Isolated ACTH Deficiency Research Articles

MON-361 Isolated ACTH Deficiency after Treatment with Immune-Checkpoint Inhibitors

Background: Immune-checkpoint inhibitors targeting PDI or CTLA-4 are promising therapies in metastatic malignancies, including metastatic melanoma, and their usage has been increasing over the last few years. As more patients are treated with these agents, there will likely be an increased incidence of the relatively rare endocrine adverse events. Clinical Case: A 58-year-old New Orleans rock musician with metastatic melanoma underwent chemotherapy in 2015 with an anti-CTLA-4 checkpoint inhibitor (Ipilimumab at 3 mg/kg IV every 3 weeks for 4 cycles, given over 3 months). He later had progression of disease on imaging so was switched to an anti-PD1 checkpoint inhibitor (Pembrolizumab at 2 mg/kg IV every 3 weeks). Within 6 weeks of starting Pembrolizumab, he developed fatigue, weakness, nausea, and a loss of appetite. Within 10 months of starting immune checkpoint inhibitor therapy, he had lost 40 lbs - 28.6% of his pre-checkpoint inhibitor body weight - and he was too weak to continue his career as a rock musician. In response to his failure to thrive, the Endocrinology service consulted on his case. His endocrine evaluation revealed a severe ACTH deficiency (8 am ACTH <1.1 pg/mL, normal 7-69) and a failed response to Cosyntropin stimulation - after a 0.25 mg IV cosyntropin injection, his cortisol level increased from <0.4 micrograms/dL to 1.2 micrograms/dL at 30 minutes and to 1.4 micrograms/dL at 60 minutes. Other pituitary hormone levels drawn at 3pm (when he would awaken from sleep) revealed normal LH (6.2 mIU/mL, normal 2.0-12.0), FSH (13.8 mIU/mL, normal 1.5-15), testosterone (577 ng/dL, normal 175-781), prolactin (4.1 ng/mL, normal 1.0-18.0), IGF-1 (118 ng/mL, normal 68-245), TSH (4.45 uIU/mL, normal 0.5-5.0), and free T4 (0.71, normal 0.60-1.15). He was started on a stress dose of IV hydrocortisone then transitioned to an oral maintenance dose of 20 mg hydrocortisone daily. He has gained back the weight he lost and has returned to a successful career as a rock musician. Conclusion: This report presents a case of isolated ACTH deficiency after treatment with immune checkpoint inhibitors targeting CTLA-4 and PD1. It is a unique case due to the rare finding of an isolated ACTH deficiency. The prolonged illness and weight loss that the patient experienced as a consequence of secondary adrenal insufficiency emphasizes the importance of selective case screening of patients on immune checkpoint inhibitors for endocrinopathies.

