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Objective Widespread use of immune checkpoint inhibitors (ICIs) in cancer treatment has led to an increase in the number of reported cases of immunotherapy-related endocrinopathies. This study aimed to analyze and compare human leukocyte antigen (HLA) signatures associated with ICI-induced type 1 diabetes (ICI-T1D) and isolated adrenocorticotropic hormone deficiency (ICI-IAD) in patients with both conditions. Methods HLA signatures were examined for their frequencies of occurrence in 22 patients with ICI-T1D without concurrent IAD, including 16 patients from nationwide reports (ICI-T1D group) and 14 patients with ICI-IAD without concurrent T1D (ICI-IAD group). The HLA signatures were also compared for their respective frequencies in 11 patients with ICI-T1D and ICI-IAD, including eight from nationwide reports (ICI-T1D/IAD group). Results In the ICI-T1D group, HLA-DRB1*09:01-DQB1*03:03 and DQA1*03:02, which are in linkage disequilibrium with DRB1*09:01-DQB1*03:03 and DRB1*13:02-DQB1*06:04, were susceptible to ICI-T1D, whereas DRB1*15:02-DQB1*06:01 was protective against ICI-T1D. In the ICI-IAD group, DPB1*09:01, C*12:02-B*52:01, and DRB1*15:02-DRB1*06:01, which are in strong linkage disequilibrium, were associated with susceptibility to ICI-IAD. Moreover, DRB1*15:02-DRB1*06:01 was not detected in the ICI-T1D/IAD group. Conclusions This study revealed specific HLA signatures associated with ICI-T1D and ICI-IAD. Moreover, HLA-DRB1*15:02-DRB1*06:01, an ICI-IAD-susceptible HLA haplotype, coincides with the ICI-T1D-protective HLA haplotype, suggesting that the presence of DRB1*15:02-DRB1*06:01 may protect against the co-occurrence of T1D in patients with ICI-IAD. [ABSTRACT FROM AUTHOR]

Childhood hypoglycaemia results from impairment or defects in glucose homeostasis and has a blood glucose (BG) operational threshold of 60 mg/dL (420 μg/dL]) and low basal adrenocorticotropic hormone (4.6 pg/mL [10–60]). A rare diagnosis of isolated secondary adrenocortical insufficiency was made, and the neuroimaging demonstrated a reduced pituitary height (3 mm). Three months later, levothyroxine was tapered and omitted as the child was euthyroid, but the SST showed a similar flat response to the synacthen. The genetic testing demonstrated a pathogenic heterozygous mutation in the nuclear factor kappa B subunit 2 (NFKB2) gene responsive for common variable immunodeficiency (CVID), and this entity has been described as deficient anterior pituitary hormone with CVID syndrome (DAVID syndrome). The immunoglobulin profile showed a decrease in three types of immunoglobulin (IgM, IgG, and IgE), meeting the diagnostic criteria for CVID. Till date, less than 35 cases are reported worldwide, and of which, less than 5 of them presented with adrenal insufficiency prior to immunodeficiency, making this case rare and teaching us a lesson to think beyond the usual causes of hypoglycaemia.

Background: Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease. Methods: We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded. Results: We identified 123 cases diagnosed as immune checkpoint inhibitorinduced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD. Conclusion: IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs. [ABSTRACT FROM AUTHOR]

Abstract Background With the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events. Methods A retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month. Results 28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up. Conclusions IAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy.

Background: With the increasing application of immune checkpoint inhibitors (ICI) in cancer therapy, the occurrence of isolated adrenocorticotropic hormone deficiency (IAD), as an adverse effect, is also on the rise. Nevertheless, there are only a few studies regarding IAD induced by ICI. This study aimed at investigating the characteristics of IAD induced by ICI and its relationship with other endocrine adverse events. Methods: A retrospective study was conducted in the Endocrinology Department from January 2019 to August 2022 to investigate characteristics of patients with IAD. Clinical features, laboratory findings and treatment information were collected. All patients underwent a follow-up of 3-6-month. Results: 28 patients with IAD were enrolled. All patients received treatment with anti-PD-1/ PD-L1. The median occurrence time of IAD was 24 (18–39) weeks after initiation of ICI treatment. Over half of the patients (53.5%) had an additional endocrinopathy, including primary hypothyroidism and fulminant type 1 diabetes mellitus (FT1DM), while other types of endocrinopathies were not identified. The interval between the occurrences of two gland damages was between 4 and 21 weeks or simultaneous. Primary hypothyroidism (46.4%) was more prevalent than FT1DM (7.1%). Fatigue and nausea were common symptoms, with a frequent occurrence of hyponatremia. All patients continued on oral glucocorticoids during follow-up. Conclusions: IAD induced by ICI could manifest independently, or more frequently in combination with hypothyroidism or FT1DM. This damage could happen at any point of ICI treatment. Given that IAD can be life-threatening, it is critical to evaluate pituitary function dynamically in patients undergoing immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract Background The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. Case presentation A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH

