Bilateral adrenal hemorrhage is a very unusual cause of severe adrenal insufficiency and hyponatremia. It can result from trauma, infections, or antiphospholipid antibody syndrome and can be fatal if not diagnosed and treated early. Here, we present a 58-year-old Caucasian man with fatigue, altered sensorium, bradycardia, and hypotension. He denied any abdominal pain, recent trauma, or anti-platelet or anti-coagulation agents. His laboratory workup showed hyponatremia with low serum cortisol levels. He was further worked up and underwent computerized tomography (CT) of the abdomen, which showed bilateral adrenal hemorrhage. He was treated with intravenous (IV) steroids followed by oral hydrocortisone and fludrocortisone. His symptoms resolved, and he was safely discharged home. Asymptomatic bilateral adrenal hemorrhage is a sporadic disease, and it should be in the differential diagnosis for disproportionately sick people with other adrenal insufficiency features.

The general medical physician will often encounter patients who develop acute complications of their cancer diagnosis or anti-cancer treatment. Here we provide an overview of emergency solid tumour oncology to guide the initial management of these patients.

Ambulatory emergency care forms a fundamental part of the strategy of trying to ensure safe and sustainable acute care services. Immune checkpoint inhibitor(ICI)-mediated hypophysitis is an important life-threatening complication of therapy. Patients presenting with clinical features and findings consistent with ICI-mediated hypophysitis were considered in the current study. In the absence of severe features (sodium <125 mmol/L, hypotension, reduced consciousness, hypoglycaemia and/or visual field defect), patients were administered a single intravenous dose of hydrocortisone (100 mg), observed for at least 4 h and then discharged on oral hydrocortisone (20 mg, 10 mg and 10 mg). Patients were then seen urgently in the endocrinology outpatient setting for further management. Fourteen patients (median age 64, 10 male) were managed using the pathway. All patients had biochemically confirmed adrenocorticotropic hormone (ACTH) deficiency. Seven of the 14 were treated with combination ICI therapy, with four having pan-anterior hypopituitarism. There were no 30-day readmissions or any associated hypophysitis-related mortality. All patients continued ICI therapy without interruption.

We report a case of a multi-trauma, brain-injured young patient with unilateral adrenal gland injury presenting with refractory shock. Acute adrenal insufficiency was revealed after an abrupt hemodynamic response to a corticosteroid; the resistant shock was quickly resolved with IV hydrocortisone. Although available data do not support the use of empiric steroids in trauma patients (with or without brain injury), this case demonstrates that adrenal insufficiency must be considered in the differential diagnosis when shock exists; adrenal gland injury, even unilateral, may play an additional factor. In these cases, an urgent decision is required in order to influence the outcome.

Introduction The present study aimed to prove the metyrapone short test in a day clinic to be suitable for examining the integrity of the hypothalamic-pituitary-adrenal (HPA) axis in patients with suspected secondary and tertiary adrenal insufficiency and to identify novel effector molecules in acute stress response. Methods 44 patients were prospectively enrolled. Based on stimulated 11-deoxycortisol levels, patients were divided into a physiological (11-deoxycortisol ≥70 µg/l) and a pathological (11-deoxycortisol <70 µg/l) response group. Clinical follow-up examination was performed for validation. Ultra-performance-liquid-chromatography-tandem-mass-spectrometry and a Fourier-transform-ion-cyclotron-resonance-mass-spectrometry were used for targeted and untargeted steroid metabolomics. Results At baseline, lower levels of cortisone (42 vs. 50 nmol/l, p=0.048) and 17-OH-progesterone (0.6 vs. 1.2 nmol/l, p=0.041) were noted in the pathological response group. After metyrapone administration, the pathological response group exhibited significantly lower 11-deoxycortisol (39.0 vs. 94.2 µg/l, p<0.001) and ACTH (49 vs. 113 pg/ml, p<0.001) concentrations as well as altered upstream metabolites. Untargeted metabolomics identified a total of 76 metabolites to be significantly up- or downregulated by metyrapone. A significant increase of the bile acid glycochenodeoxycholic acid (GCDC, p<0.01) was detected in both groups with an even stronger increase in the physiological response group. After a mean follow-up of 17.2 months, an 11-deoxycortisol cut-off of 70 µg/l showed a high diagnostic performance (sensitivity 100%, specificity 96%). Conclusion The metyrapone short test is safe and feasible in a day clinic setting. The alterations of the bile acid GCDC indicate that the liver might be involved in the acute stress response of the HPA axis.

