Adrenal Insufficiency Induced by Tislelizumab in a Patient with Advanced Esophageal Squamous Cell Carcinoma: Case Report

Adrenal Insufficiency Induced by Tislelizumab in a Patient with Advanced Esophageal Squamous Cell Carcinoma: Case Report | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Adrenal Insufficiency Induced by Tislelizumab in a Patient with Advanced Esophageal Squamous Cell Carcinoma: Case Report Li Lanyan, Liu Zhaobi, Zheng Hong This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7512846/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The recently updated guidelines from the National Comprehensive Cancer Network recommend the combination of tislelizumab and chemotherapy as a standard first-line treatment for patients with advanced esophageal squamous cell carcinoma(ESCC).However, concerns regarding the safety profile of tislelizumab have persisted.We report a case of a 71-year-old patient with advanced ESCC who developed adrenal insufficiency following tislelizumab administration. Biochemical evaluation revealed isolated adrenocorticotropic hormone༈ACTH༉deficiency, consistent with secondary adrenal insufficiency induced by tislelizumab.Nonetheless, patients with adrenal insufficiency receiving glucocorticoid therapy may require dose adjustment during physiologically stressful situations, such as infections, surgical procedures, trauma, or psychological stress, to adequately meet increased physiological demands. Clinicians should maintain a high index of suspicion for adrenal crisis, particularly in the presence of hypotension and severe hyponatremia, and remain vigilant for rare but potentially life-threatening immune-related adverse events associated with tislelizumab therapy. adrenal insufficiency adrenal crisis tislelizumab hyponatremia Background Esophageal cancer is a globally prevalent malignancy, with ESCC being the most common histological subtype worldwide. The disease is typically aggressive and often presents at an advanced stage due to the late onset of symptoms. The prognosis for patients with advanced ESCC remains poor. In a randomized controlled trial involving 649 treatment-naive patients with advanced ESCC, the combination of tislelizumab and chemotherapy demonstrated a median overall survival benefit of nearly seven months compared to the placebo plus chemotherapy group, with a 34% reduction in the risk of death 1 . As a result, tislelizumab combined with chemotherapy is now recommended as a first-line treatment for advanced ESCC 2 . However, while this therapeutic advancement represents a significant progress, it is crucial to acknowledge recognize the potential for immune-related endocrine adverse events, such as adrenal insufficiency, as detailed in this article. Early symptoms of adrenal insufficiency—including fatigue, anorexia, and unintentional weight loss—are often nonspecific, making early diagnosis challenging. In some cases, the condition is only identified during an adrenal crisis, a life-threatening emergency that occurs in a significant number of patients previously identified with adrenal insufficiency 3 . The estimated mortality rate of adrenal crisis is approximately 0.5 per 100 patient-years 4 . Delayed diagnosis and management of such immune-related adverse events can significantly worsen patient outcomes. This article reports a case of adrenal insufficiency in a patient with advanced ESCC treated with tislelizumab, illustrating the importance of regular monitoring of electrolyte levels and continuous clinical follow-up to facilitate early detection and timely intervention. Case A 71-year-old male patient was diagnosed with advanced ESCC one year ago due to dysphagia. He initially underwent radiotherapy followed by combination treatment with paclitaxel and tislelizumab. However, due to the development of radiation-induced pneumonia and severe hepatic dysfunction attributed to paclitaxel, his treatment regimen was modified to tislelizumab combined with oral anlotinib. To date, he has completed 11 cycles of tislelizumab at a dose of 200 mg per cycle. On April 29, 2025, the patient presented to the hospital due to fatigue and poor appetite persisting for approximately two weeks. He denied fever, vomiting, or diarrhea. Physical examination was unremarkable. Laboratory investigations revealed severe hyponatremia, with a serum sodium level of 114 mmol/L (reference range: 137-147mmol/L). Intravenous sodium chloride supplementation was initiated at a dosage of 12 grams daily. A follow-up test on May 9 showed a slight improvement in serum sodium to 121mmol/L, prompting an increase in sodium chloride infusion to 17.5 grams daily. Despite this adjustment, the patient's serum sodium levels remained suboptimal (see Table 1). Given the persistent hyponatremia, endocrine evaluation was conducted, including serum cortisol, ACTH, and other pituitary-related parameters (see Table 2). The results confirmed a diagnosis of adrenal insufficiency. Cortisone replacement therapy was initiated at a dose of 10 mg in the morning and 5 mg in the afternoon. As a result, the patient's fatigue and poor appetite resolved, and his serum sodium levels gradually normalized on subsequent evaluations. The patient was discharged on May 17. Table 2. Endocrine test test index detection value reference value 8am cortisol 0.93 μg/dl 4.26-24.85 μg/dl 4pm cortisol 0.93 μg/dl 2.9-17.3 μg/dl 24h urocortisol 0.30 μg/dl 76.2-701.2 μg/dl ACTH 10.33 pg/ml 7.20-63.40 pg/ml aldosterone 68.19 pg/ml 10-160 pg/ml testosterone 4.66 mIU/ml 1.87-6.84 mIU/ml free T3 2.13 pg/ml 1.75-3.81 pg/ml Free T4 14.28 pmol/L 9.14-19.31 pmol/L thyroid stimulating hormone 4.0 mIU/L 0.30-4.98 mIU/L Approximately one month later, the patient was re-admitted due to persistent symptoms, including cough, sputum production, and recurrent fever following a cold. These symptoms were accompanied by fatigue, anorexia, abdominal pain, and vomiting that lasted for two days. On the night of June 18, 2025, the patient