Low-dose short synacthen test with salivary cortisol in patients with suspected central adrenal insufficiency

Context The low-dose short synacthen test (LDSST) is recommended for patients with suspected central adrenal insufficiency (AI) if their basal serum cortisol (F) levels are not indicative of an intact hypothalamic–pituitary–adrenal (HPA) axis. Objective To evaluate diagnostic threshold for salivary F before and 30 min after administering 1 μg of synacthen, performed before 09:30 h. Design A cross-sectional study from 2014 to 2020. Setting A tertiary referral university hospital. Patients In this study, 174 patients with suspected AI, 37 with central AI and 137 adrenal sufficient (AS), were included. Main outcome measure The diagnostic accuracy (sensitivity (SE), specificity (SP)) of serum and salivary F levels measured, respectively, by chemiluminescence immunoassay and liquid chromatography-tandem mass spectrometry. Results Low basal serum or salivary F levels could predict AI. For the LDSST, the best ROC-calculated threshold for serum F to differentiate AI from AS was 427 nmol/L (SE 79%, SP 89%), serum F > 500 nmol/L reached SP 100%. A salivary F peak > 12.1 nmol/L after administering synacthen reached SE 95% and SP 84% for diagnosing central AI, indicating a conclusive reduction in the likelihood of AI. This ROC-calculated threshold for salivary F was similar to the 2.5th percentile of patients with a normal HPA axis, so it was considered sufficient to exclude AI. Considering AS those patients with salivary F > 12.1 nmol/L after LDSST, we could avoid unnecessary glucocorticoid treatment: 99/150 subjects (66%) had an inadequate serum F peak after synacthen, but salivary F was >12.1 nmol/L in 79 cases, who could, therefore, be considered AS. Conclusions Salivary F levels > 12.1 nmol/L after synacthen administration can indicate an intact HPA axis in patients with an incomplete serum F response, avoiding the need to start glucocorticoid replacement treatment.

Case Series: Four Cases of Anorexia Nervosa Concomitant with Central Adrenal Insufficiency

Objective: Widespread attention has been paid to the misdiagnosis of life-threatening Addison's disease as anorexia nervosa. However, there are no reports on the possible comorbidity of Addison's disease and other adrenal insufficiencies with anorexia nervosa.Methods: A case-series presentation of anorexia nervosa concomitant with central adrenal insufficiency.Results: Four anorexia nervosa patients (21-35 years old, all females) complained of severe fatigue during their treatment. After a thorough examination of the hypothalamus-pituitary-adrenal axis using stimulation with a rapid adenocorticotropic hormone test of 250-µg Cortrosyn®, a corticotropin-releasing hormone test, and an insulin tolerance test, central adrenal insufficiency was diagnosed. Two of the four patients had a history of exogenous steroids for their history of comorbidity. One of the residual two patient had Rathke’s cleft cyst. After the initiation of hydrocortisone replacement the patient's fatigue symptoms improved and they were able to return to school and their workplace. In some cases, their weight obsession was reduced after the initiation of hydrocortisone replacement.Conclusion: Anorexia nervosa may be concomitant with central adrenal insufficiency partly in relation to exogenous steroids used for their history of comorbidity, which needs to be kept in mind when treating such patients.Level of EvidenceLevel V, descriptive study.

Stuck at the Checkpoint: Pembrolizumab Induced Hypophysitis With ‘Normal’ Cosyntropin Response

