Two Cases of Pembrolizumab-Induced Secondary Adrenal Insufficiency

Abstract Title: Two cases of pembrolizumab-induced secondary adrenal insufficiency Background: Although few cases regarding pembrolizumab-induced secondary adrenal insufficiency were reported, it has recently been published that significantly higher prevalence of human leucocyte antigen (HLA)-DR15, B52, and Cw12 was revealed in 11 Japanese patients with immune checkpoint inhibitor-induced secondary adrenal insufficiency as compared with healthy controls and DR15 might be a predictive marker. This is based on the evidence that DR15 has associations with IL-17-mediated autoimmune disease such as Hashimoto’s thyroiditis, and that anti-programmed death 1 (PD-1) inhibitors activate the Th1 and Th17 pathways. We here introduce two Japanese patients with pembrolizumab-induced secondary adrenal insufficiency from a viewpoint of their HLA typing test results. Clinical Case: Case 1. A 52-year old male diagnosed with stage IV lung cancer (squamous non-small cell lung cancer) was treated with chemotherapy consisting of carboplatin, nab-paclitaxel, and pembrolizumab. Six days after the fourth cycle of pembrolizumab, he suffered from hypoglycemia and hyponatremia. Endocrinological examination findings showed ACTH and cortisol deficiency throughout the day, after which a diagnosis of secondary adrenal insufficiency was made based on no response shown in insulin tolerance, anterior pituitary function, and rapid ACTH stimulation tests. Pituitary cell antibody-1 was negative, and no evidence of a swollen/atrophied pituitary gland or space occupying lesion was observed in magnetic resonance imaging (MRI) results. Furthermore, Hashimoto’s thyroiditis was suspected based on anti-thyroid peroxidase antibody positivity. HLA typing test results highly corresponded with the reported results (A24, B52, Cw12, DR4, DR15). Case 2. A 70-year old male was treated with pembrolizumab for recurrence of lung squamous cell carcinoma (stage IV). Two weeks after completion of five cycles, severe diarrhea occurred, suspected to be a side effect of pembrolizumab, which was relieved with temporary use of prednisolone. However, diarrhea recured accompanied with a high fever, eosinophilia, and acute hyponatremia. Based on results showing deficiency of ACTH and cortisol, adrenal insufficiency was suspected. Anterior pituitary function and rapid ACTH stimulation test results supported that diagnosis, while pituitary cell antibody-1 was negative and MRI findings were not remarkable. Notably, completely different HLA typing test results were observed. Conclusion: Similar to the previous report, HLA-A24, B52, Cw12, DR4, and DR15 were found in case 1, whereas all subtypes including HLA-DR15 were lacking in case 2. We think that it should not be given low priority for cases lacking DR15 and the possibility of an association with IL-17 in such cases is required in feature study.

Download Full-text

Secondary Adrenal Insufficiency Is Associated with Poor Survival Outcomes in Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5631.5631 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5631-5631

Author(s):

Seo-Yeon Ahn ◽

Sung-Hoon Jung ◽

Hee Kyung Kim ◽

Ho-Cheol Kang ◽

Deok-Hwan Yang ◽

...

Keyword(s):

Multiple Myeloma ◽

Adrenal Insufficiency ◽

Clinical Significance ◽

Predictive Factors ◽

Conflicts Of Interest ◽

Hospitalized Patients ◽

Survival Outcomes ◽

Secondary Adrenal Insufficiency ◽

Poor Survival ◽

Acth Stimulation

Abstract Background: Glucocorticoids has been a backbone of various treatment regimens for multiple myeloma (MM). The repeated and chronic use of high doses of glucocorticoids is associated with development of secondary adrenal insufficiency (AI), and AI could be a major problem in critically-ill patients. However, there has been no specialized data about incidence and clinical significance of secondary AI in hospitalized patients with MM. Purpose: The objective of this retrospective study is to evaluate incidence, predictive factors, and clinical significance of secondary AI in hospitalized patients with MM. Methods: We retrospectively evaluated medical records of MM patients who were hospitalized in Chonnam National University Hwasun Hospital, South Korea from December 2014 to December 2015. The definite AI was diagnosed when the peak cortisol concentration was less than < 500 nmol/L (18 mcg/dL) after ACTH administration. Results: Between December 2014 and December 2015, 77 patients were hospitalized, and 58 underwent rapid ACTH stimulation test. The most frequent cause of hospitalization was infection (70.7%), followed by weakness (24.1%), and the others (5.3%). The definite AI was confirmed in 19 patients (32.7%). To evaluate the predictive factors of AI, all variables including clinical characteristics, laboratory results, cumulative steroid dose, and treatment duration at hospitalization were analyzed, but there were no significant predictors for AI. In addition, the patients with AI had a significantly poor survival outcomes compared to those without AI (the median overall survival of 42.3 months vs. 82.7 months; P = 0.037) (Figure 1). Conclusions: This study showed that the secondary AI is not a rare condition among hospitalized patients with MM, and there was no specific predictable symptoms or signs. In addition, development of AI in the treatment period is associated with a poor prognosis. This study suggests that evaluation of AI is routinely needed in hospitalized patients with MM. Disclosures No relevant conflicts of interest to declare.