presented with hypotension (blood pressure 89/48 mmHg). Laboratory tests again revealed hyponatremia (121 mmol/L, reference range 137-147 mmol/L), while complete blood count, liver and kidney function tests, and B-type natriuretic peptide levels were within normal ranges. Blood and urine cultures, along with cardiac function assessments, excluded sepsis and heart failure. Imaging studies, including chest computed tomography , showed mild exudative consolidation in the lower lobes of both lungs, while abdominal computed tomography revealed slight blurring of the perirenal spaces. Given the presence of fever, productive cough, and respiratory symptoms, the patient was diagnosed with a pulmonary infection. Empiric antibiotic therapy was initiated with piperacillin and tazobactam (4.5g every 8 hours), combined with levofloxacin (0.5g once daily). Additionally, cortisone was administered at 10 mg in the morning and 5 mg in the afternoon for hormone replacement and fluid resuscitation. After 72 hours of appropriate antimicrobial treatment, the patient's symptoms persisted, including fatigue, weakness, nausea, vomiting, abdominal pain, and general malaise. Despite ongoing treatment, his body temperatureremained elevated (see Table 3) , blood pressure stayed low (see Table 4), and hyponatremia was unresolved (see Table 5). Clinical deterioration was noted, with the patient developing tachypnea, progressive decline in consciousness, and becoming critically ill. Reduced food intake and vomiting likely contributed to the persistent hyponatremia. The presence of fever, cough, and dyspnea indicated a poorly controlled pulmonary infection. On June 21, the antibiotic regimen was escalated to imipenem-cliastatin sodium (0.5 g every 8 hours). However, the patient's clinical condition failed to improve, and his fever worsened, leading to a temporary therapeutic deadlock. A comprehensive reassessment revealed a disconnect between the patient's clinical severity and the relatively mild pulmonary infections observed on chest computed tomography. There was insufficient evidence to support diagnoses of septic shock, cardiogenic shock, or hypovolemic shock. Given the patient's known history of adrenal insufficiency, the current hypotension, hyponatremia, and altered mental status raised strong suspicion for an adrenal crisis. A diagnosis of adrenal crisis was promptly made. Intravenous hydrocortisone was initiated at a dose of 100 mg twice daily. Following glucocorticoid administration, the patient’s fever resolved, mental status improved, and symptoms of fatigue, vomiting, and abdominal pain subsided. Blood pressure and serum sodium levels gradually returned to normal. The patient's condition stabilized, and he eventually recovered sufficiently to be discharged. The glucocorticoid dosage was subsequently tapered to physiological maintenance levels. Discussion Adrenal insufficiency is a clinical condition characterized by inadequate synthesis and secretion of corticosteroids, including glucocorticoids and mineralocorticoids, by the adrenal cortex. Corticosteroid production is regulated by ACTH. This condition can arise from intrinsic adrenal gland pathology (primary adrenal insufficiency), hypothalamic or pituitary dysfunction (secondary adrenal insufficiency), or suppression of the hypothalamic-pituitary-adrenal axis due to prolonged exposure to glucocorticoid. Patients with adrenal insufficiency typically exhibit a range of non-specific clinical symptoms,including unintentional weight loss, anorexia, and fatigue.Due to the vague nature of these symptoms, diagnosis is often delayed 5 . The most severe clinical manifestation is an adrenal crisis, a potentially life-threatening syndrome resulting from acute cortisol deficiency. Although a universally accepted definition of adrenal crisis is lacking, most criteria emphasize acute clinical presentation along with at least two of the following: (a ≥ 20 mmHg decrease from baseline blood pressure), altered mental status and biochemical abnormalities such as hyponatremia and hypoglycemia. In those with known adrenal insufficiency, adrenal crises occur at an estimated incidence of 5–10 events per 100 patient-years, with a reported mortality rate of approximately 0.5 per 100 patient-years 6 . If not promptly recognized and treated, adrenal crisis may progress to shock and even death. Another patient with triple-negative breast cancer was previously reported to have developed immune-related adrenal insufficiency, which progressed to an adrenal crisis characterized by hypotension following treatment with pembrolizumab 7 . That case shares many clinical similarities with the current patient. Prior to this admission, the patient had been diagnosed with advanced ESCC and had undergone therapy with tislelizumab. Laboratory results revealed a serum cortisol level of 0.93 µg/dl, while ACTH levels were inappropriately within the normal range, supporting a diagnosis of secondary adrenal insufficiency. Thyroid and gonadal hormone levels remained within normal ranges. Both cases were ultimately identified as immune-related isolated ACTH deficiency, consistent with immune-related adrenal insufficiency induced by anti-programmed death antibodies 8 . What makes this case report unique is that severe hyponatremia was identified upon initial admission, and subsequent sodium supplementation proved ineffective. The observation of severe hyponatremia prompted further investigation and ultimately led to a diagnosis of adrenal insufficiency. The case underscores the close relationship between adrenal insufficiency and hyponatremia. The underlying mechanism involves cortisol’s inhibitory effect on antidiuretic hormone release and aldosterone’s role in regulating water and sodium balance. Hyponatremia is a frequently observed laboratory abnormality in patients with adrenal insufficiency; therefore, unexplained hyponatremia should prompt timely endocrine evaluation to screen for potential adrenal insufficiency 