Introduction: Pembrolizumab is an immune checkpoint inhibitor (ICI) that blocks programmed cell death receptor 1 (PD-1) and is indicated in treatment of malignancies including lung adenocarcinoma and melanoma. Anti-PD-1 therapies are responsible for immune related adverse events including endocrine dysfunction. Here we present a case of Pembrolizumab induced hypophysitis causing central adrenal insufficiency apparently missed by a 250 mcg cosyntropin test. Clinical Case: A 68 year old female with history of COPD and stage 4 lung adenocarcinoma with bone metastases presented to the ED with hypotension during her 14th cycle of treatment with Pembrolizumab. Other symptoms included fatigue and anorexia for about 4 weeks. She denied vomiting, diarrhea, bleeding episodes or chronic steroid use. On exam, patient was obese and pale appearing, with decreased bilateral breath sounds without edema. Random cortisol on admission at 4:44 pm was 6.9 ug/dl, ACTH - was in process, Na was 135 (137 - 145 mEq/L) and K was 3.7 (3.5 - 5.1 mEq/L). A 250 mcg cosyntropin stimulation test resulted in 30 min cortisol level of 22.5 µg/dL and 60 min cortisol level of 34 µg/dL. Patient was treated with fluids, salt tabs and eventually midodrine, however BP remained borderline low. On day 5, the patient was started on IV methylprednisolone 40 mg Q8 hrs for COPD exacerbation. A few days later pre-steroid ACTH was reported as <5 pg/ml (6-50 pg/ml) which prompted further workup for hypopituitarism. LH and FSH levels were inappropriately low for a postmenopausal female at 0.2 and 2.6 mIU/ml respectively, Free T3 was 2.02 pg/ ml (2.77-5.27 pg/ml), free T4 was 1.07 ng/dl (0.80-2.20 ng/dl), and TSH was 0.67 uIU/ml (0.47-4.70 uIU/ml). MRI brain showed partially empty sella. Patient was diagnosed clinically with Pembrolizumab induced hypophysitis causing central adrenal insufficiency. Eventually, steroids were tapered to prednisone 5 mg daily maintenance dose and patient was discharged with stress dosing instructions. Conclusion: Diagnosis of adrenal insufficiency is challenging as advanced malignancy and adrenal insufficiency can cause similar symptoms. The finding of an empty sella here is a confounding factor. Checkpoint inhibitors are known to cause hypophysitis, thyroiditis and primary adrenal insufficiency, however incidence is <1%. We report a case of missed adrenal insufficiency by a falsely assuring cosyntropin test. Based on our experience, we conclude that when suspecting a diagnosis of checkpoint inhibitor induced adrenal insufficiency, we should start by checking random cortisol and ACTH value. A standard 250 mcg cosyntropin test should not be used solely to completely rule out this diagnosis.

Pituitary Macroadenoma Masked by Iatrogenic Adrenal Insufficiency: A Diagnostic Blind Spot

Background: Exogenous steroid use is the most common cause of central adrenal insufficiency. Depending on the duration and strength used, it may take months to years for the hypothalamic-pituitary-adrenal (HPA) axis to recover after the steroid is stopped. We report a case of iatrogenic hypoadrenalism with persistent suppression of the HPA axis for 13 years, discovered later to be due to a second pathology. Case: A 48 year old lady presented in 2005 with weight gain of 20 kg over 1 year and florid Cushingoid features. 9AM cortisol was undetectable (<12 nmol/L). History taking revealed use of oral dexamethasone at various dosages over the past 9 years for her knee pains. A diagnosis of iatrogenic adrenal insufficiency was made. She was started on hydrocortisone replacement, and was advised to stop the over-the-counter steroids. By 2011 her short Synacthen test (SST) showed much improved functioning of the HPA axis (cortisol 182 (0 min) -> 329 (30 min) -> 408 nmol/L (60 min) [N peak>500 nmol/L]), and she was back to her usual body weight. However, subsequent monitoring revealed declining trend of 9AM cortisol from 135 nmol/L (2013) -> 99 nmol/L (2014) -> 57 nmol/L (2015) -> 64 nmol/L (2016) -> 18 nmol/L (2017) [N 166–507 nmol/L]. Hydrocortisone compliance and abstinence from exogenous steroids was confirmed with the patient. The ongoing hypofunction of the HPA axis was continually attributed by multiple physicians to her history of prolonged use of dexamethasone. In 2018, at the age of 60, the lady presented with new onset headaches, blurred vision, and bitemporal hemianopia for 3 months. MRI showed a 1.8x1.8x3.5 cm (WxAPxH) pituitary mass with suprasellar extension compressing the optic chiasm. Blood tests revealed panhypopituitarism: SST cortisol 17 -> 59 -> 49 nmol/L, ACTH 2.7 pmol/L [N <10.1 pmol/L]; fT4 9.5 pmol/L [N 12–22 pmol/L], TSH 0.97 mIU/L [N 0.27–4.2 mIU/L]; LH <0.1 IU/L, FSH 0.52 IU/L (menopause at age of 48); IGF-1 27 µg/L [N 41–279 µg/L]; prolactin 17 mIU/L [N 102–496 mIU/L]. After partial excision of the mass her vision improved, but remained dependent on hydrocortisone and thyroxine supplements. The lesion was pathologically proven to be a pituitary macroadenoma. Discussion: This case presents the uncommon course of a patient who had almost recovered from iatrogenic hypoadrenalism, only to lapse back into worsened central adrenal insufficiency, as part of panhypopituitarism related to an undiagnosed pituitary mass. In retrospect, the unusually protracted state of hypocortisolemia and the atypical waxing and waning HPA axis should have alerted one to consider alternative etiologies at work. As LH-FSH and GH deficiencies commonly develop before ACTH and TSH deficiencies in most pituitary macroadenomas, a lower threshold for testing the other anterior pituitary hormones followed by imaging of the pituitary could have picked up the tumor earlier in this patient.