Download Full-text

Type 4 Renal Tubular Acidosis (RTA) Induced by Spironolactone Use in Secondary Adrenal Insufficiency

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.329 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A162-A163

Author(s):

Claudia Villatoro Santos ◽

Lisa De Rose ◽

Nikoletta Proudan

Keyword(s):

Adrenal Insufficiency ◽

Renal Tubular Acidosis ◽

The Elderly ◽

Altered Mental Status ◽

Secondary Adrenal Insufficiency ◽

Acth Stimulation ◽

Primary Adrenal Insufficiency ◽

Inhaled Steroids ◽

Baseline Cortisol ◽

Renal Tubular

Abstract Type 4 RTA is caused by either decreased aldosterone production or resistance. Primary adrenal insufficiency results in decreased aldosterone whereas spironolactone can cause aldosterone resistance1. We present a case of spironolactone-induced type 4 RTA in a patient with suspected primary adrenal insufficiency. A 70-year-old female with liver cirrhosis on spironolactone and chronic bronchitis on inhaled steroids (ICS) presented for altered mental status. Laboratories showed hyponatremia 131 mmol/L (135–145 mmol/L) and hyperammonemia 113 µmol/L (11–51 µmol/L). She was successfully treated with oral lactulose for hepatic encephalopathy. However, on day 3, she developed worsening hyponatremia (126 mmol/L) and hyperkalemia 5.8 mmol/L (3.5–5.4 mmol/L). Spironolactone was discontinued, and hyperkalemia improved after medical treatment. Nonetheless, hyperkalemia recurred with worsening hyponatremia (125 mmol/L), hypoglycemia (57 mg/dL), and mild non-anion gap metabolic acidosis without other signs or symptoms of adrenal insufficiency. On day 5, her morning cortisol was 1.5 µg/dL (5–20 µg/dL), with ACTH 11 pg/mL (6–70 pg/mL). Her hyperkalemia persisted (6.3–6.8 mmol/L), and she was started on oral patiromer. Due to suspected adrenal insufficiency, she received dexamethasone 10 mg daily, and endocrinology was consulted. On day 7, an ACTH stimulation test (250 µg IV) showed a baseline ACTH <3 pg/mL, baseline cortisol 0.7 µg/dL (3–15 µg/dL), cortisol 30 minutes 9.9 µg/dL, and 60 minutes 12.2 µg/dL, consistent with incomplete response attributed to the supraphysiologic dexamethasone versus chronic ICS. On day 8, endocrinology discontinued dexamethasone and enoxaparin, and started hydrocortisone 10 mg orally in AM and 5 mg in PM. Aldosterone (measured at day 6) was 7.2 ng/dL (<= 31.0 ng/dL), renin activity 3.1 ng/mL/hr (0.5–4.0 ng/mL/hr), and aldosterone/renin ratio 2.3 (<= 25) consistent with hyporeninemic hypoaldosteronism since aldosterone and renin were inappropriately normal for the hyperkalemia. Repeat cosyntropin test on day 11 showed low ACTH (3 pg/mL), low baseline cortisol 1.1 µg/dL, cortisol 30 minutes 7.9 µg/dL, and 60 minutes 11.2 µg/dL, consistent with secondary adrenal insufficiency, ascribed to chronic ICS. Potassium level normalized seven days after spironolactone discontinuation, related to its approximate duration of action1. The patient was discharged with hydrocortisone 10 mg daily, and spironolactone was permanently discontinued. Spironolactone use can result in type 4 RTA due to aldosterone resistance and mimic mineralocorticoid deficits characteristic of primary adrenal insufficiency. 1. O’Connell JE, Colledge NR. Type IV renal tubular acidosis and spironolactone therapy in the elderly. Postgrad Med J. 1993;69(817):887–889.