9 . In this case, the patient presented with profound hyponatremia and was subsequently diagnosed with adrenal insufficiency through following pituitary hormone evaluation, in the context of prior treatment with tislelizumab. Despite aggressive sodium supplementation, the patient's serum sodium levels remained low. However, the patient’s fatigue improved significantly following glucocorticoid replacement therapy, and biochemical parameters gradually stabilized. The patient was maintained on regular glucocorticoid replacement therapy until discharge. One month after discharge, the patient was readmitted with cough, sputum production, and recurrent fever, indicative of a pulmonary infection. Despite aggressive anti-infection treatment, the patient's condition worsened, presenting with altered mental status and posing a critical challenge to clinical management. A review of clinical features in 371 reported cases of adrenal insufficiency and adrenal crisis has revealed infection as a significant factor 10 . Infections trigger the release of cytokines, which stimulate the hypothalamic-pituitary-adrenal axis, leading to increased cortisol secretion 11 . Cortisol plays an essential role in suppressing the inflammatory response. However, in patients with adrenal insufficiency, cortisol secretion fails to meet the increased physiological demand during stress, thereby significantly increasing the risk of mortality. Glucocorticoid replacement therapy is crucial for survival in adrenal crisis situations. The symptoms of adrenal insufficiency, such as anorexia, fatigue, abdominal pain, and vomiting, are often nonspecific, making early identification challenging. In some cases, patients are only diagnosed during an adrenal crisis, which significantly increases the risk of both adrenal crisis and mortality. Immediate treatment is crucial, as adrenal insufficiency can be life-threatening. Physicians must remain vigilant regarding the unique risks associated with this condition. Conclusion Physicians should be fully aware of the risk of drug-related adrenal insufficiency associated with the use of tislelizumab. Patients with adrenal insufficiency are at increased risk of adrenal crisis, which can be fatal. Additionally, untreated adrenal insufficiency can impair quality of life and reduce work capacity. However, adrenal crisis can be prevented and managed if adrenal insufficiency is promptly recognized and treated. We recommend regular monitoring of electrolyte levels in patients receiving tislelizumab. Hyponatremia—particularly severe or treatment-resistant cases—should not be overlooked. In cases of unexplained hyponatremia, timely endocrine evaluation is crucial to prevent drug-related adrenal insufficiency and mitigate potential health risks. Abbreviations adrenocorticotropic hormone（ACTH） esophageal squamous cell carcinoma（ESCC） Declarations ●Ethics approval and consent to participate Approved by the Ethics Committee of Chongqing University Affiliated Three Gorges Hospital, Approval Number: 2025 KeLun No. 93 ●Consent for publication Written informed consent for publication of their clinical details was obtained from the patient by Dr Liu Zhaobi. ●Availability of date and materials The original contributions presented in the study are includedin the article. Further inquiries can be directed to the corresponding author. ●Competing interests The authors declare that they have no competing interests ●Funding No applicable ●Authors’conntributions LLY:writing–original draft, writing – review & editing manuscript, LZB: supervision, writing – review & editing, obtaining patient consent. The authors contribute equally.We confirm that all listed authors have reviewed and approved the revised manuscript and are in agreement with the current version of the submission. ●Acknowledgements No applicable References Xu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. Lancet Oncol. 2023;24(5):483–495. Shiraishi K, Yamamoto S, Kato K. Tislelizumab for the treatment of advanced esophageal squamous cell carcinoma. Future Oncology. 2025;21(12):1473–1481. Dineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. Ther Adv Endocrinol Metab. 2019;10:2042018819848218. Hahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. J Clin Endocrinol Metab. 2015;100(2):407–416. Woods CP, Argese N, Chapman M, et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. Eur J Endocrinol. 2015;173(5):633–642. Li D, Genere N, Behnken E, et al. Determinants of Self-reported Health Outcomes in Adrenal Insufficiency: A Multisite Survey Study. J Clin Endocrinol Metab. 2021;106(3):e1408-e1419. Mohammed SS, Alrosan S, Asad R. Adrenal crisis due to pembrolizumab-induced hypophysitis in a patient with triple-negative breast cancer. Endocrine Oncology. 2025;5(1). Wright JJ, Johnson DB. Approach to the Patient With Immune Checkpoint Inhibitor-Associated Endocrine Dysfunction. J Clin Endocrinol Metab. 2023;108(6):1514–1525. Martin-Grace J, Dineen R, Sherlock M, Thompson CJ. Adrenal insufficiency: Physiology, clinical presentation and diagnostic challenges. Clin Chim Acta. 2020;505:78–91. Qiu Y, Luo Y, Geng X, Li Y, Feng Y, Yang Y. Clinical characteristics of adrenal crisis in 371 adult patients with glucocorticoid-induced adrenal insufficiency. Frontiers in Endocrinology. 2024;15. Prete A, Taylor AE, Bancos I, et al. Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery. J Clin Endocrinol Metab. 