We report a case of secondary adrenal insufficiency due to nivolumab. An 83-year-old man with acral lentiginous types of melanoma on the right sole visited our department in March 2017. He received primary surgery at referred hospital in June 2017, and pathological stage was IIIC (pT3bN3M0) according to AJCC (American Joint Committee on Cancer) 7th edition criteria. During the follow-up period, a lot of in-transit metastases appeared on the right leg. While we were resecting in-transit metastases, we concurrently started nivolumab in September 2018. After 17 cycles of nivolumab treatment, he developed severe nausea and anorexia. At baseline, his cortisol and adrenocorticotropic hormone levels were both at normal range, but corticotropin-releasing hormone loading test revealed secondary adrenal insufficiency. We diagnosed isolated adrenal insufficiency due to nivolumab. Treatment by hydrocortisone immediately relieved nausea and anorexia, and we could have continued treatment of nivolumab.

A 73-year-old man who presented with nonspecific general symptoms and cognitive impairment was initially diagnosed with mild cognitive impairment due to dementia with Lewy bodies (DLB) based on a reduced blood flow in the parietal and occipital lobes on single-photon emission computed tomography (SPECT) imaging. However, the patient later presented with hyponatremia and hypoglycemia, leading to impaired consciousness, and was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD). Hydrocortisone treatment improved the blood test scores and general symptoms, including cognitive impairment. IAD may show a DLB-like presentation on cerebral blood flow SPECT; therefore, caution is required for the correct diagnosis of IAD.

Background: The global COVID-19 pandemic requires urgent development of new vaccines. Endocrinological adverse effects following the new mRNA vaccine against COVID-19 have been reported in several cases. Specific to the involvement of pituitary function; however, only a single case with hypophysis has been reported. This is the first case of isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) following mRNA vaccination against COVID-19. Case presentation: A healthy 31-year-old man received the BNT162b2 SARS-CoV-2 mRNA vaccine. The first injection was uneventful. One day after the second injection, he noticed general fatigue and fever. In the following several days, he additionally developed headaches, nausea, and diarrhea. Four days after the vaccine injection, he visited a hospital with worsening of these symptoms. Physical examination revealed slight disorientation but no other deficits. Laboratory tests revealed hyponatremia, hypoglycemia, and extremely low plasma ACTH and serum cortisol levels (ACTH < 1.5 pg/ml, cortisol 1.6 μg/dl). He was diagnosed with adrenal crisis and was emergently treated with hydrocortisone. The symptoms responded well and he recovered within a few days. Magnetic resonance images after the replacement with hydrocortisone revealed an atrophic pituitary gland. The patient was referred to our tertiary hospital for further endocrinological examination. Pituitary endocrine load tests revealed isolated adrenocortical response deficiency. After other clinical assessments, he was diagnosed as having isolated ACTH deficiency. After initiation of hydrocortisone replacement, there has been no recurrence of symptoms related to adrenocortical insufficiency nor involvement of other pituitary functions. Conclusion: This is the first reported case of IAD potentially associated with COVID-19 immunization. Recent reports have emphasized the importance of adjuvants in the mRNA vaccine that induce the endocrinological adverse effects through disturbance of the autoimmune system, but details are still unclear. Given the broad and rapid spread of vaccinations against COVID-19, it is clinically important to consider that there could be cases with a rare but emergent adrenal crisis even among those who present common symptoms of adverse effects following inactive SARS-CoV-2 mRNA vaccination. [ABSTRACT FROM AUTHOR]

We report a case of secondary adrenal insufficiency due to nivolumab. An 83-year-old man with acral lentiginous types of melanoma on the right sole visited our department in March 2017. He received primary surgery at referred hospital in June 2017, and pathological stage was IIIC (pT3bN3M0) according to AJCC (American Joint Committee on Cancer) 7th edition criteria. During the follow-up period, a lot of in-transit metastases appeared on the right leg. While we were resecting in-transit metastases, we concurrently started nivolumab in September 2018. After 17 cycles of nivolumab treatment, he developed severe nausea and anorexia. At baseline, his cortisol and adrenocorticotropic hormone levels were both at normal range, but corticotropin-releasing hormone loading test revealed secondary adrenal insufficiency. We diagnosed isolated adrenal insufficiency due to nivolumab. Treatment by hydrocortisone immediately relieved nausea and anorexia, and we could have continued treatment of nivolumab. [ABSTRACT FROM AUTHOR]