SUN-412 A Unique Case of Isolated ACTH Deficiency Caused by Pembrolizumab

Background: The anti-programmed-death-receptor-1 (PD-1) antibody, pembrolizumab, is one of the key immunomodulators for different types of refractory cancers. It is known to cause a variety of endocrinopathies including hypothyroidism, hyperthyroidism, diabetes mellitus, hypophysitis and primary adrenal insufficiency. However, to our knowledge, there are no reports of isolated ACTH deficiency caused by pembrolizumab. Clinical Case: A 61 yo man with a history of Stage IVA (T3, N3, M1b) poorly differentiated pleomorphic NSCLC presented to hospital with 2 weeks of worsening weakness and lightheadedness. Biopsy results revealed >95% PD-L1 expression and he was started on pembrolizumab 200 mg (4.5 mg/kg) every 3 weeks, along with palliative radiation to the right upper chest. Approximately 1 week after the patient’s 6th dose of pembrolizumab, he became weak and lightheaded and was admitted for further management. BP was 95/58 mmHg and biochemical studies demonstrated hyponatremia with a Na 119 mEq/L and K 4.3 mEq/L. . Due to a high suspicion for adrenal insufficiency, an AM cortisol was checked and was undetectable (<1 mcg/dl). Radiologic images were reviewed and the adrenal glands normal in appearance, ruling out metastatic involvement. Subsequent studies demonstrated an undetectable ACTH but FSH, LH, PRL, TSH, free T4 and IGF-1 were all within normal limits. Aldosterone was also normal (13 ng/dL). A Cortrosyn stimulation test demonstrated a flat response (0 min: cortisol <1 microg/dL ; 60 min: cortisol 1.6 microg/dL), consistent with adrenal atrophy. Adrenal antibodies were absent. The patient was started on hydrocortisone, 10 mg in AM and 5 mg at PM. Sodium improved to 133 mEq/L on discharge and remained at 134 mEq/L on follow up with K of 4.0 mEq/L.. Conclusion: Although multiple endocrinopathies have been observed with pembrolizumab, isolated ACTH deficiency has not been previously reported. As immune checkpoint inhibitors are used widely for the treatment of multiple refractory cancers, one should have a heighted awareness for the development of autoimmune endocrine disorders that may include primary or secondary adrenal insufficiency.

SAT-LB079 Clinical Heterogeneity of Acquired Idiopathic ACTH Deficiency: A New Classification Based on the Clinical Characteristics and Autoantibodies

[Background] In acquired idiopathic isolated ACTH deficiency (IAD), anti-pituitary antibodies are reportedly detected in a part of the patients; however, the significance of the antibodies remains unclarified. [Subjects and methods] Forty-six patients with IAD who diagnosed between 1992 and 2018 were retrospectively analyzed. Serum anti-corticotroph and anti-follicular stellate cell (FSC) antibody were analyzed using immunofluorescence staining in 33 patients, whose serum was available. We performed principle component and cluster analysis for the clarification of pathophysiology of IAD based on the clinical characteristics and autoantibodies. [Results] Among 46 patients, male was predominant (63%). The average age of the onset of IAD was 58.1 ± 12.3 years and that in male was significantly older (male vs. female: 62.8 ± 9.3 vs. 50.1 ± 13.0 years, P < 0.01). Forty-one % of the patients exhibited other autoimmune diseases including chronic thyroiditis. Interestingly, 58% of the patients exhibited anti-corticotroph antibody and 6% exhibited anti-FSC antibody in the serum. Principle component analysis demonstrated that 69.6% of the patients were explained by following 3 components; 1) age and gender, 2) the presence of antibody against corticotroph or FSC and the serum ACTH level, 3) the presence of other autoimmune disease. Cluster analysis demonstrated that the patients can be divided into 3 groups; A) middle-aged male (60.9 ± 10.3 years) with low ACTH values at the onset (2.2 ± 5.6 pg/mL) and positive for the anti-coricotroph antibody (73.3%), B) elderly male (72.8 ± 3.8 years) with relatively high ACTH values (21.1 ± 10.3 pg/mL), including positive for the anti-FSC antibody (50%), C) middle-aged female (45.3 ± 11.2 years) with low ACTH values at the onset (3.8 ± 5.8 pg/mL), and positive for the anti-corticotroph antibody (60%). [Discussion] These data clearly showed the clinical heterogeneity of IAD and suggested a presence of different pathogenesis. Group A and C were characterized by a high prevalence of anti-corticotroph antibody and low levels of serum ACTH, suggesting a presence of specific autoimmunity against corticotroph resulting in a severe injury of corticotrophs. Interestingly, group B was characterized by the most elderly male with relatively high ACTH levels and half of the patients exhibited anti-FSC antibody. It is suggested that anti-FSC antibody is a novel marker for IAD especially in elderly male patients. In this group, it is speculated that the corticotroph function was indirectly impaired because of the injury of FSCs. Although further investigations are necessary, our data enabled a useful classification of IAD especially for the clarification of the pathogenesis. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

Late-onset isolated adrenocorticotropic hormone deficiency caused by nivolumab: a case report