2020;105(7):2262–2274. Tables Tables are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.pdf Table3.pdf Table4.pdf Table5.pdf Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7512846","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":528650853,"identity":"deba0db6-c38e-4461-8d5e-19cac67eb276","order_by":0,"name":"Li Lanyan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Li","middleName":"","lastName":"Lanyan","suffix":""},{"id":528650854,"identity":"2577a39e-78cd-4dcf-9cce-83b3ae8c7152","order_by":1,"name":"Liu Zhaobi","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Liu","middleName":"","lastName":"Zhaobi","suffix":""},{"id":528650855,"identity":"29617273-9784-4e64-98d5-c4e96729771a","order_by":2,"name":"Zheng Hong","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAx0lEQVRIiWNgGAWjYBAC+/b+xw8/VLDV729vIFKLAc8ZNmOJM3yMG3gOEKtFIodBgrdFjnGDRAKRWswZcg8YSDaYMZtLPt54g6HGJpqgFsuGcwkPCneksVnOTiu2YDiWlttAUM/BBgMDyTPHeBhu55hJMDYcJkLLYaB3eNv+SzDcPEOkFoNjPCAtbAYGN3iI1CLZw5YGDGS2BMkeoF8SiPELv/zjw6CoTOBnP7zxxocaGyL8guxIoqMGSQupOkbBKBgFo2BkAACC7EB0UJGe5AAAAABJRU5ErkJggg==","orcid":"","institution":"","correspondingAuthor":true,"prefix":"","firstName":"Zheng","middleName":"","lastName":"Hong","suffix":""}],"badges":[],"createdAt":"2025-09-02 03:23:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7512846/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7512846/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":93804778,"identity":"3f86fcea-c3f5-4bd8-9cad-b6d49cf78864","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":662236,"visible":true,"origin":"","legend":"","description":"","filename":"AdrenalInsufficiencyInducedbyTislelizumab.docx","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/bbe43e2af0ea3c1e3c8155b6.docx"},{"id":93805330,"identity":"154bd776-6135-4cb4-91d3-865d5b9172b5","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":4883,"visible":true,"origin":"","legend":"","description":"","filename":"7d4e524cc71e41e5b3becc46fc5119ec.json","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/b9e5524b9113492ead96c486.json"},{"id":93805328,"identity":"c1704ac4-cb3c-4485-9909-d11996f9b8b7","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":113968,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/f5cb672c7543e5878a53ec2a.pdf"},{"id":93804782,"identity":"430536ae-e206-40f4-b5e2-98be5fdf87c9","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":109176,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/49bcdc450a33dfde4b2ccdd1.pdf"},{"id":93805332,"identity":"ca7123d7-1dd2-47e4-8664-2fc0c2cf5cd2","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5242,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/37a017299aff691992b4e8bd.pdf"},{"id":93804790,"identity":"3dca7acb-736c-4a2c-bcd1-7fdd030d177c","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"pdf","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":5274,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/d19f8fb6399e4532862d7fc9.pdf"},{"id":93805331,"identity":"e9dc68bc-23c3-4dd8-a909-2f310878aea2","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"xml","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":37011,"visible":true,"origin":"","legend":"","description":"","filename":"7d4e524cc71e41e5b3becc46fc5119ec1enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/7678827332f463174786dba1.xml"},{"id":93804785,"identity":"2593e6dd-a149-462a-9125-d15e5016b51e","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"eps","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":388,"visible":true,"origin":"","legend":"","description":"","filename":"drawingimage1.eps","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/481d973f753c452d7765e030.eps"},{"id":93805995,"identity":"dfe951bf-2a7a-4dcd-a43b-fad5f1202e70","added_by":"auto","created_at":"2025-10-17 18:07:25","extension":"jpeg","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":1074,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/396da125b307d1a6187447fb.jpeg"},{"id":93805997,"identity":"d78e8e34-bb7d-49b9-9864-d67ba951145d","added_by":"auto","created_at":"2025-10-17 18:07:25","extension":"jpeg","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":191718,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/e01356593dfb484ef965367e.jpeg"},{"id":93805339,"identity":"3b0008ab-04b2-4ff3-96bd-e902e358f8cb","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"jpeg","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":245972,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/bb8df9c9d8da969dcb17c55f.jpeg"},{"id":93804792,"identity":"9cc5571d-d04e-4218-aea9-c5f0a60695f3","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"jpeg","order_by":11,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":194906,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage4.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/40c16a8dd1893e7976713679.jpeg"},{"id":93805334,"identity":"ed200f50-d4a9-48cc-a9eb-05a24a180e09","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"png","order_by":12,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":40516,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/7ccdb2aabd943867c2ff8ca5.png"},{"id":93805338,"identity":"f6a3991a-2e7d-425f-ae69-6972b813c967","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"png","order_by":13,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":935,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/ccb683d2ea8051bb2ea3c143.png"},{"id":93806489,"identity":"d1103bf2-d9ff-4878-95fb-6e4af359b0cd","added_by":"auto","created_at":"2025-10-17 18:15:25","extension":"png","order_by":14,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":29045,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/002a07693bb1260f590d090c.png"},{"id":93804788,"identity":"9010a40f-6269-43d1-8de0-3eeb9e73dd03","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"png","order_by":15,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":45955,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/895a80fe7b60b6c478d1cd6b.png"},{"id":93804783,"identity":"14b10a61-b622-45a5-addc-1ca572906fe6","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"png","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33368,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/902c21503ccb1ebfb7fe7f90.png"},{"id":93805336,"identity":"e0b4bc5e-473e-4510-bc34-3e46f93595ea","added_by":"auto","created_at":"2025-10-17 