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  1. Cushing’s disease is a progressive pituitary disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. This is one of the approved medications that assist in controlling cortisol levels in people with Cushing’s disease. Recorlev Recorlev was approved by the FDA in December 2021 to treat those Cushing’s patients for whom surgery is not a choice or has failed to lower cortisol levels. The medication is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms. Recorlev (levoketoconazole) is a treatment that Strongbridge Biopharma — now acquired by Xeris Pharmaceuticals — developed for endogenous Cushing’s syndrome. Endogenous Cushing’s is a form of the disease in which symptoms occur because the body produces too much cortisol. Abnormally high cortisol levels in Cushing’s syndrome may be primarily due to a tumor in the brain’s pituitary gland — a type of the condition called Cushing’s disease. The first treatment option is surgery to remove those tumors. However, in some patients, this procedure is not an option or is ineffective at lowering cortisol levels. Recorlev was approved by the U.S. Food and Drug Administration (FDA) in December 2021 to treat those Cushing’s patients for whom surgery is not a choice or has failed to lower cortisol levels. How does Recorlev works? Cortisol plays several important roles in the body, including regulating salt and sugar levels, blood pressure, inflammation, breathing, and metabolism. Too much cortisol, however, throws the body off balance, causing a wide range of symptoms, such as obesity, high blood sugar levels, bone problems, and fatigue. Recorlev is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms. Recorlev in clinical trials Recorlev’s approval was mainly supported by data from two Phase 3 clinical trials: one called SONICS (NCT01838551) and the other LOGICS (NCT03277690). SONICS was a multicenter, open-label, three-part trial that evaluated the safety and effectiveness of Recorlev in 94 patients with endogenous Cushing’s syndrome who were not candidates for radiation therapy or surgery, and whose cortisol levels in the urine were at least 1.5 times higher than normal. Top-line data from SONICS revealed that nearly a third of patients saw their urinary cortisol levels drop to a normal range after six months of maintenance treatment with Recorlev, without requiring any dose increments in that period of time. A subgroup analysis of the study also showed Recorlev helped control cortisol and blood sugar levels in patients with both Cushing’s and diabetes. The study also showed that Recorlev was able to lessen symptoms, ease depression, and improve patients’ quality of life. LOGICS was a double-blind, randomized, withdrawal and rescue study that assessed the safety, efficacy, and pharmacological properties of Recorlev in patients with endogenous Cushing’s syndrome who had previously participated in SONICS, or who had never been treated with Recorlev. After a period of taking Recorlev, some participants were switched to a placebo while others remained on the medication. This design allowed researchers to assess the effects of treatment withdrawal. According to patients who stopped using Recorlev and moved to a placebo saw their urine cortisol levels rise in response to the lack of treatment, compared with those who remained on Recorlev. Additional data from the study also showed that patients who switched to a placebo lost Recorlev’s cholesterol-lowering benefits. Safety data from an ongoing open-label Phase 3 extension study called OPTICS (NCT03621280) also supported Recorlev’s approval. This trial, which is expected to conclude in June 2023, is designed to assess the long-term effects of Recorlev in patients who completed one or both previous studies, for up to three years. Other details Recorlev’s starting dose is 150 mg twice daily and should be taken orally with or without food. The maximum recommended dose is 1,200 mg per day, given as 600 mg twice daily. The most common side effects associated with Recorlev include nausea, vomiting, increased blood pressure, abnormally low blood potassium levels, fatigue, headache, abdominal pain, and unusual bleeding. Liver enzymes should be monitored before and during the treatment since this therapy can cause hepatotoxicity, or liver damage, in some individuals. For this reason, it is contraindicated in people with liver diseases