Acute ST-segment elevation myocardial infarction (STEMI) can typically complicate with the development of cardiogenic shock; nevertheless, other less frequent types of shock may occur, including adrenal crisis (AC). We describe a case of STEMI complicated by AC and, for the first time, AC-induced focal takotsubo syndrome.

Paracoccidioidomycosis (PCM) is a systemic mycosis endemic in Latin America, mostly in Brazil. The involvement of the gastrointestinal tract is uncommon and usually associated with the acute form. Recently, a cluster of acute PCM cases has been described in Rio de Janeiro, Brazil. We report a 42-year-old male, resident of Rio de Janeiro, presenting chronic diarrhea and abdominal pain in the past 3 years, previously diagnosed as Chron´s disease. When immunosuppressive therapy was prescribed, the patient evolved with worsening of the previous symptoms in addition to odynophagia, 20 kg-weight loss, disseminated skin lesions, diffuse lymphadenopathy and adrenal insufficiency. Histopathological and mycological examination of a skin lesion were compatible with PCM. Itraconazole was prescribed in high doses (400 mg/day). After seven months of treatment, the patient presented with acute abdominal pain which led to an emergent appendectomy, revealing the presence of the fungus. After 24 months, the patient reached clinical cure and recovered from adrenal insufficiency. We emphasize the importance of PCM as a differential diagnosis in patients with chronic diarrhea. The risk of fungal infections should be considered prior to initiating immunosupressive therapies, particularly in endemic areas.

The etiology, presentation and mortality of patients with primary adrenal insufficiency (PAI) in developing countries may differ from economically developed nations. However, information in this regard is scanty. The aim of this study was to determine the etiology and compare the clinical characteristics and mortality in infectious and autoimmune causes of PAI in Indian patients. All eligible (n=89) patients (ages 15-83 years) diagnosed with PAI in between 2006-2019 were studied. Patients were followed for a median duration of 5.9 (range 0.1-15.7) years. Eighty-six subjects underwent an abdominal CT scan or ultrasonography and adrenal biopsy was performed in 60 patients. The most frequent aetiologies of PAI were histoplasmosis (AH, 45%), tuberculosis (AT, 15%), autoimmunity (AI, 25%) and primary lymphoma (6%). Forty two percent of patients presented in an acute adrenal crisis. AH and AT could not be differentiated on the basis of clinical features, except for a greater frequency of hepatomegaly-splenomegaly and type 2 diabetes mellitus (63% vs. 15%, p<0.01) in the former. Patients with an autoimmune etiology had a higher frequency of 21-hydroxylase antibodies (41% vs. 3%) and autoimmune thyroid disease (46% vs. 5%) versus those with infectious aetiologies. Mortality was significantly higher in AH (45%) compared with AT (8%) or AI (5%) (p=0.001). Causes of death included adrenal crises, progressive histoplasmosis and unexplained acute events occurring at home. In conclusion, infections, especially AH, were the most frequent cause of PAI in north India. Despite appropriate therapy, AH had very high mortality as compared with AT and AI.