17:59:25","extension":"png","order_by":17,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":17701,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/41e5f16c2ea4a83b6f1464b3.png"},{"id":93804797,"identity":"70eb9e45-e0c2-4472-b817-de2815512cd6","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"xml","order_by":18,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":33597,"visible":true,"origin":"","legend":"","description":"","filename":"7d4e524cc71e41e5b3becc46fc5119ec1structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/425270a5420f2e8e5f0f56ae.xml"},{"id":93804795,"identity":"172afa9d-4598-4e69-8ce6-240bf4600ab8","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"html","order_by":19,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":40898,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/2a5107f31e9a24fe8196dc0c.html"},{"id":106442437,"identity":"8a6dc3b8-706c-4de5-9e92-fb663e41e0b2","added_by":"auto","created_at":"2026-04-08 14:58:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":294348,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/c43d5f55-3f45-460a-b22b-8a9778435630.pdf"},{"id":93804774,"identity":"e228a17d-ba29-4880-ab96-2238f970fe75","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":5274,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/fb007a34682434655ff92e6d.pdf"},{"id":93805994,"identity":"1da9e8b2-b90c-42a8-bc0d-a7f36b304f24","added_by":"auto","created_at":"2025-10-17 18:07:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":113968,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/81e38ef7474508f61706e711.pdf"},{"id":93804780,"identity":"d6cf2571-db4a-46e0-bfa1-76e13f9da440","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":109176,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/242fa1c912bce1e7465461d1.pdf"},{"id":93804777,"identity":"ae1b5716-54d7-4eab-973c-fa956ebb3b66","added_by":"auto","created_at":"2025-10-17 17:51:25","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":5242,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7512846/v1/973aad3359eeba3ce13b0c71.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Adrenal Insufficiency Induced by Tislelizumab in a Patient with Advanced Esophageal Squamous Cell Carcinoma: Case Report","fulltext":[{"header":"Background","content":"\u003cp\u003e\u003c/p\u003e\u003cp\u003eEsophageal cancer is a globally prevalent malignancy, with ESCC being the most common histological subtype worldwide. The disease is typically aggressive and often presents at an advanced stage due to the late onset of symptoms. The prognosis for patients with advanced ESCC remains poor. In a randomized controlled trial involving 649 treatment-naive patients with advanced ESCC, the combination of tislelizumab and chemotherapy demonstrated a median overall survival benefit of nearly seven months compared to the placebo plus chemotherapy group, with a 34% reduction in the risk of death\u003csup\u003e1\u003c/sup\u003e. As a result, tislelizumab combined with chemotherapy is now recommended as a first-line treatment for advanced ESCC\u003csup\u003e2\u003c/sup\u003e. However, while this therapeutic advancement represents a significant progress, it is crucial to acknowledge recognize the potential for immune-related endocrine adverse events, such as adrenal insufficiency, as detailed in this article. Early symptoms of adrenal insufficiency\u0026mdash;including fatigue, anorexia, and unintentional weight loss\u0026mdash;are often nonspecific, making early diagnosis challenging. In some cases, the condition is only identified during an adrenal crisis, a life-threatening emergency that occurs in a significant number of patients previously identified with adrenal insufficiency\u003csup\u003e3\u003c/sup\u003e. The estimated mortality rate of adrenal crisis is approximately 0.5 per 100 patient-years\u003csup\u003e4\u003c/sup\u003e. Delayed diagnosis and management of such immune-related adverse events can significantly worsen patient outcomes. This article reports a case of adrenal insufficiency in a patient with advanced ESCC treated with tislelizumab, illustrating the importance of regular monitoring of electrolyte levels and continuous clinical follow-up to facilitate early detection and timely intervention.\u003c/p\u003e"},{"header":"Case ","content":"\u003cp\u003eA 71-year-old male patient was diagnosed with advanced ESCC one year ago due to dysphagia. He initially underwent radiotherapy followed by combination treatment with paclitaxel and tislelizumab. However, due to the development of radiation-induced pneumonia and severe hepatic dysfunction attributed to paclitaxel, his treatment regimen was modified to tislelizumab combined with oral anlotinib. To date, he has completed 11 cycles of tislelizumab at a dose of 200 mg per cycle. On April 29, 2025, the patient presented to the hospital due to fatigue and poor appetite persisting for approximately two weeks. He denied fever, vomiting, or diarrhea. Physical examination was unremarkable. Laboratory investigations revealed severe hyponatremia, with a serum sodium level of 114 mmol/L (reference range: 137-147mmol/L). Intravenous sodium chloride supplementation was initiated at a dosage of 12 grams daily. A follow-up test on May 9 showed a slight improvement in serum sodium to 121mmol/L, prompting an increase in sodium chloride infusion to 17.5 grams daily. Despite this adjustment, the patient\u0026apos;s serum sodium levels remained suboptimal (see Table 1). Given the persistent hyponatremia, endocrine evaluation was conducted, including serum cortisol, ACTH, and other pituitary-related parameters (see Table 2). The results confirmed a diagnosis of adrenal insufficiency. Cortisone replacement therapy was initiated at a dose of 10 mg in the morning and 5 mg in the afternoon. As a result, the patient\u0026apos;s fatigue and poor appetite resolved, and his serum sodium levels gradually normalized on subsequent evaluations. The patient was discharged on May 17.