BackgroundImmune checkpoint inhibitors including nivolumab, an anti-programmed cell death protein 1 antibody, are recently developed cancer immunotherapy agents. Immune checkpoint inhibitors are known to cause autoimmune-related side effects including endocrine dysfunctions. However, there are few reports on late-onset isolated adrenocorticotropic hormone (ACTH) deficiency caused by nivolumab.Case presentationThe patient was a 72-year-old female. When she was 64 years old, she was diagnosed with malignant melanoma of the left thigh accompanied by left inguinal lymph node metastases, and she received several courses of chemotherapy for malignant melanoma followed by the resection of these lesions. At 71 years of age, multiple metastases were found and treatment with nivolumab 2 mg/kg every 3 weeks was initiated. Six months later, replacement with levothyroxine was started because of hypothyroidism following mild transient thyrotoxicosis. Eleven months after the beginning of nivolumab, the treatment was discontinued because of tumor expansion. Four months after the discontinuation of nivolumab, general malaise and appetite loss worsened, and 2 months later, hyponatremia (Na; 120–127 mEq/L) and hypoglycemia (fasting plasma glucose; 62 mg/dL) appeared. Her ACTH and cortisol levels were extremely low (ACTH; 9.6 pg/mL, cortisol; undetectable). Challenge tests for anterior pituitary hormones showed that responses of ACTH and cortisol secretion to corticotropin-releasing hormone were disappeared, although responses of other anterior pituitary hormones were preserved. Thus, she was diagnosed with isolated ACTH deficiency. Her symptoms were improved after treatment with hydrocortisone.ConclusionsThe present report showed a case of late-onset isolated ACTH deficiency accompanied by hyponatremia, which was diagnosed 6 months after the discontinuation of nivolumab. The effects of nivolumab last for a long time and the side effects of nivolumab can also appear several months after discontinuation of the drug. Repeated monitoring of serum sodium levels may be a beneficial strategy to find the unexpected development of adrenal insufficiency even after discontinuation of nivolumab.

A Case of Isolated Adrenocorticotropin Deficiency with Flexion Contractures Improved by Steroid Replacement Therapy and Rehabilitation

A Case of Isolated Adrenocorticotropin Deficiency with Flexion Contractures Improved by Steroid Replacement Therapy and Rehabilitation

Isolated adrenocorticotropic hormone deficiency potentially induced by nivolumab following pseudo-progression in clear cell renal cell carcinoma: A case report.

Nivolumab is a monoclonal immunoglobulin G antibody blocking programmed death receptor-1 (PD-1) that promotes the restoration of the natural T-cell-mediated immune response against cancer cells; however, it also causes a number of autoimmune-related adverse events (irAEs) that often involve the endocrine system. The present report describes a 71-year-old man with clear cell renal cell carcinoma metastasis in the lung. Following the 14th course of nivolumab therapy, the patient complained of general malaise, loss of appetite and mild consciousness disturbance. Laboratory tests revealed a severely elevated eosinophil ratio (26.2%) and low sodium value (122 mmol/l). Endocrine system tests revealed that the patient's adrenocorticotropic hormone (ACTH; 4.5 pg/ml) and cortisol (0.1 µg/dl) levels were lower than normal, while those of other pituitary hormones were higher than normal. This case was therefore diagnosed as isolated ACTH deficiency induced by nivolumab. Magnetic resonance imaging (MRI) showed normal pituitary glands. Hydrocortisone replacement therapy improved the clinical symptoms early and enabled the patient to restart nivolumab therapy. Isolated ACTH deficiency due to nivolumab, a PD-1 immune checkpoint inhibitor antibody, is a rare occurrence. This report may be useful for avoiding delays in the diagnosis and treatment of this life-threatening irAE even if no pituitary abnormalities are identified via MRI.