such as cirrhosis. Recorlev should be immediately stopped if signs of hepatotoxicity are observed. Recorlev also can influence heartbeat. As such, patients with certain heart conditions should be closely monitored before and during treatment. Hypocortisolism, or lower-than-normal levels of cortisol, also may occur during treatment with Recorlev. For this reason, patients should have their cortisol levels closely monitored, and lessen or interrupt treatment if necessary. Recorlev interacts with medicines on which certain liver enzymes act, such as CYP3A4. Treatment also is an inhibitor of P-gp, OCT2, and MATE1, which are transporters of certain medicines. The use of Recorlev with these medicines may increase the risk of adverse reactions.
  2. This article is based on reporting that features expert sources. Adrenal Fatigue: Is It Real? More You may have heard of so-called 'adrenal fatigue,' supposedly caused by ongoing emotional stress. Or you might have come across adrenal support supplements sold online to treat it. But if someone suggests you have the controversial, unproven condition, seek a second opinion, experts say. And if someone tries to sell you dietary supplements or other treatments for adrenal fatigue, be safe and save your money. (GETTY IMAGES) Physicians tend to talk about 'reaching' or 'making' a medical diagnosis. However, when it comes to adrenal fatigue, endocrinologists – doctors who specialize in diseases involving hormone-secreting glands like the adrenals – sometimes use language such as 'perpetrating a diagnosis,' 'misdiagnosis,' 'made-up diagnosis,' 'a fallacy' and 'nonsense.' About 20 years ago, the term "adrenal fatigue" was coined by Dr. James Wilson, a chiropractor. Since then, certain practitioners and marketers have promoted the notion that chronic stress somehow slows or shuts down the adrenal glands, causing excessive fatigue. "The phenomenon emerged from the world of integrative medicine and naturopathic medicine," says Dr. James Findling, a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. "It has no scientific basis, and there's no merit to it as a clinical diagnosis." An online search of medical billing code sets in the latest version of the International Classification of Diseases, or the ICD-10, does not yield a diagnostic code for 'adrenal fatigue' among the 331 diagnoses related either to fatigue or adrenal conditions or procedures. In a March 2020 position statement, the American Association of Clinical Endocrinologists and American College of Endocrinology addressed the use of adrenal supplements "to treat common nonspecific symptoms due to 'adrenal fatigue,' an entity that has not been recognized as a legitimate diagnosis." The position statement warned of known and unknown health risks of off-label use and misuse of hormones and supplements in patients without an established endocrine diagnosis, as well as unnecessary costs to patients and the overall health care system. Study after study has refuted the legitimacy of adrenal fatigue as a medical diagnosis. An August 2016 systematic review combined and analyzed data from 58 studies on adrenal fatigue including more than 10,000 participants. The conclusion in a nutshell: "Adrenal fatigue does not exist," according to review authors in the journal BMC Endocrine Disorders. Adrenal Action You have two adrenal glands in your body. These small triangular glands, one on top of each kidney, produce essential hormones such as aldosterone, cortisol and male sex hormones such as DHEA and testosterone. Cortisol helps regulate metabolism: How your body uses fat, protein and carbohydrates from food, and cortisol increases blood sugar as needed. It also plays a role in controlling blood pressure, preventing inflammation and regulating your sleep/wake cycle. As your body responds to stress, cortisol increases. This response starts with signals between two sections in the brain: The hypothalamus and the pituitary gland, which act together to release a hormone that stimulates the adrenal glands to make cortisol. This interactive unit is called the hypothalamic pituitary adrenal axis. While some health conditions really do affect the body's cortisol-making ability, adrenal fatigue isn't among them. "There's no evidence to support that adrenal fatigue is an actual medical condition," says Dr. Mary Vouyiouklis Kellis, a staff endocrinologist at Cleveland Clinic. "There's no stress connection in