\u003c/p\u003e\n\u003cp\u003eTable 2. Endocrine test\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003etest index\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003edetection value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003ereference value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e8am cortisol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e0.93\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e4.26-24.85\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e4pm cortisol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e0.93\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e2.9-17.3\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e24h urocortisol\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e0.30\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e76.2-701.2\u0026nbsp;\u0026mu;g/dl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003eACTH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e10.33 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e7.20-63.40 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003ealdosterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e68.19 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e10-160 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003etestosterone\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e4.66 mIU/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e1.87-6.84 mIU/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003efree T3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e2.13 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e1.75-3.81 pg/ml\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003eFree T4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e14.28 pmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e9.14-19.31 pmol/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003ethyroid stimulating hormone\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e4.0 mIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 184px;\"\u003e\n \u003cp\u003e0.30-4.98 mIU/L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eApproximately one month later, the patient was re-admitted due to persistent symptoms, including cough, sputum production, and recurrent fever following a cold. These symptoms were accompanied by fatigue, anorexia, abdominal pain, and vomiting that lasted for two days. On the night of June 18, 2025, the patient presented with hypotension (blood pressure 89/48 mmHg). Laboratory tests again revealed hyponatremia (121 mmol/L, reference range 137-147 mmol/L), while complete blood count, liver and kidney function tests, and B-type natriuretic peptide levels were within normal ranges. Blood and urine cultures, along with cardiac function assessments, excluded sepsis and heart failure. Imaging studies, including chest computed tomography , showed mild exudative consolidation in the lower lobes of both lungs, while abdominal computed tomography revealed slight blurring of the perirenal spaces. Given the presence of fever, productive cough, and respiratory symptoms, the patient was diagnosed with a pulmonary infection. Empiric antibiotic therapy was initiated with piperacillin and tazobactam (4.5g every 8 hours), combined with levofloxacin (0.5g once daily). Additionally, cortisone was administered at 10 mg in the morning and 5 mg in the afternoon for hormone replacement and fluid resuscitation.\u003c/p\u003e\n\u003cp\u003eAfter 72 hours of appropriate antimicrobial treatment, the patient\u0026apos;s symptoms persisted, including fatigue, weakness, nausea, vomiting, abdominal pain, and general malaise. Despite ongoing treatment, his body temperatureremained elevated (see Table 3) , blood pressure stayed low (see Table 4), and hyponatremia was unresolved (see Table 5). Clinical deterioration was noted, with the patient developing tachypnea, progressive decline in consciousness, and becoming critically ill. Reduced food intake and vomiting likely contributed to the persistent hyponatremia. The presence of fever, cough, and dyspnea indicated a poorly controlled pulmonary infection. On June 21, the antibiotic regimen was escalated to imipenem-cliastatin sodium (0.5 g every 8 hours). However, the patient\u0026apos;s clinical condition failed to improve, and his fever worsened, leading to a temporary therapeutic deadlock. A comprehensive reassessment revealed a disconnect between the patient\u0026apos;s clinical severity and the relatively mild pulmonary infections observed on chest computed tomography. There was insufficient evidence to support diagnoses of septic shock, cardiogenic shock, or hypovolemic shock. Given the patient\u0026apos;s known history of adrenal insufficiency, the current hypotension, hyponatremia, and altered mental status raised strong suspicion for an adrenal crisis. A diagnosis of adrenal crisis was promptly made. Intravenous hydrocortisone was initiated at a dose of 100 mg twice daily. Following glucocorticoid administration, the patient\u0026rsquo;s fever resolved, mental status improved, and symptoms of fatigue, vomiting, and abdominal pain subsided. Blood pressure and serum sodium levels gradually returned to normal. The patient\u0026apos;s condition stabilized, and he eventually recovered sufficiently to be discharged. The glucocorticoid dosage was subsequently tapered to physiological maintenance levels.