Central adrenal insufficiency (AI) due to isolated adrenocorticotropic hormone (ACTH) deficiency (IAD) has been recently associated with immune checkpoint inhibitor (ICI) therapy. Our aim was to analyze the prevalence, clinical characteristics, and therapeutic outcomes in cancer patients with IAD induced by ICI therapy. A retrospective and multicenter study was performed. From a total of 4447 cancer patients treated with ICI antibodies, 37 (0.8%) (23 men (62.2%), mean age 64.7 ± 8.3 years (range 46-79 years)) were diagnosed with IAD. The tumor most frequently related to IAD was lung cancer (n = 20, 54.1%), followed by melanoma (n = 8, 21.6%). The most common ICI antibody inhibitors reported were nivolumab (n = 18, 48.6%), pembrolizumab (n = 16, 43.2%), and ipilimumab (n = 8, 21.6%). About half of the patients (n = 19, 51.4%) had other immune-related adverse events, mainly endocrine adverse effects (n = 10, 27.0%). IAD was diagnosed at a median time of 7.0 months (IQR, 5-12) after starting immunotherapy. The main reported symptom at presentation was fatigue (97.3%), followed by anorexia (81.8%) and general malaise (81.1%). Mean follow-up time since IAD diagnosis was 15.2 ± 12.5 months (range 0.3-55 months). At last visit, all patients continued with hormonal deficiency of ACTH. Median overall survival since IAD diagnosis was 6.0 months. In conclusion, IAD is a rare but a well-established complication associated with ICI therapy in cancer patients. It develops around 7 months after starting the treatment, mainly anti-PD1 antibodies. Recovery of the corticotropic axis function should not be expected. [ABSTRACT FROM AUTHOR]

Abstract Background Several human monoclonal antibodies directed against immune checkpoints, including T lymphocyte antigen 4 and programmed cell death protein 1, have been implemented for cancer treatment in order to promote effector T cell response to tumors. Despite the antitumor activity of these agents, a significant number of patients demonstrated immune-related adverse events that affected the functions of multiple organs, including the endocrine system. We report the first case of immune checkpoint inhibitor–induced simultaneous diabetic ketoacidosis and isolated adrenocorticotropic hormone deficiency following combination treatment with immune checkpoint inhibitors. Case presentation A 70-year-old Thai man with no previous history of diabetes mellitus was diagnosed with stage IVB non–small cell lung with pleural and liver metastases. After 14 weeks of combination treatment with pembrolizumab and ipilimumab, he presented with fatigue, nausea, and vomiting. Laboratory investigation revealed random plasma glucose 794 mg/dl, serum ketone 6.3 mmol/L, bicarbonate 13 mmol/L, and high anion gap 24 mmol/L. New-onset diabetes mellitus and diabetic ketoacidosis were diagnosed. Insulin therapy was initiated a favorable outcome within 10 hours. Despite improvement of hyperglycemia, the patient had persistent nausea and hyponatremia. Further investigation revealed cortisol 0.8 μg/dl and adrenocorticotropic hormone 21.7 pg/ml. His other pituitary hormone levels were normal, except for mild elevation of gonadotropin hormone. Magnetic resonance imaging of the pituitary showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, resulting in an improvement of his symptoms. Conclusion Our patient developed new-onset diabetes mellitus, diabetic ketoacidosis, and isolated adrenocorticotropic hormone deficiency during cancer treatment with pembrolizumab and ipilimumab. The present case highlights the need for physicians to be aware that immune-related adverse events can occur in multiple organs at the same time.

