role in the stress response and their hemodynamic and antiinflammatory effects. Whereas short-term therapy with high doses of corticosteroids (up to 42 g hydrocortisone equivalent for 1-2 days) has been ineffective or potentially harmful, prolonged therapy with lower doses (200-300 mg hydrocortisone for 5-7 days or longer) in septic shock has recently revealed beneficial effects in several randomized, controlled trials. Assuming relative adrenal insufficiency (RAI) and peripheral cortisol resistance, treatment with low-dose hydrocortisone improved shock reversal, reduced inflammation, and improved outcome. Shock reversal and reduction of mortality were more effective in patients with RAI, and most significant in patients with severe shock. Diagnosis of RAI with corticotropin tests in septic shock, however, is highly dependent on cut-off values and definition of RAI. Thus, it is not clear yet which patients benefit most from low-dose hydrocortisone and if treatment should be restricted to patients with RAI. In addition the role of fludrocortisone is uncertain. Nevertheless, based on current data, low-dose hydrocortisone therapy should definitely be considered in vasopressor-dependent septic shock. This review will address some critical points.