Download Full-text

SUN-276 Pembrolizumab-Induced Secondary Adrenal Insufficiency Presenting as Severe Hyponatremia in an 80-Year-Old Male

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.703 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Cited By ~ 1

Author(s):

Leslie Daphne R Kawaji ◽

Mary Grace M Villanueva ◽

Michael L Villa

Keyword(s):

Adverse Events ◽

Adrenal Insufficiency ◽

Endocrine System ◽

Stage Iv ◽

Blood Chemistry ◽

Oral Feeding ◽

Low Grade ◽

Thyroid Function Tests ◽

Secondary Adrenal Insufficiency ◽

Severe Hyponatremia

Abstract Background Pembrolizumab is an anti-programmed death 1 (PD-1) antibody designed to incite an immune response against malignant cells. By virtue of this mechanism of action, its use has given rise to immune-related adverse events including those affecting the endocrine system. Adrenal insufficiency can occur rarely with anti-PD-1 therapy, and symptoms are usually non-specific. Clinical Case An 80-year-old male, known case of non-small cell lung cancer stage IV presented with a 2-week history of progressive body weakness with anorexia, shortness of breath and low-grade fever. He had just received the 4th cycle of pembrolizumab prior to the onset of symptoms. Past medical history was significant for hypertension and type 2 diabetes mellitus which were both controlled, and pulmonary tuberculosis with completed treatment. On physical examination, he was drowsy but oriented. He was normotensive (110/70 mmHg) and tachypneic (28 cpm) with rales on both lung fields. Baseline capillary glucose level was 107 mg/dL. Chest radiograph showed hazy opacities in the right upper to middle region. Blood chemistry revealed severe hyponatremia (114 mmol/L, NV 135-145 mmol/L) and low serum osmolality (247 mOsm/kg, NV 280-300 mOsm/kg). Random (taken 1230H) ACTH and cortisol were <5.00 pg/mL (NV <46 pg/mL) and 2.00 μg/dL (NV 4.30-22.40 μg/dL), respectively. Such levels were judged to be low in the background of an acute illness. Thyroid function tests were normal – TSH 0.993 μIU/mL (NV 0.55-4.78 uIU/mL), FT3 3.890 pg/mL (2.30-4.20 pg/mL), FT4 1.450 ng/dL (0.89-1.76 ng/dL). Magnetic resonance imaging of the pituitary gland did not show abnormal parenchymal enhancement or enlargement. Pembrolizumab-induced secondary adrenal insufficiency was the most probable cause of the hyponatremia. He was started on IV hydrocortisone, as well as piperacillin-tazobactam for pneumonia. Oxygen support via nasal cannula was given. Feeding via nasogastric tube was decided to ensure nutrition and prevent aspiration. He was transferred to the intensive care unit for careful monitoring. Serum sodium level was corrected gradually, with marked clinical improvement thereafter. Within 48 hours, he was transferred to regular room and oral feeding commenced. Hydrocortisone was shifted to prednisone on discharge, with steroid tapering schedule and close follow-up with endocrinologist advised. Conclusion We presented a case of secondary adrenal insufficiency which likely resulted from hypophysitis induced by pembrolizumab. Hypophysitis following anti-PD1 treatment occurs in <1% of patients on immunotherapy. In such cases, ACTH deficiency is usually isolated and pituitary imaging is frequently normal. Since more patients are being placed on immune-checkpoint inhibition, clinicians should be vigilant for these adverse events, particularly the endocrinopathies which may have non-specific symptoms and may be irreversible.

Download Full-text

Careful Evaluation of Cosyntropin Dose in the Diagnosis of Adrenal Insufficiency

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.246 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A122-A123

Author(s):

Clio Musurakis ◽

Solab Chitrakar ◽

Randa Eldin Sharag ◽

Ekta Shrestha ◽

Gauri Pethe ◽

...

Keyword(s):