Pembrolizumab (Keytruda®) is an anti-programmed cell death 1-specific monoclonal antibody that has become the standard second-line chemotherapy for unresectable advanced microsatellite instability-high colorectal cancer. Several immune-related adverse events (irAEs), particularly endocrinopathy, are linked to the administration of pembrolizumab. We report here a case of pembrolizumab-induced isolated adrenocorticotropic hormone deficiency in a patient with metastatic colon cancer. A 65-year-old woman visited our hospital for complaints of fatigue with a recent history of primary resection of cecal mucinous cancer and hepatectomy for liver metastasis 3 years ago. Peritoneal dissemination was detected 2 years after surgery. Several chemotherapeutic regimens of cytotoxic and molecular targeted drugs were administered; however, the metastases progressed gradually. Pembrolizumab monotherapy was started because of resistance to treatment. After 2 cycles of pembrolizumab, the patient was severely fatigued. Laboratory data demonstrated that the cortisol level was extremely low. All the other values were within the normal range. Magnetic resonance imaging indicated no mass in the pituitary gland. From multiple tolerance tests, we diagnosed isolated adrenocorticotropic hormone deficiency caused by pembrolizumab. The patient’s symptoms improved promptly with cortisol treatment. An abdominal contrast-enhanced computed tomography scan after 5 cycles of pembrolizumab demonstrated that the size of the peritoneal dissemination remained unchanged. However, her serum level of carcinoembryonic antigen had decreased to normal levels. Endocrine disorders are very rarely seen as irAEs. Careful laboratory data follow-up is required to inhibit the progression of severe endocrine disorders.

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare pituitary disorder that can cause adrenal insufficiency. However, due to its nonspecific symptoms, its diagnosis is often difficult and may be delayed. Patients with IAD require lifelong glucocorticoid (GC) replacement therapy. Contrastingly, GC-induced secondary adrenal insufficiency is a reversible condition that arises when patients receiving GC therapy reduce their GC dosage or discontinue therapy. Differentiating between IAD and GC-induced secondary adrenal insufficiency is clinically crucial. We report a unique case that required differentiation between these two conditions. A 71-year-old Japanese woman presented with symptoms of adrenal insufficiency after discontinuation of GC therapy for eosinophilic esophagitis. We conducted detailed interviews and repeated the endocrinological examinations. We concluded that her symptoms were owing to IAD rather than GC-induced secondary adrenal insufficiency. She began a lifelong hydrocortisone replacement therapy. This case suggests that when caring for patients undergoing GC therapy, it is important to consider the possibility of coexisting IAD and arrange endocrinological examinations if signs of adrenal insufficiency arise during the gradual reduction of GC treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Iwamura et al.)

Pembrolizumab, an anti-programmed death-1 specific monoclonal antibody is a second-line treatment for metastatic urothelial carcinoma. Physicians should be aware of adverse immune-related events associated with the use of immune checkpoint inhibitors, particularly adrenocortical insufficiency, which poses a risk of death.We report a case of secondary adrenocortical insufficiency due to isolated adrenocorticotropic hormone deficiency with empty sella syndrome after pembrolizumab treatment in a patient with metastatic renal pelvic cancer. Fortunately, a therapeutic effect was observed 4 months after discontinuation of pembrolizumab, and a durable antitumor response has persisted for 5 months.

Abstract Introduction Immune checkpoint inhibitors are a promising class of anticancer drugs. The clinical benefits afforded by immune checkpoint inhibitors can be accompanied by immune-related adverse events that affect multiple organs, and endocrine immune-related adverse events include thyroiditis and hypophysitis. Hypophysitis is less frequent and has a less severe clinical presentation in patients treated with other immune checkpoint inhibitors, such as nivolumab, pembrolizumab, and atezolizumab, than in those treated with ipilimumab. However, studies have described isolated adrenocorticotropic hormone deficiency cases associated with nivolumab, pembrolizumab, and atezolizumab therapy, most of which occurred during the course of immune checkpoint inhibitor therapy. We report a rare case of patient with isolated adrenocorticotropic hormone deficiency that occurred after nivolumab therapy. Case presentation A 69-year-old Japanese woman with advanced lung adenocarcinoma developed painless thyroiditis with transient elevations of serum thyroid hormones during 3 months of cancer treatment with nivolumab and began thyroid hormone replacement therapy for subsequent primary hypothyroidism. Four months after nivolumab therapy was discontinued, she developed isolated adrenocorticotropic hormone deficiency; corticosteroid replacement therapy relieved her secondary adrenal insufficiency symptoms, such as anorexia and fatigue. Human leukocyte antigen typing revealed the presence of DRB1*04:05-DQB1*04:01-DQA1*03:03 and DRB1*09:01-DQB1*03:03-DQA1*03:02 haplotypes, which increase susceptibility to autoimmune polyendocrine syndrome associated with thyroid and pituitary disorders in the Japanese population. Conclusions Our patient developed thyroiditis during cancer treatment with nivolumab and subsequently exhibited isolated adrenocorticotropic hormone deficiency 4 months after discontinuing the drug. Administration of nivolumab in combination with a genetic predisposition to polyglandular autoimmunity probably caused both the thyroiditis and hypophysitis, resulting in primary hypothyroidism and isolated adrenocorticotropic hormone deficiency, respectively, in our patient. The present case highlights the need for physicians to be aware that endocrine immune-related adverse events, including hypophysitis, can occur more than several months after discontinuing a drug.