the sense that someone's adrenal glands will all of a sudden just stop producing cortisol because they're so inundated with emotional stress." If anything, adrenal glands are workhorses that rise to the occasion when chronic stress occurs. "The last thing in the body that's going to fatigue are your adrenal glands," says Dr. William F. Young Jr., an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota. "Adrenal glands are built for stress – that's what they do. Adrenal glands don't fatigue. This is made up – it's a fallacy." The idea of adrenal glands crumbling under stress is "ridiculous," Findling agrees. "In reality, if you take a person and subject them to chronic stress, the adrenal glands don't shut down at all," Findling says. "They keep making cortisol – it's a stress hormone. In fact, the adrenal glands are just like the Energizer Bunny – they just keep going. They don't stop." Home cortisol tests that allow consumers to check their own levels can be misleading, Findling says. "Some providers who make this (adrenal fatigue) diagnosis, provide patients with testing equipment for doing saliva cortisol levels throughout the day," he says. "And then, regardless of what the results are, they perpetrate this diagnosis of adrenal fatigue." Saliva cortisol is a legitimate test that's frequently used in diagnosing Cushing's syndrome, or overactive adrenal glands, Findling notes. However, he says, a practitioner pursuing an adrenal fatigue diagnosis could game the system. "What they do is: They shape a very narrow normal range, so narrow, in fact, that no normal human subject could have all their saliva cortisol (levels) within that range throughout the course of the day," he says. "Then they convince the poor patients that they have adrenal fatigue phenomena and put them on some kind of adrenal support." Loaded Supplements How do you know what you're actually getting if you buy a dietary supplement marketed for adrenal fatigue or 'adrenal support' use? To find out, researchers purchased 12 such supplements over the counter in the U.S. Laboratory tests revealed that all supplements contained a small amount of thyroid hormone and most contained at least one steroid hormone, according to the study published in the March 2018 issue of Mayo Clinic Proceedings. "These results may highlight potential risks for hidden ingredients in unregulated supplements," the authors concluded. Supplements containing thyroid hormones or steroids can interact with a patient's prescribed medications or have other side effects. "Some people just assume they have adrenal fatigue because they looked it up online when they felt tired and they ultimately buy these over-the-counter supplements that can be very dangerous at times," Vouyiouklis Kellis says. "Some of them contain animal (ingredients), like bovine adrenal extract. That can suppress the pituitary axis. So, as a result, your body stops making its own cortisol or starts making less of it, and as a result, you can actually worsen the condition rather than make it better." Any form of steroid from outside the body, whether a prescription drug like prednisone or extract from cows' adrenal glands, "can shut off the pituitary," Vouyiouklis Kellis explains. "Because it's signaling to the pituitary like: Hey, you don't need to stimulate the adrenals to make cortisol, because this patient is taking it already. So, as a result, the body ultimately doesn't produce as much. And, so, if you rapidly withdraw that steroid or just all of a sudden decide not to take it anymore, then you can have this acute response of low cortisol." Some adrenal support products, such as herbal-only supplements, may be harmless. However, they're unlikely to relieve chronic fatigue. Fatigue: No Easy Answers If you're suffering from ongoing fatigue, it's frustrating. And you're not alone. "I have fatigue," Young Jr. says. "Go to the lobby any given day and say, 'Raise your hand if you have fatigue.' Most of the people are going to raise their hands. It's a common human symptom and people would like an easy answer for it. Usually there's not an easy answer. I think 'adrenal fatigue' is attractive because it's like: Aha, here's the answer." There aren't that many causes of endocrine-related fatigue, Young Jr. notes. "Hypothyroidism – when the thyroid gland is not working – is one." Addison's disease, or adrenal insufficiency, can also lead to fatigue among a variety of other