A 77-year-old male patient on maintenance hemodialysis therapy who underwent unilateral adrenonephrectomy 9 years ago was transferred to our hospital after 4 months of acute treatment for skull base osteomyelitis. He presented with unexplained hypotension during dialysis sessions. Further evaluation led to a diagnosis of primary adrenal insufficiency, followed by the start of oral hydrocortisone. Six months after admission, the patient was found to have a positive COVID-19 result on a rapid antigen test and mild symptoms. The patient complained of fatigue after the disappearance of the symptoms. Subsequently, the systolic blood pressure gradually declined despite the additional administration of fludrocortisone and caused difficulties in undergoing hemodialysis. The patient's lasting fatigue raised a suspicion of post-COVID-19 syndrome, requiring larger dosages of corticosteroids by stress dosing. Hypotension was interpreted as a symptom associated with adrenal insufficiency. The dosages of corticosteroids were increased beyond the upper recommended limits. The effect eventually stabilized the patient's hemodynamics. Hydrocortisone was increased as follows: 35 mg/day for nondialysis days and 55 mg/day for dialysis days, divided into three or four doses per day (20 mg in the morning, 20 mg before dialysis, 10 mg in the afternoon, and 5 mg in the evening). The dosage of fludrocortisone was increased up to 0.5 mg/day. In conclusion, the requirement for corticosteroids significantly increased in association with post-COVID-19 syndrome. The management of patients with adrenal insufficiency in the context of concomitant post-COVID-19 syndrome needs further investigation.

A man in his 20s with a history of acute disseminated encephalomyelitis (ADEM) was brought into the emergency department (ED) after his family found him at home collapsed on the floor unresponsive with a blood glucose of 28 mg/dL at the field. In the ED, the patient was tachycardic, tachypnoeic and hypotensive, requiring pressors and intubation at 9 hours and 12 hours after arrival, respectively. Laboratory results revealed a positive COVID-19 test, serum sodium of 125 mmol/L and persistent hypoglycaemia. The patient was given a high dose of dexamethasone for COVID-19 treatment 1 hour before pressors were started. He was then continued on a stress dose of intravenous hydrocortisone with rapid clinical improvement leading to his extubation, and discontinuation of vasopressors and glucose on day 2 of admission. The patient received his last dose of intravenous hydrocortisone on day 4 in the early afternoon with the plan to order adrenal testing the following morning prior to discharge. On day 5, the aldosterone <3.0 ng/dL, adrenocorticotropic hormone (ACTH) level >1250 pg/mL, and ACTH stimulation test showed cortisol levels of 3 and 3 µg/dL at 30 and 60 min, respectively. The anti-21-hydroxylase antibody was positive. The patient was discharged on hydrocortisone and fludrocortisone. The patient's symptoms, elevated ACTH, low cortisol and presence of 21-hydroxylase antibodies are consistent with autoimmune Addison's disease. This is the first case reporting autoimmune Addison's disease in a patient with COVID-19 with a history of ADEM. The case highlights the importance of considering adrenal insufficiency as a diagnostic differential in haemodynamically unstable patients with COVID-19.

Traumatic brain injury (TBI) is a major health problem affecting millions of people worldwide and leading to death or permanent damage. TBI affects the hypothalamic-pituitary-adrenal (HPA) axis either by primary injury to the hypothalamic-hypophyseal region or by secondary vascular damage, brain, and/or pituitary edema, vasospasm, and inflammation. Neuroendocrine dysfunctions after TBI have been clinically described in all hypothalamic-pituitary axes. We established a mild TBI (mTBI) in rats by using the controlled cortical impact (CCI) model. The hypothalamus, pituitary, and adrenals were collected in the acute (24 h) and chronic (30 days) groups after TBI, and we investigated transcripts and protein-related autophagy (Lc3, Bcln1, P150, Ulk, and Atg5) and apoptosis (pro-caspase-3, cleaved caspase-3). Transcripts related to autophagy were reduced in the hypothalamus, pituitary, and adrenals after TBI, however, this was not reflected in autophagy-related protein levels. In contrast, protein markers related to apoptosis increased in the adrenals during the acute phase and in the pituitary during the chronic phase. TBI stresses induce a variation of autophagy-related transcripts without modifying the levels of their proteins in the HPA axis. In contrast, protein markers related to apoptosis are increased in the acute phase in the adrenals, which could lead to impaired communication via the hypothalamus, pituitary, and adrenals. This may then explain the permanent pituitary damage with increased apoptosis and inflammation in the chronic phase. These results contribute to the elucidation of the mechanisms underlying endocrine dysfunctions such as pituitary and adrenal insufficiency that occur after TBI. Although the adrenals are not directly affected by TBI, we suggest that the role of the adrenals along with the hypothalamus and pituitary should not be ignored in the acute phase after TBI.