Pembrolizumab (Keytruda®) is an anti-programmed cell death 1-specific monoclonal antibody that has become the standard second-line chemotherapy for unresectable advanced microsatellite instability-high colorectal cancer. Several immune-related adverse events (irAEs), particularly endocrinopathy, are linked to the administration of pembrolizumab. We report here a case of pembrolizumab-induced isolated adrenocorticotropic hormone deficiency in a patient with metastatic colon cancer. A 65-year-old woman visited our hospital for complaints of fatigue with a recent history of primary resection of cecal mucinous cancer and hepatectomy for liver metastasis 3 years ago. Peritoneal dissemination was detected 2 years after surgery. Several chemotherapeutic regimens of cytotoxic and molecular targeted drugs were administered; however, the metastases progressed gradually. Pembrolizumab monotherapy was started because of resistance to treatment. After 2 cycles of pembrolizumab, the patient was severely fatigued. Laboratory data demonstrated that the cortisol level was extremely low. All the other values were within the normal range. Magnetic resonance imaging indicated no mass in the pituitary gland. From multiple tolerance tests, we diagnosed isolated adrenocorticotropic hormone deficiency caused by pembrolizumab. The patient's symptoms improved promptly with cortisol treatment. An abdominal contrast-enhanced computed tomography scan after 5 cycles of pembrolizumab demonstrated that the size of the peritoneal dissemination remained unchanged. However, her serum level of carcinoembryonic antigen had decreased to normal levels. Endocrine disorders are very rarely seen as irAEs. Careful laboratory data follow-up is required to inhibit the progression of severe endocrine disorders. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency (IAD) is a rare but potentially fatal disease., Methods: We comprehensively searched the PubMed database and made a systematic review of immune checkpoint inhibitor-induced isolated adrenocorticotropic hormone deficiency. If the status of other anterior pituitary hormones was not mentioned, the case was excluded., Results: We identified 123 cases diagnosed as immune checkpoint inhibitor-induced IAD, consisting of 44 female and 79 male patients. The average age of these patients was 64.3 ± 12.6 years old, and 67.5% were 60 years old or above. The majority (78.9%) of these patients received anti-programmed cell death protein-1 (anti-PD-1) antibodies or anti-programmed cell death ligand 1 (anti-PD-L1) antibodies or both, and 19.5% received combined therapy, sequential therapy, or both. A total of 26 patients received anti-cytotoxic T lymphocyte antigen 4 antibodies (anti-CTLA-4). The median ICI treatment cycle before the diagnosis of adrenal insufficiency was 8 (6, 12), and the median ICI treatment duration before the diagnosis of adrenal insufficiency was 6 (4, 8) months. Eleven cases developed IAD 1 to 11 months after discontinuation of ICIs. Fatigue and appetite loss were the most common symptoms, and surprisingly, there were two asymptomatic cases of IAD. Most patients (88 cases) had normal pituitary magnetic resonance imaging, only 14 cases reported mild atrophy or swelling pituitary gland, and 21 cases reported no imaging results. Most diagnoses were made by basal hormone levels, and pituitary stimulation tests were performed in only a part of the cases. No cases had been reported of discontinuation of ICI use due to IAD nor had there been any deaths due to IAD., Conclusion: IAD was predominant in elderly male patients mainly receiving anti-PD-1 or anti-PD-L1 antibodies. It was sometimes difficult to recognize IAD at first glance since non-specific symptoms were common and asymptomatic cases of IAD were also reported. Although IAD can be deadly, it usually does not affect the continued use of ICIs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wang, Shi, Yu and Yang.)