An Overlooked Sequela of Long-Term Opioid Analgesic Use: A Case Report on Central Adrenal Insufficiency

Background: Opioid use began to surge since late 1990s and has evolved into a full-fledge opioid epidemic. 2 million Americans aged 12 or older are estimated to have opioid use disorder. We hereby present a case of opioid-induced adrenal insufficiency (OIAI), an overlooked endocrinopathy in which chronic opioid use suppresses the hypothalamic-pituitary-adrenal axis. Clinical Case: A 53-year-old African American female with past medical history of chronic pain syndrome presented with worsening fatigue and generalized weakness for a week, to the extent that she required full assistance to ambulate at home. Upon further inquiry, she also suffered from postprandial eipgastric pain and non-bloody diarrhea for several months. She has a 2-year use of Norco 10 mg/325 mg three times daily to manage her chronic pain. Her blood pressure was running low at 85/57 mmHg with no other abnormal vitals. Our first visual impression of her was a debilitated lady with low voice and slow body movements. Adrenal insufficiency was suspected and subsequently confirmed with low morning cortisol level (1.1 mcg/dL), low DHEAS level (25.3 mcg/dL) and subnormal response of cortisol (16.8 mcg/dL) to the cosyntropin stimulation test. Her ACTH level was less than 3 pg/mL. These laboratory findings were consistent with central adrenal insufficiency. Chronic steroid use, the most common culprit for adrenal insufficiency, was not found in her home medication list or prescription records. To further evaluate the underlying etiologies, we checked the pituitary hormones and found normal levels of LH, FSH, TSH, prolactin and IGF-1. Head CT 2 years prior was negative for any discernible mass. The suspicion for pituitary mass that markedly suppresses ACTH secretion only was reasonably low. The diagnosis of OIAI was made by excluding other causes. Endocrinology was consulted for the dosing of hydrocortisone. She improved physically after receiving hydrocortisone replacement therapy. Collaborative efforts were made to cut down her opioid dose. Conclusions: OIAI is a longstanding overlooked condition in chronic opioid users of which clinicians should raise their awareness. The estimated prevalence of OIAI ranges from 9% to 29% depending on the daily dosage and total duration of opioid use. The case reports of OIAI, however, are only a few. Patients with OIAI could present with fatigue, weight loss, gastrointestinal symptoms, headache or muscular aches. Not only does OIAI impair patients’ quality of life and potentially escalate their opioid dosage by inexperienced prescribers, it also leads to catastrophic adrenal crisis following acute insults. The challenge clinicians face is to uncover the clinical clues suggesting OIAI, which are often hidden in a myriad of symptoms caused by chronic pain and other co-morbidities. Timely diagnosing OIAI is thus never more important in the midst of the unprecedented opioid epidemic.

Silent, isolated ACTH deficiency in malignant melanoma patients treated with immune checkpoint inhibitors

Treatment with immune checkpoint inhibitors (ICI) has drastically improved the prognosis for melanoma patients, but immune-mediated adverse events can occur in any organ, including the pituitary. In ICI-induced hypophysitis, lymphocytic infiltration and hypersensitivity reactions cause headache and pituitary deficiency. Most cases with ICI-induced hypophysitis develop central adrenal insufficiency. Here, we describe three patients treated with anticytotoxic T-lymphocyte-associated protein 4 (ipilimumab) for metastatic malignant melanoma: case 1 was asymptomatic when hypocortisolism was suspected; case 2 had symptoms of hypocortisolism and suspected severe systemic infection; case 3 had unspecific fatigue. In all cases, routine cortisol measurements and clinical suspicion (cases 2 and 3) led to the diagnosis of adrenocortical hormone (ACTH) deficiency and thereby central adrenal insufficiency. Undiagnosed and untreated, central adrenal insufficiency results in adrenal crisis. In patients treated with ICI, particularly, ipilimumab, hypophysitis and ACTH deficiency must be considered if morning cortisol is low or unspecific clinical symptoms of hypocortisolism are present.