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAdrenal insufficiency is a clinical condition characterized by inadequate synthesis and secretion of corticosteroids, including glucocorticoids and mineralocorticoids, by the adrenal cortex. Corticosteroid production is regulated by ACTH. This condition can arise from intrinsic adrenal gland pathology (primary adrenal insufficiency), hypothalamic or pituitary dysfunction (secondary adrenal insufficiency), or suppression of the hypothalamic-pituitary-adrenal axis due to prolonged exposure to glucocorticoid. Patients with adrenal insufficiency typically exhibit a range of non-specific clinical symptoms,including unintentional weight loss, anorexia, and fatigue.Due to the vague nature of these symptoms, diagnosis is often delayed\u003csup\u003e5\u003c/sup\u003e. The most severe clinical manifestation is an adrenal crisis, a potentially life-threatening syndrome resulting from acute cortisol deficiency. Although a universally accepted definition of adrenal crisis is lacking, most criteria emphasize acute clinical presentation along with at least two of the following: (a\u0026thinsp;\u0026ge;\u0026thinsp;20 mmHg decrease from baseline blood pressure), altered mental status and biochemical abnormalities such as hyponatremia and hypoglycemia. In those with known adrenal insufficiency, adrenal crises occur at an estimated incidence of 5\u0026ndash;10 events per 100 patient-years, with a reported mortality rate of approximately 0.5 per 100 patient-years\u003csup\u003e6\u003c/sup\u003e. If not promptly recognized and treated, adrenal crisis may progress to shock and even death.\u003c/p\u003e\u003cp\u003eAnother patient with triple-negative breast cancer was previously reported to have developed immune-related adrenal insufficiency, which progressed to an adrenal crisis characterized by hypotension following treatment with pembrolizumab\u003csup\u003e7\u003c/sup\u003e. That case shares many clinical similarities with the current patient. Prior to this admission, the patient had been diagnosed with advanced ESCC and had undergone therapy with tislelizumab. Laboratory results revealed a serum cortisol level of 0.93 \u0026micro;g/dl, while ACTH levels were inappropriately within the normal range, supporting a diagnosis of secondary adrenal insufficiency. Thyroid and gonadal hormone levels remained within normal ranges. Both cases were ultimately identified as immune-related isolated ACTH deficiency, consistent with immune-related adrenal insufficiency induced by anti-programmed death antibodies\u003csup\u003e8\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eWhat makes this case report unique is that severe hyponatremia was identified upon initial admission, and subsequent sodium supplementation proved ineffective. The observation of severe hyponatremia prompted further investigation and ultimately led to a diagnosis of adrenal insufficiency. The case underscores the close relationship between adrenal insufficiency and hyponatremia. The underlying mechanism involves cortisol\u0026rsquo;s inhibitory effect on antidiuretic hormone release and aldosterone\u0026rsquo;s role in regulating water and sodium balance. Hyponatremia is a frequently observed laboratory abnormality in patients with adrenal insufficiency; therefore, unexplained hyponatremia should prompt timely endocrine evaluation to screen for potential adrenal insufficiency\u003csup\u003e9\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn this case, the patient presented with profound hyponatremia and was subsequently diagnosed with adrenal insufficiency through following pituitary hormone evaluation, in the context of prior treatment with tislelizumab. Despite aggressive sodium supplementation, the patient's serum sodium levels remained low. However, the patient\u0026rsquo;s fatigue improved significantly following glucocorticoid replacement therapy, and biochemical parameters gradually stabilized. The patient was maintained on regular glucocorticoid replacement therapy until discharge. One month after discharge, the patient was readmitted with cough, sputum production, and recurrent fever, indicative of a pulmonary infection. Despite aggressive anti-infection treatment, the patient's condition worsened, presenting with altered mental status and posing a critical challenge to clinical management. A review of clinical features in 371 reported cases of adrenal insufficiency and adrenal crisis has revealed infection as a significant factor\u003csup\u003e10\u003c/sup\u003e. Infections trigger the release of cytokines, which stimulate the hypothalamic-pituitary-adrenal axis, leading to increased cortisol secretion\u003csup\u003e11\u003c/sup\u003e. Cortisol plays an essential role in suppressing the inflammatory response. However, in patients with adrenal insufficiency, cortisol secretion fails to meet the increased physiological demand during stress, thereby significantly increasing the risk of mortality.\u003c/p\u003e\u003cp\u003eGlucocorticoid replacement therapy is crucial for survival in adrenal crisis situations. The symptoms of adrenal insufficiency, such as anorexia, fatigue, abdominal pain, and vomiting, are often nonspecific, making early identification challenging. In some cases, patients are only diagnosed during an adrenal crisis, which significantly increases the risk of both adrenal crisis and mortality. Immediate treatment is crucial, as adrenal insufficiency can be life-threatening. Physicians must remain vigilant regarding the unique risks associated with this condition.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003ePhysicians should be fully aware of the risk of drug-related adrenal insufficiency associated with the use of tislelizumab. Patients with adrenal insufficiency are at increased risk of adrenal crisis, which can be fatal. Additionally, untreated adrenal insufficiency can impair quality of life and reduce work capacity. However, adrenal crisis can be prevented and managed if adrenal insufficiency is promptly recognized and treated. We recommend regular monitoring of electrolyte levels in patients receiving tislelizumab. Hyponatremia\u0026mdash;particularly severe or treatment-resistant cases\u0026mdash;should not be overlooked. In cases of unexplained hyponatremia, timely endocrine evaluation is crucial to prevent drug-related adrenal insufficiency and mitigate potential health risks.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eadrenocorticotropic hormone（ACTH）\u003c/p\u003e\n\u003cp\u003eesophageal squamous cell carcinoma（ESCC）\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e●Ethics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eApproved by the Ethics Committee of Chongqing University Affiliated Three Gorges Hospital, Approval Number: 2025 KeLun No. 93\u003c/p\u003e\n\u003cp\u003e●Consent for publication\u003c/p\u003e\n\u003cp\u003eWritten informed consent for publication of their clinical details was obtained from the patient by Dr Liu Zhaobi.