A 50-year-old man was admitted to our hospital for vomit, nausea, diplopia, and headache resistant to analgesic drugs. Symptoms started the day after his third COVID-19 mRNA vaccine (Moderna) whereas SARS-CoV-2 nasal swab was negative. Pituitary MRI showed recent bleeding in macroadenoma, consistent with pituitary apoplexy. Adverse Drug Reaction was reported to AIFA (Italian Medicines Agency).A stress dexamethasone dose was administered due to the risk of adrenal insufficiency and to reduce oedema. Biochemistry showed secondary hypogonadism; inflammatory markers were elevated as well as white blood cells count, fibrinogen and D-dimer. Pituitary tumour transsphenoidal resection was performed and pathology report was consistent with pituitary adenoma with focal haemorrhage and necrosis; we found immunohistochemical evidence for SARS-CoV-2 proteins next to pituitary capillaries, in the presence of an evident lymphocyte infiltrate.Few cases of pituitary apoplexy after COVID-19 vaccination and infection have been reported. Several hypotheses have been suggested to explain this clinical picture, including cross-reactivity between SARS-CoV-2 and pituitary proteins, COVID-19-associated coagulopathy, infection-driven acutely increased pituitary blood demand, anti-Platelet Factor 4/heparin antibodies development after vaccine administration. Ours is the first case of SARS-CoV-2 evidence in pituitary tissue, suggesting that endothelial infection of pituitary capillaries could be present before vaccination, possibly due to a previous asymptomatic SARS-CoV-2 infection. Our case underlines that SARS-CoV-2 can associate with apoplexy by penetrating the central nervous system, even in cases of negative nasal swab. Patients with pituitary tumours may develop pituitary apoplexy after exposure to SARS-CoV-2, therefore clinicians should be aware of this risk.

A 6-year-old castrated male Labradoodle was referred in uncompensated hypovolemic shock, with a 72-h history of lethargy, vomiting and diarrhea that had acutely worsened with subsequent development of profuse hemorrhagic diarrhea in the last 24 h after a visit to the groomer. In most respects this case was classic for a patient with a primary hypoadrenocortical crisis. After initial attempts to address hypovolemia and refractory hypotension, no clinical improvement was seen, and the respiratory rate had increased acutely to 80 bpm with crackles detected on thoracic auscultation and serosanguineous fluid began draining from the nose and mouth. An arterial blood gas sample while breathing room air revealed moderate hypoxemia (PaO2 59.9: RI 95-100 mmHg), an elevated alveolar-arterial (A-a) gradient at 54.7 (RI < 15 mmHg) and a PaO2:FiO2 ratio of 285 mmHg. Thoracic radiographs revealed severe bilateral alveolar lung pattern largely limited to the perihilar and caudodorsal lung fields. The radiographic findings, along with signs of ongoing hypovolemia, the lack of evidence of typical long-standing acquired cardiac disease, and the rapid resolution of the pulmonary edema without the need for diuretics or long-term cardiac medications supported non-cardiogenic pulmonary edema. The proposed cause of the non-cardiogenic pulmonary edema was speculated to be neurogenically mediated. Oxygen supplementation along with mineralocorticoid and glucocorticoid replacement therapy was sufficient for the management of the non-cardiogenic pulmonary edema in this case.