symptoms. Established adrenal conditions – like adrenal insufficiency – need to be treated. "In adrenal insufficiency, there is an intrinsic problem in the adrenal gland's inability to produce cortisol," Vouyiouklis Kellis explains. "That can either be a primary problem in the adrenal gland or an issue with the pituitary gland not being able to stimulate the adrenal to make cortisol." Issues can arise even with necessary medications. "For example, very commonly, people are put on steroids for various reasons: allergies, ear, nose and throat problems," Vouyiouklis Kellis says. "And with the withdrawal of the steroids, they can ultimately have adrenal insufficiency, or decrease in cortisol." Opioid medications for pain also result in adrenal sufficiency, Vouyiouklis Kellis says, adding that this particular side effect is rarely discussed. People with a history of autoimmune disease can also be at higher risk for adrenal insufficiency. Common symptoms of adrenal insufficiency include: Fatigue. Weight loss. Decreased appetite. Salt cravings. Low blood pressure. Abdominal pain. Nausea, vomiting or diarrhea. Muscle weakness. Hyperpigmentation (darkening of the skin). Irritability. Medical tests for adrenal insufficiency start with blood cortisol levels, and tests for the ACTH hormone that stimulates the pituitary gland. "If the person does not have adrenal insufficiency and they're still fatigued, it's important to get to the bottom of it," Vouyiouklis Kellis says. Untreated sleep apnea often turns out to be the actual cause, she notes. "It's very important to tease out what's going on," Vouyiouklis Kellis emphasizes. "It can be multifactorial – multiple things contributing to the patient's feeling of fatigue." The blood condition anemia – a lack of healthy red blood cells – is another potential cause. "If you are fatigued, do not treat yourself," Vouyiouklis Kellis says. "Please seek a physician or a primary care provider for evaluation, because you don't want to go misdiagnosed or undiagnosed. It's very important to rule out actual causes that would be contributing to symptoms rather than ordering supplements online or seeking an alternative route like self-treating rather than being evaluated first." SOURCES The U.S. News Health team delivers accurate information about health, nutrition and fitness, as well as in-depth medical condition guides. All of our stories rely on multiple, independent sources and experts in the field, such as medical doctors and licensed nutritionists. To learn more about how we keep our content accurate and trustworthy, read our editorial guidelines. James Findling, MD Findling is a professor of medicine and director of the Community Endocrinology Center and Clinics at the Medical College of Wisconsin. Mary Vouyiouklis Kellis, MD Vouyiouklis Kellis is a staff endocrinologist at Cleveland Clinic. William F. Young Jr., MD Young Jr. is an endocrinology clinical professor and professor of medicine in the Mayo Clinic College of Medicine at Mayo Clinic in Rochester, Minnesota From https://health.usnews.com/health-care/patient-advice/articles/adrenal-fatigue-is-it-real?
  3. Published:November 18, 2021DOI:https://doi.org/10.1016/S2213-8587(21)00291-6 COVID-19 develops due to infection with SARS-CoV-2, which particularly in elderly with certain comorbidities (eg, metabolic syndrome) 1 can cause severe pneumonia and acute respiratory distress syndrome. Some patients with severe COVID-19 will develop a life-threatening sepsis with its typical manifestations including disseminated intravascular coagulation and multiorgan dysfunction. 2 Latest evidence suggests that even early treatment with inhaled steroids such as budesonide might prevent clinical deterioration in patients with COVID-19. 3 This evidence underlines the potentially important role for adrenal steroids in coping with COVID-19. The adrenal gland is an effector organ of the hypothalamic–pituitary–adrenal axis and the main source of glucocorticoids, which are critical to manage and to survive sepsis. Therefore, patients with pre-existing adrenal insufficiency are advised to double their doses of glucocorticoid supplementation after developing moderate to more severe forms of COVID-19. 4 • View related content for this article Adrenal glands are vulnerable to sepsis-induced organ damage and their high vascularisation and blood supply makes them particularly susceptible to endothelial dysfunction and haemorrhage. Accordingly, adrenal endothelial damage, bilateral haemorrhages, and infarctions have been already reported in patients with COVID-19. 