\u003c/p\u003e\n\u003cp\u003e●Availability of date and materials\u003c/p\u003e\n\u003cp\u003eThe original contributions presented in the study are includedin the article. Further inquiries can be directed to the corresponding author.\u003c/p\u003e\n\u003cp\u003e●Competing interests\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003e●Funding\u003c/p\u003e\n\u003cp\u003eNo applicable\u003c/p\u003e\n\u003cp\u003e●Authors’conntributions\u003c/p\u003e\n\u003cp\u003eLLY:writing–original draft, writing – review \u0026amp; editing manuscript, LZB: supervision, writing – review \u0026amp; editing, obtaining patient consent. The authors contribute equally.We confirm that all listed authors have reviewed and approved the revised manuscript and are in agreement with the current version of the submission.\u003c/p\u003e\n\u003cp\u003e●Acknowledgements\u003c/p\u003e\n\u003cp\u003eNo applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eXu J, Kato K, Raymond E, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first-line treatment for advanced or metastatic oesophageal squamous cell carcinoma (RATIONALE-306): a global, randomised, placebo-controlled, phase 3 study. \u003cem\u003eLancet Oncol.\u003c/em\u003e 2023;24(5):483–495.\u003c/li\u003e\n\u003cli\u003eShiraishi K, Yamamoto S, Kato K. Tislelizumab for the treatment of advanced esophageal squamous cell carcinoma. \u003cem\u003eFuture Oncology.\u003c/em\u003e 2025;21(12):1473–1481.\u003c/li\u003e\n\u003cli\u003eDineen R, Thompson CJ, Sherlock M. Adrenal crisis: prevention and management in adult patients. \u003cem\u003eTher Adv Endocrinol Metab.\u003c/em\u003e 2019;10:2042018819848218.\u003c/li\u003e\n\u003cli\u003eHahner S, Spinnler C, Fassnacht M, et al. High incidence of adrenal crisis in educated patients with chronic adrenal insufficiency: a prospective study. \u003cem\u003eJ Clin Endocrinol Metab.\u003c/em\u003e 2015;100(2):407–416.\u003c/li\u003e\n\u003cli\u003eWoods CP, Argese N, Chapman M, et al. Adrenal suppression in patients taking inhaled glucocorticoids is highly prevalent and management can be guided by morning cortisol. \u003cem\u003eEur J Endocrinol.\u003c/em\u003e 2015;173(5):633–642.\u003c/li\u003e\n\u003cli\u003eLi D, Genere N, Behnken E, et al. Determinants of Self-reported Health Outcomes in Adrenal Insufficiency: A Multisite Survey Study. \u003cem\u003eJ Clin Endocrinol Metab.\u003c/em\u003e 2021;106(3):e1408-e1419.\u003c/li\u003e\n\u003cli\u003eMohammed SS, Alrosan S, Asad R. Adrenal crisis due to pembrolizumab-induced hypophysitis in a patient with triple-negative breast cancer. \u003cem\u003eEndocrine Oncology.\u003c/em\u003e 2025;5(1).\u003c/li\u003e\n\u003cli\u003eWright JJ, Johnson DB. Approach to the Patient With Immune Checkpoint Inhibitor-Associated Endocrine Dysfunction. \u003cem\u003eJ Clin Endocrinol Metab.\u003c/em\u003e 2023;108(6):1514–1525.\u003c/li\u003e\n\u003cli\u003eMartin-Grace J, Dineen R, Sherlock M, Thompson CJ. Adrenal insufficiency: Physiology, clinical presentation and diagnostic challenges. \u003cem\u003eClin Chim Acta.\u003c/em\u003e 2020;505:78–91.\u003c/li\u003e\n\u003cli\u003eQiu Y, Luo Y, Geng X, Li Y, Feng Y, Yang Y. Clinical characteristics of adrenal crisis in 371 adult patients with glucocorticoid-induced adrenal insufficiency. \u003cem\u003eFrontiers in Endocrinology.\u003c/em\u003e 2024;15.\u003c/li\u003e\n\u003cli\u003ePrete A, Taylor AE, Bancos I, et al. Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery. \u003cem\u003eJ Clin Endocrinol Metab.\u003c/em\u003e 2020;105(7):2262–2274.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"adrenal insufficiency, adrenal crisis, tislelizumab, hyponatremia","lastPublishedDoi":"10.21203/rs.3.rs-7512846/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7512846/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe recently updated guidelines from the National Comprehensive Cancer Network recommend the combination of tislelizumab and chemotherapy as a standard first-line treatment for patients with advanced esophageal squamous cell carcinoma(ESCC).However, concerns regarding the safety profile of tislelizumab have persisted.We report a case of a 71-year-old patient with advanced ESCC who developed adrenal insufficiency following tislelizumab administration. Biochemical evaluation revealed isolated adrenocorticotropic hormone༈ACTH༉deficiency, consistent with secondary adrenal insufficiency induced by tislelizumab.Nonetheless, patients with adrenal insufficiency receiving glucocorticoid therapy may require dose adjustment during physiologically stressful situations, such as infections, surgical procedures, trauma, or psychological stress, to adequately meet increased physiological demands. Clinicians should maintain a high index of suspicion for adrenal crisis, particularly in the presence of hypotension and severe hyponatremia, and remain vigilant for rare but potentially life-threatening immune-related adverse events associated with tislelizumab therapy.\u003c/p\u003e","manuscriptTitle":"Adrenal Insufficiency Induced by Tislelizumab in a Patient with Advanced Esophageal Squamous Cell Carcinoma: Case Report","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-17 17:51:20","doi":"10.21203/rs.3.rs-7512846/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2fd53553-07a4-475d-b673-cc394342e241","owner":[],"postedDate":"October 17th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-08T14:57:10+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-17 17:51:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7512846","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7512846","identity":"rs-7512846","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}