Missplicing due to a silent exonic substitution in the T-box transcription factor TBX19 resulting in Isolated ACTH deficiency

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

Two cases of traumatic isolated ACTH deficiency

Case 1: A 65- year-old man was accidentally injured by wooden hammer on his top of head on 34 years before. He was suffered from vomiting, diarrhea and hypotension, and the laboratory examination revealed increased CRP level, hyponatremia and decreased plasma cortisol and ACTH levels, suggesting isolated ACTH deficiency and Crohn disease diagnosed by colonoscopic biopsy, and finally transferred to University Hospital. LH-RH, TRH, CRH and GHRP stimulation tests showed normal response of plasma pituitary hormones except for no response of plasma ACTH and cortisol levels by CRH stimulation. ACTH stimulation test showed no response of plasma cortisol levels although hydrocotisone replacement therapy had already been started. MRI imaging showed bottom of anterior lobe was crushed and pituitary gland was atrophied, which suggested brain might be injured by any strong trauma.

Prolonged QT intervals in a patient with empty sella and isolated ACTH deficiency.

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

Avoiding diagnostic errors in psychosomatic medicine: a case series study

BackgroundNon-organic lesions or diseases of unknown origin are sometimes misdiagnosed as “psychogenic” disorders or “psychosomatic” diseases. For the quality of life and safety of patients, recent attention has focused on diagnostic error. The aim of this study was to clarify the factors that affected misdiagnoses in psychosomatic medicine by examining typical cases and to explore strategies that reduce diagnostic errors.Case presentationThe study period was from January 2001 to August 2017. The data of patients who had visited the Department of Psychosomatic Medicine, Kindai University Hospital and its branches, Sakai Hospital and Nihonbashi Clinic, were collected. All patients were aged 16 years or over. Multiple factors, such as age, sex, presenting symptoms, initial diagnosis, final diagnosis, sources of re-diagnosis and types of diagnostic errors were retrospectively analyzed from the medical charts of 20 patients. Among them, four typical cases can be described as follows. Case 1; a 79-year-old woman, initially diagnosed with psychogenic vomiting due to depression that was changed to gastric torsion as the final diagnosis. Case 2; a 24-year-old man, diagnosed with an eating disorder that was later changed to esophageal achalasia. Case 10; a 60-year-old woman’s diagnosis changed from conversion disorder to localized muscle atrophy. Case 19; a 68-year-old man, appetite loss from depression due to cancer changed to secondary adrenal insufficiency, isolated ACTH deficiency (IAD).ConclusionThis study showed that multiple factors related to misdiagnoses were combined and had a mutual influence. However, they can be summarized into two important clinical observations, diagnostic system-related problems and provider issues. Provider issues contain mainly cognitive biases such as Anchoring, Availability, Confirmation bias, Delayed diagnosis, and Representativeness. In order to avoid diagnostic errors, both a diagnostic system approach and the reduction of cognitive biases are needed. Psychosomatic medicine doctors should pay more attention to physical symptoms and systemic examination and can play an important role in accepting a perception of patients based on a good, non prejudicial patient/physician relationship.

Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review: Erratum.

Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review: Erratum.

Clinical features and autoimmune associations in patients presenting with Idiopathic Isolated ACTH deficiency.

Idiopathic Isolated ATCH deficiency (IIAD) is a rare cause of secondary adrenal insufficiency. As the condition is rare, and the diagnostic criteria ill-defined, there are few good clinical descriptions in the literature. We have described presenting features, autoimmune associations, natural history and responses to CRF, in a large case series of patients presenting with IIAD. This is a retrospective case note analysis with data derived from the recently commenced National Pituitary Database of Ireland. Twenty-three patients with isolated ACTH deficiency were identified. A thorough chart and biochemistry review was performed. Twenty-three patients were examined (18 women and 5 men). Age at presentation ranged from 17 to 88years, (median 48years). Most patients complained of fatigue; 9 patients presented with hyponatraemia, 13 had autoimmune illnesses (primary hypothyroidism, n=9). CRF stimulation testing was available in 12 of the 23 patients, 5 of whom demonstrated a rise in plasma ACTH concentrations, indicating hypothalamic, rather than pituitary aetiology. Two patients recovered ACTH secretion, and 2 patients progressed to have other pituitary hormone deficiencies. IIAD typically presents with insidious symptoms. Euvolaemic hyponatraemia is common at diagnosis. It is associated with autoimmune diseases, particularly primary hypothyroidism. As two patients recovered ACTH secretion, and two progressed to other pituitary hormone deficits, repeat pituitary testing should be considered, to identify recovery of function, or progression to other hormone deficits.