5 Adrenal glands contain the highest concentration of antioxidants to compensate enhanced generation of reactive oxygen species, side products of steroidogenesis, which together with elevated intra-adrenal inflammation can contribute to adrenocortical cell death. 6 Furthermore, sepsis-associated critical illness-related corticosteroid insufficiency, which describes coexistence of the hypothalamic–pituitary–adrenal dysfunction, reduced cortisol metabolism, and tissue resistance to glucocorticoids, was reported in critically ill patients with COVID-19. 7 Low cortisol and adrenocorticotropic hormone (ACTH) responses during acute phase of infections consistent with critical illness-related corticosteroid insufficiency diagnosis (random plasma cortisol level lower than 10 μg/dL) were reported in one study with patients suffering from mild to moderate COVID-19 manifestations. 8 It is however possible those other factors triggered by COVID-19 such as hypothalamic or pituitary damage, adrenal infarcts, or previously undiagnosed conditions, such as antiphospholipid syndrome, might be responsible for reduced function of adrenal glands. However, contrary to this observation, a study with patients with moderate to severe COVID-19 revealed a very high cortisol response with values exceeding 744 nmol/L, which were positively correlated with severity of disease. 9 In this clinical study, 9 highly elevated cortisol concentrations showed an adequate adrenal cortisol production possibly reflecting the elevated stress level of those severely affected patients. 9 However, since ACTH measurements were not done, it is impossible to verify whether high concentrations of cortisol in those patients resulted from an increment of cortisol, or were confounded by reduced glucocorticoid metabolism. 9 A critical and yet unsolved major question is whether SARS-CoV-2 infection can contribute either directly or indirectly to adrenal gland dysfunction observed in some patients with COVID-19 or contribute to the slow recovery of some patients with long COVID. We performed a comprehensive histopathological examination of adrenal tissue sections from autopsies of patients that died due to COVID-19 (40 cases), collected from three different pathology centres in Regensburg, Dresden, and Zurich (appendix pp 1–3). We observed evidence of cellular damage and frequently small vessel vasculitis (endotheliitis) in the periadrenal fat tissue (six cases with low and 13 cases with high density; appendix p 10) and much milder occurrence in adrenal parenchyma (ten cases with low and one case with moderate score; appendix p 10), but no evidence of thrombi formation was found (appendix p 10). Endotheliitis has been scored according to a semi-quantitative immunohistochemistry analysis as described in the appendix (p 4). Additionally, in the majority of cases (38 cases), we noticed enhanced perivascular lymphoplasmacellular infiltration of different density and sporadically a mild extravasation of erythrocytes (appendix p 10). However, no evidence of widespread haemorrhages and degradation of adrenocortical cells were found, which is consistent with histological findings reported previously. 5 In another autopsy study analysing adrenal glands of patients with COVID-19, additional signs of acute fibrinoid necrosis of small vessels in adrenal parenchyma, subendothelial vacuolisation and apoptotic debris were found. 5 Adrenal gland is frequently targeted by bacteria and viruses, including SARS-CoV, 10 which was responsible for the 2002–04 outbreak of SARS in Asia. Considering that SARS-CoV-2 shares cellular receptors with SARS-CoV, including angiotensin-converting enzyme 2 and transmembrane protease serine subtype 2, its tropism to the adrenal gland is therefore conceivable. To investigate whether adrenal vascular cells and possibly steroid-producing cells are direct targets of SARS-CoV-2, we examined SARS-CoV-2 presence in adrenal gland tissues obtained from the 40 patients with COVID-19 (appendix pp 1–3). Adrenal tissues from patients who died before the COVID-19 pandemic were used as negative controls to validate antibody specificity. Using a monoclonal antibody (clone 1A9; appendix p 11), we detected SARS-CoV-2 spike protein in adrenocortical cells in 18 (45%) of 40 adrenal