Isolated Central Adrenal Insufficiency Due to Nivolumab: A Case Report

Background: Immune checkpoint inhibitors are immunomodulatory antibodies directed against programmed cell death 1 (PD-1), Nivolumab, or cytotoxic T-lymphocyte antigen-4 (CTLA-4) Ipilimumab. They have improved outcomes in patients with advanced cancers including renal cell carcinoma, non-small cell lung cancer and melanoma. Several immune related adverse events (irAEs) have been recognized with use of immune checkpoint inhibitors, including those involving the endocrine system. We present a case of a patient presenting with isolated central adrenal insufficiency in the context of Nivolumab use. Clinical Case: Our patient is a 54-year old man with pre-existing primary hypothyroidism and metastatic renal cell carcinoma treated with Nivolumab. After receiving a total of 14 cycles of Nivolumab, he presented to the Emergency room with his sister, who found him confused and lethargic. On presentation, he was found to be hypoglycemic (random glucose was 2.2 mmol/L). On physical examination, his vital signs were stable and he appeared euvolemic. He was disoriented without focal neurological deficits. Initial blood work revealed sodium 134 mmol/L, (Normal 135-145mmol/L), potassium 4.5 mmol/L (Normal 3.5-5 mmol/L), and TSH being 12.6 mIU/L (Normal 0.4-4 mIU/L). He was resuscitated with IV Dextrose 50% bolus then admitted to hospital and kept on an IV dextrose infusion. While his glucose improved, he was found to have hyponatremia, and confusion persisted. His nadir sodium was 116 mmol/L without seizures or loss of consciousness and required treatment with hypertonic saline. Giving hypoglycemia and hyponatremia, morning cortisol and ACTH were checked and came back 4 nmol/L (Normal 133-537 nmol/L) and undetectable (< 0.7 pmol/L, Normal 1.6-13.9 pmol/L) respectively. The diagnosis of central adrenal insufficiency was made likely secondary to Nivolumab. He was started on Dexamethasone 8 mg daily. Sodium level normalized and glucose level improved with steroids. He was discharged home on prednisone 50 mg and then switched to hydrocortisone. Further work up confirmed preserved other anterior pituitary hormones. MRI of Sella did not show pituitary enlargement or inflammation. Conclusion: Our patient presented with hypoglycemia and hyponatremia; both could be the presenting manifestations of central adrenal insufficiency. Nivolumab has been commonly associated with thyroid dysfunction and thyroiditis. Given lack of expression of PD-1 in the pituitary, PD-1 inhibitors are less likely to be associated with hypopituitarism in general, or central adrenal insufficiency in particular. However, our report adds to the growing body of literature associating it with central adrenal insufficiency, which can be isolated. In so doing, it underscores the need for early recognition this association with Nivolumab, so as to avoid the potentially life threatening consequences of this condition.

Immune checkpoint inhibitor related hypophysitis: diagnostic criteria and recovery patterns

Data on the diagnosis, natural course and management of immune checkpoint inhibitor (ICI) related hypophysitis (irH) are limited. We propose this study to validate the diagnostic criteria, describe characteristics and hormonal recovery and investigate factors associated with occurrence and recovery of irH. A retrospective study including patients with suspected irH at the University of Texas MD Anderson Cancer Center from 5/2003 to 8/2017 was conducted. IrH was defined as: (1) ACTH or TSH deficiency plus MRI changes or (2) ACTH and TSH deficiencies plus headache/fatigue in the absence of MRI findings. We found that of 83 patients followed for a median of 1.75 years (range 0.6-3), the proposed criteria used at initial evaluation accurately identified 61/62 (98%) irH cases. In the irH group (n=62), the most common presentation were headache (60%), fatigue (66%), central hypothyroidism (94%), central adrenal insufficiency (69%) and MRI changes (77%). Compared with non-Ipilimumab (Ipi) regimens, Ipi has a stronger association with irH occurrence (p=0.004) and a shorter time to irH development (p<0.01). Thyroid, gonadal and adrenal axis recovery occurred in 24%, 58% and 0% patients, respectively. High dose steroids (HDS) or ICI discontinuation were not associated with hormonal recovery. In the non-irH group (n=19), one patient had isolated central hypothyroidism and 6 had isolated central adrenal insufficiency. All remained on hormone therapy at last follow up. We propose a strict definition of irH that identifies the vast majority of patients. HDS and ICI discontinuation is not always beneficial. Long term follow up to assess recovery is needed.