Isolated Adrenocorticotropic Hormone Deficiency and Severe Hypercalcemia After Destructive Thyroiditis in a Patient on Nivolumab Therapy With a Malignant Melanoma

We describe a 58-year-old man with a malignant melanoma metastasis to the liver. After initiation of nivolumab therapy, he developed destructive thyroiditis and subsequently simultaneous isolated adrenocorticotropic hormone (ACTH) deficiency and severe hypercalcemia. Although isolated ACTH deficiency and hypercalcemia due to nivolumab therapy are both rare occurrences, these conditions can often cause a severe clinical course accompanied by a disturbance of consciousness. Therefore, clinicians should pay attention to these possible side effects of nivolumab if the patients have clinical symptoms, such as fatigue and a disturbance of consciousness.

Two Cases of Isolated ACTH Deficiency Presenting As Hyponatremia - Case Report

Non-specific symptoms such as asthenia, anorexia, unintentional weight loss, nausea/vomiting particularly in the elderly population are often overlooked both by caretakers and physicians. Deteriorating general health and neuro-psychiatric symptoms are often attributed to depression in the elderly population. The most common electrolyte abnormality, hyponatremia is again more common in the elderly population. Often neglected chronic hyponatremia remains asymptomatic in many cases. Once hyponatremia is detected clinicians should establish a proper diagnosis before supplementation. Failure to diagnose such cases will lead to repeated hospitalization, poor quality of life, wastage of resources and even death. Isolated ACTH deficiency (IAD) is a rare disorder and potentially fatal. IAD can present rarely as hyponatremia and diagnosis can easily be missed if not suspected. IAD may not be as rare as earlier thought as more and more such cases are been reported. Here we report two cases of generalized weakness and nausea; they were repeatedly hospitalized and treated for hyponatremia and ultimately diagnosed as IAD in our hospital.

Adrenal Insufficiency Related to Anti-Programmed Death-1 Therapy.

Adrenal insufficiency is one of the adverse events (AEs) associated with anti-programmed death-1 (PD1) therapy. Delaying diagnoses can lead to serious conditions. It is necessary to elucidate detailed clinical features of these AEs. Patients treated with anti-PD-1 monotherapy or in combination with anti-cytotoxic T cell lymphocyte-4 therapy at our hospital from January 2013 to December 2016 were identified. The patients' clinical characteristics and laboratory and radiologic findings were collected. Adrenal insufficiency occurred in 3% of the patients. All patients were male. At the onset of symptoms, eosinophilia (>500/μl) was observed in four cases. Eosinophilia was observed more than a month before onset of symptoms in three cases. Other pituitary hormones remained relatively stable. Radiological evidence of pituitary inflammation was detected only in one case. Most anti-PD1-related adrenal insufficiency cases involved an isolated ACTH deficiency. Eosinophilia may be an early indicator before the onset of symptoms.

Isolated ACTH deficiency in a patient with empty sella as revealed by severe hyponatremia

Hyponatremia due to isolated adrenocorticotropic hormone (ACTH) deficiency is difficult to diagnose as it is usually indistinguishable from non-endocrine syndrome of inappropriate antidiuretic hormone secretion (SIADH). We present a case secondary to empty sella. Most patients with empty sella remain asymptomatic throughout life and require no treatment; however, in cases involving the development of isolated ACTH deficiency, corticosteroid treatment should be enforced to avoid fatal consequences.