gland tissues (figure B; appendix p 12). In the same number of adrenal tissues (18 [45%] of 40), we have detected SARS-CoV-2 mRNA using in situ hybridisation (ISH; figure A; appendix p 12). The concordance rate between immunohistochemistry and ISH methods was 90% (36/40). Scattered and rather focal expression pattern of SARS-CoV-2 spike protein was found in the adrenal cortex (figure A and B; appendix p 12). In addition, SARS-CoV-2 expression was confirmed in 15 out of 30 adrenal gland tissues of patients with COVID-19 by multiplex RT-qPCR (appendix pp 6–7). The concordance between ISH, immunohistochemistry, and RT-qPCR techniques for SARS-CoV-2 positivity was only 23%, which is a technical limitation of our study possibly reflecting the low number of virus-positive cells. However, when considering triple-negative samples, an overall 53% consensus was found (appendix pp 7–8). FigureDetection of SARS-CoV-2 in human adrenal gland from a patient who died due to COVID-19 Show full caption View Large Image Figure Viewer Download Hi-res image Download (PPT) Finally, to confirm the identity of infected cells, we have performed an ultrastructural analysis of adrenal tissue from a triple-positive patient case (by immunohistochemistry, ISH, and RT-qPCR), and found numerous SARS-CoV-2 virus-like particles in cells enriched with liposomes, which are typical markers of adrenocortical cells (figure C). The cortical identity of SARS-CoV-2 spike positive cells was also shown using serial tissue sections, demarcating regions with double positivity for viral protein and StAR RNA (appendix p 12). Furthermore, susceptibility of adrenocortical cells to SARS-CoV-2 infection was confirmed by in-vitro experiments (appendix p 7) showing detection of viral spike protein in adrenocortical carcinoma cells (NCI-H295R) cultured in a medium containing SARS-CoV-2 (figure D), and its absence in mock-treated control cells (figure E). We showed an uptake of viral particles in the adrenocortical cells, by ISH, immunohistochemistry, RT-qPCR and electron microscopy (figure A–C). Mechanistically, an uptake of SARS-CoV-2 like particles might involve expression of ACE2 in vascular cells (appendix p 13) and perhaps of the shorter isoform of ACE2 together with TMPRSS2 and other known or currently unknown virus-entry facilitating factors in adrenocortical cells (appendix p 13). An example of such factor is scavenger receptor type 1, which is highly expressed in adrenocortical cells. 11 Several forms of regulated cell necrosis were implicated in sepsis-mediated adrenal gland damage. 6 One of the prime examples of regulated necrosis triggered by sepsis-associated tissue inflammation is necroptosis. The necrotic process is characterised by loss of membrane integrity and release of danger-associated molecular patterns, which further promote tissue inflammation (necroinflammation) involving enhanced activation of the complement system and related activation of neutrophils. Whether necroptosis might be involved in COVID-19-associated adrenal damage is currently unknown. In our study, we showed prominent expression of phospho Mixed Lineage Kinase Domain Like Pseudokinase (pMLKL) indicating necroptosis activation in adrenomedullary cells (appendix p 14) in adrenal glands of COVID-19 patients. However, since we have also observed pMLKL expression in adrenal glands obtained from autopsies done before the COVID-19 pandemic (controls), necroptosis activation in medullary cells might be a rather frequent and SARS-CoV-2 independent event. However, contrary to the adrenal medulla, pMLKL positivity in the adrenal cortex was only found in virus-positive regions (appendix p 14). This finding suggests that SARS-CoV-2 infection might have directly triggered activation of necroptosis in infected cells in the adrenal cortex, whereas pMLKL expression in the adrenal medulla seems rather an indirect consequence of systemic inflammation. In summary, in our study of 40 patients who died from COVID-19, we did not observe widespread degradation of human adrenals that might lead to manifestation of the adrenal crisis. However, our study shows that the adrenal gland is a prominent target for the viral infection and ensuing cellular damage, which could trigger a predisposition for adrenal dysfunction. Whether those changes directly contribute to adrenal insufficiency seen in some patients with COVID-19 or lead to its complications (such as long