Adrenal hemorrhage is an uncommon underrecognized condition that can be encountered in several clinical contexts. Diagnosing adrenal hemorrhage is challenging due to the non-specific clinical features. Therefore, it remains a diagnosis that is made serendipitously on imaging of acutely unwell patients rather than with prospective clinical suspicion. Adrenal hemorrhage can follow abdominal trauma or on a background of predisposing conditions such as adrenal tumors, sepsis, or coagulopathy. Adrenal hemorrhage is also increasingly reported in patients with COVID-19 infection and in the context of vaccine-induced immune thrombocytopenia and thrombosis, in both cases likely as a consequence of adrenal vein thrombosis. Unexplained abdominal pain with hemodynamic instability in a patient with a predisposing condition should alert the physician to the possibility of adrenal hemorrhage. Bilateral adrenal hemorrhage can lead to adrenal insufficiency and potentially fatal adrenal crisis without timely recognition and treatment. In this article, we highlight the clinical circumstances that are associated with higher risk of adrenal hemorrhage, encouraging clinicians to prospectively consider the diagnosis, and share a diagnostic and management strategy.

Adrenal hemorrhage is an uncommon disorder characterized by bleeding into the suprarenal glands. The hematoma may be unilateral or bilateral, and the clinical presentation can range from nonspecific abdominal pain to catastrophic cardiovascular collapse. The etiologies for this unusual disorder are diverse. Potential causes include blunt abdominal trauma, septicemia, coagulopathies, anti-coagulant use, pregnancy, stress, antiphospholipid syndrome, and essential thrombocytosis.[1][2][3][2][4][5][6][7] A high index of clinical suspicion is necessary for prompt diagnosis. A plethora of clinical presentations makes the diagnosis challenging. The signs and symptoms range from nonspecific abdominal pain to acute adrenal insufficiency, depending on the site and extent of hemorrhage. Imaging and biochemical evaluation provide the mainstay for diagnosis. The adrenal glands are a pair of endocrine organs located in the retroperitoneum on the upper poles of the kidneys. They comprise two embryologically and functionally distinct parts, the outer mesodermally derived adrenal cortex, which produces glucocorticoids, mineralocorticoids, and adrenal androgens, and the inner adrenal medulla, which originates from the neural crest secretes catecholamines. The suprarenal glands are one of the most well-perfused organs in the human body. The superior, middle, and inferior adrenal arteries originate from the inferior phrenic artery, the abdominal aorta, and the renal artery, respectively, form the chief arterial supply. In contrast, the venous drainage is limited and often utilizing a single adrenal vein, which drains into the inferior vena cava on the right and the renal vein on the left. This difference between the arterial inflow and venous drainage may explain the anatomic predisposition to developing hemorrhagic infarction.[8]

Adrenal insufficiency is a serious pathologic condition characterized by decreased production or action of glucocorticoids and/or mineralocorticoids and adrenal androgens. This life-threatening disorder may be classified as primary, secondary or tertiary, resulting from diseases affecting the adrenal cortex, the anterior pituitary gland or the hypothalamus, respectively. The clinical manifestations of adrenal insufficiency include anorexia, abdominal pain, weakness, weight loss, fatigue, hypotension, salt craving and hyperpigmentation of the skin in case of primary adrenal insufficiency. The diagnosis of adrenal insufficiency can be confirmed by demonstrating inappropriately low cortisol secretion, determining whether the cortisol deficiency is secondary or primary, and defining the cause of the disorder. Treatment with glucocorticoid and/or mineralocorticoid replacement should be initiated when glucocorticoid and or mineralocorticoid deficiency is suspected. This chapter will provide an overview of the epidemiology, etiology, pathophysiology, clinical manifestations, diagnosis and treatment of adrenal insufficiency. Finally, special conditions of adrenal insufficiency, including critical illness, pregnancy, infancy and childhood will also be discussed. For complete coverage of this and related areas of Endocrinology, please visit our free online textbook, WWW.ENDOTEXT.ORG.