Prolonged QT Intervals in Isolated ACTH Deficiency: Case Report and Mini Review of Literature

Isolated adrenocorticotropic hormone (ACTH) deficiency is a rare disorder, characterized by secondary adrenal insufficiency. We experienced a case of isolated ACTH deficiency presented with prolonged QT intervals which was helpful in diagnosis. Hereby we report our case and review the previous cases. We describe a 77 year-old female whose major complaints were general malaise, anorexia, and depression. On admission, QT intervals of ECG were prolonged. Endocrine tests indicated that she was suffering from isolated ACTH deficiency. After hydrocortisone replacement therapy was started, QT intervals were shortened and all of her complaints were resolved. There are only six reports about isolated ACTH deficiency associated with prolonged QT intervals until now. Prolongation of QT intervals is known to be a risk factor for cardiovascular events such as ventricular fibrillation, but interestingly prolonged QT intervals associated with isolated ACTH deficiency infrequently cause lethal arrhythmia. The initial symptoms of adrenal deficiency in elderly patients are obscure and adrenal deficiency is often misdiagnosed as unidentified clinical syndrome. It is important to consider isolated ACTH deficiency when recognizing unexplained prolonged QT intervals.

Treatable Bedridden Elderly -Recovery from Flexion Contracture after Cortisol Replacement in a Patient with Isolated Adrenocorticotropic Hormone Deficiency

Isolated adrenocorticotropic hormone deficiency (IAD) is a rare disorder with diverse clinical presentations. A 79-year-old man was bedridden for six months due to flexion contractures of the bilateral hips and knees, along with hyponatremia. He was diagnosed with IAD based on the results of endocrine tests. After one month of corticosteroid replacement, he recovered and was able to stand up by himself. Although flexion contracture is a rare symptom of IAD, steroid replacement therapy may be effective, even for seemingly irreversibly bedridden elderly patients. In bedridden elderly patients with flexion contractures, we should consider and look for any signs of adrenal insufficiency.

A case of isolated ACTH deficiency detected by NST

A case of isolated ACTH deficiency detected by NST

Spontaneous and tetracosactide-induced anti-ACTH antibodies in man.

SummaryContextDuring a clinical trial of regular tetracosactide depot injections, four of 13 patients with autoimmune Addison's disease (AAD) developed adverse reactions immediately following tetracosactide injections. We wished to investigate whether these adverse effects could be due to the production of circulating antitetracosactide (ACTH1–24) antibodies.DesignAnti‐ACTH binding activity was investigated using immunoblotting and ELISA on sera from participants in the trial (n = 13; baseline and after tetracosactide exposure), 131 unrelated patients with AAD, 92 patients with Graves’ disease (GD), 15 patients with isolated ACTH deficiency and 102 controls. Immunohistochemistry of human pituitary tissue sections was also performed using pooled sera.ResultsBands at approximately 4 and 6 kDa, corresponding to ACTH1–24 and full‐length ACTH1–39, respectively, were found in 10 of 13 (77%) of sera from trial patients exposed to tetracosactide, including all those who had an adverse reaction. This is in contrast with healthy control sera, which showed no binding. The same 10 subjects also showed high levels of binding to tetracosactide by ELISA, along with 21% of patients with AAD, 14% of patients with GD (both P < 0·001 compared to controls) and 1 isolated ACTH deficiency patient (7% of 15). These sera also recognized native ACTH in human pituitary sections.ConclusionOur study demonstrates that repeated administration of depot tetracosactide can lead to anti‐ACTH1–24 autoreactivity. In addition, a significant number of patients with AAD and GD also had similar, spontaneous, anti‐ACTH reactivity. The presence of these antibodies could mediate some of the adverse effects or explain the well‐described phenomenon of resistance to chronic ACTH therapy.