Adrenal Insufficiency ◽

Gold Standard ◽

Low Dose ◽

Treatment Plan ◽

Stimulation Test ◽

Diagnostic Process ◽

High Dose ◽

Secondary Adrenal Insufficiency ◽

Acth Stimulation ◽

Primary Adrenal Insufficiency

Abstract Introduction: The use of the 250μg cosyntropin dose or otherwise called high-dose ACTH test is the gold standard test for diagnosis of primary adrenal insufficiency. The 1μg dose test or the low-dose test is mostly reserved for diagnosis of secondary adrenal insufficiency. Careful consideration of the results produced during the diagnostic process is imperative to avoid mislabeling of patients with a disease that requires lifelong treatment. Case Report: This is the case of a 45-year-old female with a history of asthma and psoriasis who presented with emesis. Home medications included monthly TNF-alpha inhibitor injections for psoriasis, triamcinolone acetonide topical spray and budesonide-formoterol inhaler. On admission, she also had nausea, chills and diaphoresis, as well as palpitations, lightheadedness, and shortness of breath. When she arrived at the ER, vitals were remarkable for low blood pressure. Labs were unremarkable except for CMP concerning for anion gap metabolic acidosis, hyponatremia, and hypokalemia. A random serum cortisol was 6.4 mcg/dL, which was relatively low. ACTH was within normal range. Due to concern for adrenal insufficiency, a 1μg cosyntropin test was performed which showed a peak cortisol concentration of less than 18 mcg/dL. As the response was assessed as suboptimal, endocrinology was consulted to offer a treatment plan for steroids. However, the test was repeated using the gold standard 250μg cosyntropin dose and the patient then showed an adequate response and she was not started on steroids. Conclusions: This is a case that demonstrates how the 250 μg ACTH or high-dose stimulation test should be used for diagnosis of primary adrenal insufficiency (AI), as it is the gold standard. The 1 μg ACTH or low-dose stimulation test can be used for diagnosis of primary AI but only when the high dose test is not available. On the other hand, the 1 μg ACTH stimulation test has been shown to be more sensitive than the 250 μg test in diagnosing secondary adrenal insufficiency. When using the most appropriate test correctly, the clinician can only then offer the patient the best treatment strategies. Our patient did not require chronic replacement therapy. The steroids in this case could have harmed the patient as chronic administration could cause adrenal gland suppression.

Download Full-text

The diagnosis of secondary adrenal insufficiency: Low dose vs high dose ACTH stimulation test

Journal of Endocrinological Investigation ◽

10.1007/bf03345114 ◽

2003 ◽

Vol 26 (1) ◽

pp. 1-2 ◽

Cited By ~ 6

Author(s):

A. Colao ◽

R. Pivonello

Keyword(s):

Adrenal Insufficiency ◽

Low Dose ◽

Stimulation Test ◽

High Dose ◽

Acth Stimulation Test ◽

Secondary Adrenal Insufficiency ◽

Acth Stimulation

Download Full-text

Adrenal cortex function impairment in chronic fatigue syndrome

Srpski arhiv za celokupno lekarstvo ◽

10.2298/sarh0310370z ◽

2003 ◽

Vol 131 (9-10) ◽

pp. 370-374 ◽

Cited By ~ 1

Author(s):

Milos Zarkovic ◽

Milorad Pavlovic ◽

Ana Pokrajac-Simeunovic ◽

Jasmina Ciric ◽

Biljana Beleslin ◽

...

Keyword(s):