COVID) remains unclear. Large multicentre clinical studies should address this question. WK, HC, and SRB declare funds from Deutsche Forschungsgemeinschaft (project number 314061271, TRR 205/1 [“The Adrenal: Central Relay in Health and Disease”] to WK and SRB; HA 8297/1-1 to HC), during the conduct of this Correspondence. All other authors declare no competing interests. We thank Maria Schuster, Linda Friedrich, and Uta Lehnert for performing some of the immunohistochemical staining and in-situ hybridisation. Supplementary Material Download .pdf (1.48 MB) Help with pdf files Supplementary appendix References 1. Bornstein SR Rubino F Khunti K et al. Practical recommendations for the management of diabetes in patients with COVID-19. Lancet Diabetes Endocrinol. 2020; 8: 546-550 View in Article Scopus (382) PubMed Summary Full Text Full Text PDF Google Scholar 2. Li H Liu L Zhang D et al. SARS-CoV-2 and viral sepsis: observations and hypotheses. Lancet. 2020; 395: 1517-1520 View in Article Scopus (507) PubMed Summary Full Text Full Text PDF Google Scholar 3. Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med 202; 9: 763–72. View in Article Google Scholar 4. Isidori AM Pofi R Hasenmajer V Lenzi A Pivonello R Use of glucocorticoids in patients with adrenal insufficiency and COVID-19 infection. Lancet Diabetes Endocrinol. 2020; 8: 472-473 View in Article Scopus (23) PubMed Summary Full Text Full Text PDF Google Scholar 5. Iuga AC Marboe CC Yilmaz MM Lefkowitch JH Gauran C Lagana SM Adrenal vascular changes in COVID-19 autopsies. Arch Pathol Lab Med. 2020; 144: 1159-1160 View in Article Scopus (17) PubMed Crossref Google Scholar 6. Tonnus W Gembardt F Latk M et al. The clinical relevance of necroinflammation-highlighting the importance of acute kidney injury and the adrenal glands. Cell Death Differ. 2019; 26: 68-82 View in Article Scopus (7) PubMed Crossref Google Scholar 7. Hashim M Athar S Gaba WH New onset adrenal insufficiency in a patient with COVID-19. BMJ Case Rep. 2021; 14e237690 View in Article Scopus (0) PubMed Crossref Google Scholar 8. Alzahrani AS Mukhtar N Aljomaiah A et al. The impact of COVID-19 viral infection on the hypothalamic-pituitary-adrenal axis. Endocr Pract. 2021; 27: 83-89 View in Article PubMed Summary Full Text Full Text PDF Google Scholar 9. Tan T Khoo B Mills EG et al. Association between high serum total cortisol concentrations and mortality from COVID-19. Lancet Diabetes Endocrinol. 2020; 8: 659-660 View in Article Scopus (69) PubMed Summary Full Text Full Text PDF Google Scholar 10. Ding Y He L Zhang Q et al. Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol. 2004; 203: 622-630 View in Article Scopus (606) PubMed Crossref Google Scholar 11. Wei C Wan L Yan Q et al. HDL-scavenger receptor B type 1 facilitates SARS-CoV-2 entry. Nat Metab. 2020; 2: 1391-1400 View in Article Scopus (52) PubMed Crossref Google Scholar Article Info Publication History Published: November 18, 2021 Identification DOI: https://doi.org/10.1016/S2213-8587(21)00291-6 From https://www.thelancet.com/journals/landia/article/PIIS2213-8587(21)00291-6/fulltext
  4. Cushing’s syndrome patients with tumors on both adrenal glands — which sit on top of the kidneys — could undergo adrenal venous sampling, a procedure where blood samples are taken from both adrenal glands to determine which tumors to remove, researchers suggest. Their study, “Outcomes of Adrenal Venous Sampling in Patients with Bilateral Adrenal Masses and ACTH-Independent Cushing’s Syndrome,” was published in the World Journal of Surgery. The work was a collaboration between SUNY Upstate Medical University in Syracuse and the University of Pittsburgh. Cushing’s syndrome, a condition characterized by excess cortisol, can be divided into two main subtypes. In some patients, the disease is dependent on tumors secreting the adrenocorticotropic hormone (ACTH), which stimulates the release of cortisol from the adrenal glands. In others, adrenal tumors are solely responsible for excess cortisol and do not require ACTH for functioning. ACTH-independent Cushing’s syndrome (AICS), the latter subtype, constitutes about 10% to 15% of endogenous — an overproduction of cortisol within the body — Cushing’s syndrome cases, with cortisol-secreting adenomas in just one gland (unilateral) being the most common cause. Compared to unilateral adenomas, adrenal tumors in both glands (bilateral) in patients with AICS are difficult