Adrenal insufficiency ranges from mild nonspecific symptoms to life-threatening shock condition. Adrenal insufficiency is a diagnosis that will not be made unless the clinician maintains a level of suspicion. The decreasing or suppressed adrenal function may be masked until stress or illness triggers an adrenal crisis.[1][2][3] An important distinction in these patients is the presence of mineralocorticoid deficiency. Those with secondary or tertiary adrenal insufficiency will typically have preserved mineralocorticoid function due to the separate feedback systems. Mineralocorticoid levels are regulated by the renin-angiotensin system, independent of hypothalamic or pituitary signals. Another important distinction is the acute versus chronic nature of the disease. Acute adrenal insufficiency patients often present in a critically ill state while chronic presentations can be insidious.

The adrenal gland is made up of two parts, the cortex and the medulla. The adrenal cortex produces hormones necessary for normal body functioning; deficiency of these hormones results in adrenal insufficiency. The cortex is responsible for producing glucocorticoids, mineralocorticoids, and androgens. Destruction or dysfunction of the adrenal cortex mainly causes glucocorticoid and mineralocorticoid deficiency. Primary adrenal insufficiency is also known as autoimmune adrenalitis or Addison disease. Adrenal insufficiency ranges from mild nonspecific symptoms to life-threatening shock conditions. Due to its vague symptoms and varying degree of clinical presentation, a clinician must maintain a high level of suspicion for this disease. The decreasing or suppressed adrenal function may be masked until stress or illness triggers an adrenal crisis. Adrenal insufficiency can be classified into primary, secondary, and tertiary causes. Primary adrenal insufficiency occurs when there is a pathology affecting the adrenal gland itself. Secondary adrenal insufficiency results from a decreased level of adrenocorticotrophin hormone (ACTH) released from the pituitary gland, and tertiary adrenal insufficiency results from a decreased level of corticotrophin-releasing hormone (CRH) released from the hypothalamus.   An important distinction in these patients is the presence of mineralocorticoid deficiency. Those with secondary or tertiary adrenal insufficiency will typically have preserved mineralocorticoid function due to the separate feedback systems. Mineralocorticoid levels are regulated by the renin-angiotensin system that is independent of hypothalamic or pituitary signals. Another important distinction is the acute versus chronic nature of the disease. Acute adrenal insufficiency patients often present in a critically ill state, while chronic presentation can be insidious.[1][2][3][4][5]

Immune checkpoint inhibitor (ICI)-induced hypophysitis is an immune-mediated pituitary inflammation that tends to cause long-term pituitary deficiency. Management of ICI-induced hypophysitis includes corticosteroids for acute inflammation and long-term hormone replacement due to irreversible pituitary cell damage. We report a case of recurrent hypophysitis following ICI rechallenge for metastatic melanoma. A 33-year-old woman with recurrent metastatic melanoma with adrenal, pelvic, and inguinal metastases developed recurrent hypophysitis during treatment with ipilimumab and nivolumab which recurred with rechallenge >5 years later. In both cases, headache was the most notable symptom and brain MRI showed pituitary enlargement and edema without evidence of metastases. Central adrenal insufficiency and symptoms caused by mass effect were treated with acute high-dose corticosteroids and long-term replacement corticosteroids. Based on recurrence and failure of symptomatic treatment with continued steroid treatment, ICI was discontinued. This case illustrates that hypophysitis may recur with ICI rechallenge, challenging traditional assumptions that chronic, irreversible irAEs are unlikely to recur or flare. The regenerative potential of pituitary cells after ICI-induced damage or additional damage to previously unaffected cells may be more conceivable than previously realized. Additional research on the potential for recurrent ICI-induced endocrinopathies are needed.