Autoimmune mechanisms have been hypothesized to underlie a number of human disorders in which both disease pathogenesis and diagnostic biomarkers remain poorly understood. This is partly due to a lack of efficient techniques for identification of plasma autoantibodies associated with specific pathophysiological conditions. We have developed a novel proteomic methodology to comprehensively identify plasma IgG-bound proteins using liquid chromatography tandem mass spectrometry (LC-MS/MS) after denaturing enriched plasma IgG to solubilize and release low molecular weight proteins. In total, we identified 44 proteins using this method that were undetectable in unprocessed plasma, 21 of which were not identified in the Human Plasma Proteome Draft of 2017. Comparison of plasma IgGbound proteins between healthy subjects and patients with isolated adrenocorticotropic hormone deficiency, a rare endocrine disorder speculated to involve autoimmune mechanisms, revealed several distinct IgG-bound proteins specifically detected in patient plasma but not in healthy subjects. Our results suggest that solubilization of low molecular weight proteins bound to enriched plasma IgG and subsequent proteomic analysis by LC-MS/MS could provide a promising strategy for identification of autoantigens in human peripheral blood. [ABSTRACT FROM AUTHOR]

A 63-year-old man with hepatitis C was treated with atezolizumab plus bevacizumab for unresectable diffuse hepatocellular carcinoma (HCC). After four cycles of atezolizumab plus bevacizumab, the diffuse HCC markedly shrank; however, he complained of general fatigue, loss of appetite, and slight loss of muscle strength in the lower legs. He was diagnosed with isolated adrenocorticotropic hormone deficiency (IAD), hypothyroidism, and myopathy, suggesting multisystem immune-related adverse events (irAEs). After administration of hydrocortisone, the clinical symptoms rapidly disappeared. Patients with multisystem irAEs can have favorable outcomes; thus, to continue immune-checkpoint inhibitors therapy, a correct diagnosis and management of multisystem irAEs are important.

A 23-year-old man was admitted to our hospital for fatigue, anorexia, proteinuria, and peripheral edema. Proteinuria was first pointed out at the age of 15, but no further studies were performed. Six years prior to admission, the patient noted becoming easily fatigued. Laboratory tests on admission showed marked peripheral eosinophilia (29.2%, count: 1,071/μL) and proteinuria. Endocrinological studies revealed isolated adrenocorticotropic hormone deficiency with primary hypothyroidism, but a lack of autoimmune thyroiditis. Renal biopsy showed focal segmental glomerulosclerosis. Hydrocortisone therapy (30 mg/day) for isolated adrenocorticotropic hormone deficiency resulted in marked improvement of adrenal and thyroid functions, and amelioration of proteinuria (from 2.8 to 1.0 g/day) over a two-month period. Renal function remains normal at five years after the start of hydrocortisone treatment. The findings suggest that both hydrocortisone therapy and normalized thyroid hormone status played a pivotal role in the improvement of proteinuria associated with focal segmental glomerulosclerosis. [ABSTRACT FROM AUTHOR]

Objective: It was the aim of this study to describe a patient with isolated adrenocorticotropic hormone deficiency presenting with a variety of involuntary movements who developed an adrenal crisis due to transient thyroiditis. Clinical Presentation and Intervention: A 61-year-old man was hospitalized with a variety of involuntary movements that were suspected manifestations of metabolic encephalopathy. After admission, his general status rapidly deteriorated to a life-threatening condition that included a degree of hyponatremia. The hyponatremia and metabolic encephalopathy provided clues toward a definitive diagnosis. After corticosteroid and sodium supplementation improved the status of the patient, endocrinological examinations revealed that he suffered from isolated adrenocorticotropic hormone deficiency followed by transient thyroiditis that induced an adrenal crisis. Conclusion: This case emphasizes the importance of considering hypoadrenalism when encountering hyponatremia or metabolic encephalopathy of unknown etiology. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Isolated adrenocorticotropic hormone deficiency (IAD) is a cause of adrenal insufficiency (AI), which shows impaired secretion of adrenocorticotropic hormone (ACTH) with the preserved secretion of other anterior pituitary gland hormones. We herein report a case of IAD complicated by chronic thyroiditis presenting with neuropsychiatric symptoms without other signs indicative of AI that showed complete improvement of the cognitive function after the administration of corticosteroids. The clinical features of our case may be confused with autoimmune encephalopathies (AEs); however, IAD should be strictly differentiated from AEs, as it requires permanent hormone replacement without addition of immunosuppressive agents.

The delayed diagnosis of adrenal insufficiency is relatively common because its symptoms are non-specific. One of the causes of adrenal insufficiency is isolated adrenocorticotropic hormone deficiency (IAD), which is sometimes caused by traumatic brain injury. Indeed, severe head trauma is considered to contribute to the incidence of this disease. However, the relationship between milder head trauma-such as chronic subdural hematoma - and the occurrence of hormonal deficiency is uncertain. We herein report the case of a 79-year-old man with IAD who presented with leg edema and pain in his extremities following a recent history of chronic subdural hematoma.