to diagnose. Disease management in these rare cases depends on the challenging determination of the lesion’s exact location and of the functional status of the benign tumors (if they are actively secreting cortisol). Surgical removal of both adrenal glands, also known as bilateral adrenalectomy, “ensures cure of AICS, but leads to permanent corticosteroid dependence and a lifelong risk of adrenal crisis,” investigators explained. Therefore, screening for the presence of unilateral or bilateral adenomas is essential to avoid unnecessary surgery. “Adrenal venous sampling (AVS) has been reported in a single institutional series … to aid in successful localization of cortisol-secreting adrenal adenomas in patients with bilateral adrenal masses and AICS,” researchers wrote. Researchers retrospectively assessed the usefulness of AVS in guiding management of patients with bilateral adrenal masses plus AICS. Nine women (age 51-73) with bilateral adrenal masses and AICS were included in the study. All subjects had undergone AVS at the University of Pittsburgh Medical Center from 2008 to 2016. None of the patients had apparent symptoms of Cushing’s syndrome. “Samples were obtained for testing of epinephrine [also called adrenaline] and cortisol from both [adrenal veins] and the external iliac vein. Multiple samples were obtained to ensure adequate sampling,” they wrote. Adrenal glands produce cortisol and epinephrine, among other hormones, which are critical for maintaining good health. In AICS, there’s an overproduction of both hormones that’s independent on the release of ACTH, which is produced by the brain’s pituitary gland. Successful adrenal venous sampling was achieved in eight women. “One patient with unsuccessful catheterization had [other additional diseases] and passed away from unrelated reasons,” researchers reported. AVS results indicated that all patients had bilateral cortisol-secreting adenomas. “Surgical management was strongly influenced by adrenal mass size. However, AVS may have influenced surgical decision-making in some cases, particularly when minimal difference in size was noted in adrenal mass sizes,” they reported. Six women underwent adrenalectomy: three had the gland with larger size mass removed (unilateral type of surgery); two had both glands removed; and one had the right gland removed followed by the left one, five months later, due to continuous hormonal overproduction without experiencing symptoms of Cushing’s syndrome. Evidence suggests that removal of the larger adrenal mass in patients with bilateral cortisol-secreting adenomas improves Cushing’s syndrome presentation. In theory, unilateral adrenalectomy reduces cortisol production through the removal of the oversecreting mass. Because of this, unilateral adrenalectomy of the larger adrenal mass was chosen in half of this study’s surgical cases, instead of bilateral adrenalectomy. Tissue analysis revealed multiple-lump masses, also known as macronodular adrenal hyperplasia (MAH), in all six surgical cases. In addition, computed tomography (CT) scan findings were predictive of bilateral MAH, with scans showing evidence of one or multiple nodules on one or both adrenal glands. “To the best of our knowledge, this is the second study to evaluate the utility of AVS in guiding management of patients with bilateral adrenal masses and AICS,” investigators said. The first study was by Young and included 10 patients with a more severe presentation of Cushing’s syndrome and other individual characteristics, which contributed to the differences in results, compared to the current study. In Young’s study, half the subjects had unilateral adrenal masses. Patients with bilateral cortisol-secreting masses frequently have a milder form of Cushing’s syndrome, which corroborates researchers’ findings. Despite suggesting that adrenal venous sampling is useful in excluding a unilateral adenoma as the cause of AICS, this study’s sample size is small. “More data are needed before AVS can be advocated as essential for management of patients with bilateral adrenal masses and AICS,” researchers concluded. From https://cushingsdiseasenews.com/2018/10/02/adrenal-venous-sampling-helps-surgical-decisions-type-cushings-syndrome/?utm_source=Cushing%27s+Disease+News&utm_campaign=a990429aad-RSS_WEEKLY_EMAIL_CAMPAIGN&utm_medium=email&utm_term=0_ad0d802c5b-a990429aad-72451321
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