Chronic Fatigue Syndrome ◽

Adrenal Insufficiency ◽

Response Curve ◽

Low Dose ◽

Chronic Fatigue ◽

Cortisol Response ◽

Acth Test ◽

Secondary Adrenal Insufficiency ◽

Acth Stimulation ◽

Fatigue Syndrome

Chronic fatigue syndrome (CFS) is defined as constellation of the prolonged fatigue and several somatic symptoms, in the absence of organic or severe psychiatric disease. However, this is an operational definition and conclusive biomedical explanation remains elusive. Similarities between the signs and symptoms of CFS and adrenal insufficiency prompted the research of the hypothalamo-pituitary-adrenal axis (HPA) derangement in the pathogenesis of the CFS. Early studies showed mild glucocorticoid deficiency, probably of central origin that was compensated by enhanced adrenal sensitivity to ACTH. Further studies showed reduced ACTH response to vasopressin infusion. The response to CRH was either blunted or unchanged. Cortisol response to insulin induced hypoglycaemia was same as in the control subjects while ACTH response was reported to be same or enhanced. However, results of direct stimulation of the adrenal cortex using ACTH were conflicting. Cortisol and DHEA responses were found to be the same or reduced compared to control subjects. Scott et all found that maximal cortisol increment from baseline is significantly lower in CFS subjects. The same group also found small adrenal glands in some CFS subjects. These varied and inconsistent results could be explained by the heterogeneous study population due to multifactorial causes of the disease and by methodological differences. The aim of our study was to assess cortisol response to low dose (1 ?g) ACTH using previously validated methodology. We compared cortisol response in the CFS subjects with the response in control and in subjects with suppressed HPA axis due to prolonged corticosteroid use. Cortisol responses were analyzed in three subject groups: control (C) secondary adrenal insufficiency (AI), and in CFS. The C group consisted of 39 subjects, AI group of 22, and CFS group of nine subjects. Subject data are presented in table 1. Low dose ACTH test was started at 0800 h with the iv injection of 1 ?g ACTH (Galenika, Belgrade, Serbia). Blood samples for cortisol determination were taken from the iv cannula at 0,15, 30, and 60 min. Data are presented as mean standard error (SE). Statistical analysis was done using ANOVA with the Games-Howell post-hoc test to determine group differences. ACTH dose per kg or per square meter of body surface was not different between the groups. Baseline cortisol was not different between the groups. However, cortisol concentrations after 15 and 30 minutes were significantly higher in the C group than in the AI group. Cortisol concentration in the CFS group was not significantly different from any other group (Graph 1). Cortisol increment at 15 and 30 minutes from basal value was significantly higher in C group than in other two groups. However there was no significant difference in cortisol increment between the AI and CFS groups at any time of the test. On the contrary, maximal cortisol increment was not different between CFS and other two groups, although it was significantly higher in C group than in the AI group. Maximal cortisol response to the ACTH stimulation and area under the cortisol response curve was significantly larger in C group compared to AI group, but there was no difference between CFS and other two groups. Several previous studies assessed cortisol response to ACTH stimulation. Hudson and Cleare analysed cortisol response to 1 ?g ACTH in CFS and control subjects.They compared maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve.There was no difference between the groups in any of the analysed parameters. However, authors commented that responses were generally low. On the contrary Scott et all found that cortisol increment at 30 min is significantly lower in the CFS than in the control group. Taking into account our data it seems that the differences found in previous studies papers are caused by the methodological differences. We have shown that cortisol increment at 15 and 30 min is significantly lower in CFS group than in C group. Nevertheless, maximum cortisol attained during the test, maximum cortisol increment, and area under the cortisol response curve were not different between the C and CFS groups. This is in agreement with our previous findings that cortisol increment at 15 minutes has the best diagnostic value of all parameters obtained during of low dose ACTH test. However, there was no difference between CFS and AI group in any of the parameters, although AI group had significantly lower cortisol concentrations at 15 and 30 minutes, maximal cortisol response, area under the cortisol curve, maximal cortisol increment, and maximal cortisol change velocity than C group. Consequently reduced adrenal responsiveness to ACTH exists in CFS. In conclusion, we find that regarding the adrenal response to ACTH stimulation CFS subjects present heterogeneous group. In some subjects cortisol response is preserved, while in the others it is similar to one found in secondary adrenal insufficiency.

Download Full-text

Diagnostic Threshold for Postoperative Secondary Adrenal Insufficiency After Transsphenoidal Resection of Pituitary Adenomas

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1276 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A626-A626

Author(s):

Massiell German ◽

Anu Sharma

Keyword(s):

Adrenal Insufficiency ◽

Pituitary Adenomas ◽

Optic Chiasm ◽

Pituitary Hormone ◽

Secondary Adrenal Insufficiency ◽

Acth Stimulation ◽

Diagnostic Threshold ◽

Secondary Hypothyroidism ◽

Tertiary Center ◽

Secondary Hypogonadism

Abstract Transsphenoidal surgery (TSS) is the first line treatment for pituitary adenomas. A well-known complication of TSS is secondary adrenal insufficiency with a reported risk of 4-9% after TSS. Currently, glucocorticoid replacement is recommended if postoperative AM cortisol is < 3 ug/dL. Postoperative adrenal insufficiency is ruled out if AM cortisol is > 15 ug/dL. However, further evaluation of the adrenal axis with ACTH stimulation test is recommended for intermediate cortisol levels 3-15 ug/dL. Other studies have proposed postoperative cortisol threshold of < 4-14 ug/dL for glucocorticoid replacement. Retrospective analysis of all patients undergoing TSS at a tertiary center from January 2013 through April 2016 was performed. ACTH producing adenomas (Cushing’s disease) were excluded. Of the 97 patients included, 17.5% (n=17) had secondary adrenal insufficiency requiring glucocorticoid replacement at 1 year post operatively. Mean age at presentation was 56 ± 16 years and 52% were female. Mean adenoma size was 25.3 ± 11.3 mm. Factors associated with adrenal insufficiency at 1 year post operatively were preoperative secondary adrenal insufficiency (AM cortisol 4.5 ± 1.9 vs 11.0 ± 1.0 µg/dL; p = 0.03), and preoperative adenoma contact with optic chiasm (15.7% vs 2.1%; p = 0.01). Day 1-7 postoperative cortisol was lower in the group with adrenal insufficiency at 1 year (5.6 µg/dL (IQR 1.9-11.5) vs 19.8 µg/dL (IQR 12.75-43.2); p=0.02). Age, gender, adenoma size, and cavernous sinus involvement were not associated with adrenal insufficiency at 1 year. A day 1-7 postoperative cortisol concentration of ≥8.0 µg/dL had a sensitivity of 75% and specificity of 92% in predicting adrenal insufficiency at 1 year. In patients with secondary adrenal insufficiency at 1 year (n=17), there was a higher frequency of concomitant loss of other pituitary hormone function at 1 year: secondary hypothyroidism 82% (n=14), secondary hypogonadism 70.6% (n=12) and diabetes insipidus 17.7% (n=3). A lower postoperative cortisol threshold of 8 µg/dL can be adopted for glucocorticoid replacement on discharge after TSS.

Download Full-text

Nivolumab Induced Multiple Endocrinopathies; Adrenal Insufficiency and Primary Hypothyroidism in a Patient With Stage IV Gastric Cancer - A Case Report

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.293 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A145-A145

Author(s):

Randa Abdelmasih ◽

Ramy Abdelmaseih ◽

Rima Gandhi ◽

Marines Faya ◽

Josef James Karl Vesely

Keyword(s):

Side Effects ◽

Adrenal Insufficiency ◽

Human Monoclonal Antibody ◽

Laboratory Data ◽

Stage Iv ◽

Thyroid Stimulating Hormone ◽

Primary Hypothyroidism ◽

Pituitary Cells ◽

Acth Stimulation ◽

Wide Range

Abstract Introduction: Nivolumab is a revolutionary immune check point inhibitor (ICI) that changed the world of oncology. It prevents interaction of Program Death Receptor-1 (PD-1) and Program Death Ligand-1 (PD-L1) releasing a cascade of anti-tumor response. However, it has been associated with wide range of autoimmune side effects including gastrointestinal, hepatic, and endocrine side effects. The incidence of nivolumab induced endocrinopathies is relatively rare but increasingly reported. Adrenal insufficiency occurring in <1% of patients, hyperthyroidism in 15.3% and subclinical hypothyroidism in 4.2%. Case Presentations: 81 year old male with stage IV stomach cancer treated with Nivolumab. Prior to immunotherapy initiation, a set of baseline hormones was obtained and was within normal range. 6 months after, routine monitoring showed elevated thyroid stimulating hormone 6.33 mU/L and low FT4 0.59 ng/dL and FT3 0.1 ng/dL. Patient was started on thyroid replacement therapy. After 1 year of Nivolumab therapy, he presented with dizziness and orthostatic hypotension. Laboratory testing was remarkable for low sodium 130 mEq/L, which raised concerns for adrenal insufficiency. Subsequently, ACTH stimulation test showed low cortisol level 15 mcg/dL. Morning cortisol was also low 1.3 mcg/dL. Other pituitary hormones were normal. Patient was started on hydrocortisone with subsequent improvement of symptoms. Discussion: Nivolumab is a human monoclonal antibody that blocks PD-1 and turns off the tumor mediated immune system inhibition. In the meanwhile, ICI also disrupt normal immune signaling mechanisms that lead to decrease immune tolerance and autoimmune diseases. The mechanism of thyroid dysfunction due to ICI remains unclear. PD-1/PD-L1 blockade could induce thyroiditis by diminishing regulatory T cells function. Disruption of interaction between PD-1-expressing lymphocytes and PD-L-expressing thyrocytes –which protects the thyroid gland from autoimmunity– leads to infiltration of the thyroid with autoreactive T and B lymphocytes. Nivolumab induced Adrenal insufficiency is an extremely rare and unclear event, currently, there is no clear evidence that pituitary cells express PD-1. Recently, it was found that the PD-L1 and PD-L2 are expressed in mouse anterior and intermediate pituitary gland, but not the posterior pituitary. This suggests the possibility that specific injury can take place affecting only certain anterior pituitary cells, such as those producing ACTH. Awareness of such endocrinopathies is crucial. Patients should have certain baseline of laboratory data prior to therapy initiation and over the course of treatment. The risk of endocrinopathies is greater at the start of treatment, justifying closer monitoring every visit over the first 6 months, followed by regular monitoring every second visit over the next 6 months and less frequently thereafter.

Download Full-text