Adrenal insufficiency (AI), first described by Thomas Addison in 1855, is characterised by inadequate hormonal production by the adrenal gland, which could either be primary, due to destruction of the adrenal cortex, or secondary/tertiary, due to lack of adrenocorticotropic hormone or its stimulation by corticotropin-releasing hormone. This was an invariably fatal condition in Addison's days with most patients dying within a few years of diagnosis. However, discovery of cortisone in the 1940s not only improved the life expectancy of these patients but also had a dramatic effect on their overall quality of life. The diagnosis, easily confirmed by demonstrating inappropriately low cortisol secretion, is often delayed by months, and many patients present with acute adrenal crisis. Sudden withdrawal from chronic glucocorticoid therapy is the most common cause of AI. Currently, there remains a wide variation in the management of this condition across Europe. As primary AI is a relatively rare condition, most medical specialists will only manage a handful of these patients in their career. Despite many advances in recent years, there is currently no curative option, and modern cortisol replacement regimens fail to adequately mimic physiological cortisol rhythm. A number of new approaches including allograft of adrenocortical tissue and stem cell therapy are being tried but remain largely experimental.

The ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global health crisis affecting millions of people worldwide. SARS-CoV-2 enters the host cells by binding to angiotensin-converting enzyme 2 (ACE2) after being cleaved by the transmembrane protease serine 2 (TMPRSS2). In addition to the lung, gastrointestinal tract and kidney, ACE2 is also extensively expressed in endocrine tissues, including the pituitary and adrenal glands. Although glucocorticoids could play a central role as immunosuppressants during the cytokine storm, they can have both stimulating and inhibitory effects on immune response, depending on the timing of their administration and their circulating levels. Patients with adrenal insufficiency (AI) or Cushing's syndrome (CS) are therefore vulnerable groups in relation to COVID-19. Additionally, patients with adrenocortical carcinoma (ACC) could also be more vulnerable to COVID-19 due to the immunosuppressive state caused by the cancer itself, by secreted glucocorticoids, and by anticancer treatments. This review comprehensively summarizes the current literature on susceptibility to and outcome of COVID-19 in AI, CS and ACC patients and emphasizes potential pathophysiological mechanisms of susceptibility to COVID-19 as well as the management of these patients in case of SARS-CoV-2. Finally, by performing an in silico analysis, we describe the mRNA expression of ACE2, TMPRSS2 and the genes encoding their co-receptors CTSB, CTSL and FURIN in normal adrenal and adrenocortical tumors (both adenomas and carcinomas).

Primary adrenal insufficiency (PAI) is a rare disease and potentially fatal if unrecognized. It is characterized by destruction of the adrenal cortex, most frequently of autoimmune origin, resulting in glucocorticoid, mineralocorticoid, and adrenal androgen deficiencies. Initial signs and symptoms can be nonspecific, contributing to late diagnosis. Loss of zona glomerulosa function may precede zona fasciculata and reticularis deficiencies. Patients present with hallmark manifestations including fatigue, weight loss, abdominal pain, melanoderma, hypotension, salt craving, hyponatremia, hyperkalemia, or acute adrenal crisis. Diagnosis is established by unequivocally low morning serum cortisol/aldosterone and elevated ACTH and renin concentrations. A standard dose (250 µg) Cosyntropin stimulation test may be needed to confirm adrenal insufficiency (AI) in partial deficiencies. Glucocorticoid and mineralocorticoid substitution is the hallmark of treatment, alongside patient education regarding dose adjustments in periods of stress and prevention of acute adrenal crisis. Recent studies identified partial residual adrenocortical function in patients with AI and rare cases have recuperated normal hormonal function. Modulating therapies using rituximab or ACTH injections are in early stages of investigation hoping it could maintain glucocorticoid residual function and delay complete destruction of adrenal cortex.

A novel CYP11A1: c.1236 + 5G > A was identified, expanding the mutation spectrum of the congenital adrenal insufficiency with 46,XY sex reversal. In a now 17-year-old girl delivered full-term (G2P2, parents unrelated), adrenal failure was diagnosed in the first year of life based on clinical picture of acute adrenal crisis with vomiting, dehydration, weight loss, hypotension, and electrolyte disturbances. At the time, hormonal tests revealed primary adrenocortical insufficiency and steroid profiles showed lack of products of steroidogenesis, and since then the patient has been treated with substitution doses of hydrocortisone and fludrocortisone. At the age of 14, considering the absence of puberty symptoms, extended diagnostic tests revealed elevated LH levels (26.5 mIU/mL) with pre-puberty FSH levels (4.9 mIU/mL), low estradiol (28 pmol/L), testosterone (<2.5 ng/mL), and extremely high levels of ACTH (4961 pg/mL). A cytogenetic study revealed a 46 XY karyotype. A molecular examination confirmed the missense mutation and a novel splice-site mutation of CYP11A1 gene. Compound heterozygosity for the CYP11A1 gene with a known pathogenic variant in one allele and a novel splice site mutation in the second allele is most probably responsible for congenital adrenal insufficiency with 46,XY sex reversal. We discuss the necessity of cytogenetic test in the case of early onset of adrenal failure in the absence of steroidogenesis metabolites in the steroid profile.

Congenital adrenal hypoplasia is a rare cause of primary adrenocortical failure, which was first described in 1948. During the last two decades, the genetic basis for several forms of familial adrenal insufficiency syndromes has been elucidated. The molecular mechanisms for these disorders involve a broad spectrum of cellular and physiologic processes, including metabolism, nuclear protein import, oxidative stress defense-mechanisms, and regulation of cell cycle. Adrenal hypoplasia can occur: 1) secondary to defects in transcription factors involved in pituitary development or 2) defects in ACTH synthesis and secretion; 3) as a primary defect in the development of the adrenal gland; 4) as part of rare syndromes associated with adrenal hypoplasia/aplasia, which are inherited in an autosomal recessive or autosomal dominant manner; and 5) in the context of chromosomal abnormalities. Early diagnosis and management are crucial because of the life-threatening nature of the condition. Depending on the etiology, adrenal crisis may occur in early infancy or could insidiously develop over the course of childhood or adolescence. Moreover, some of these conditions previously thought to occur only in childhood, may also be diagnosed later in adulthood and present with variable phenotypes, including isolated infertility or disorders of sex differentiation. The clinical manifestations of primary adrenal insufficiency (PAI) result from deficiency of all adrenocortical hormones (aldosterone, cortisol, androgens). The acute presentation can be precipitated by physiologic stress, such as surgery, trauma, or an intercurrent infection. Patients may present with signs and symptoms of complete adrenal insufficiency, usually early in life, including hypoglycemic convulsions, hyponatremia, hyperkalemia, metabolic acidosis or later with hyperpigmentation, vomiting and poor weight gain. It should be remembered, that the most common cause of PAI in children is congenital adrenal hyperplasia due to 21-hydroxylase deficiency and can be excluded by measuring baseline or ACTH-stimulated 17-hydroxyprogesterone levels in serum. Screening for autoimmune Addison disease includes detection of 21-hydroxylase antibodies. Males with negative 21-hydroxylase antibodies should be tested for adrenoleukodystrophy measuring very–long-chain fatty acids concentrations in plasma. The presence of alacrima in patients with PAI should raise suspicion for Triple A syndrome, whereas the combination of PAI and hypogonadotropic hypogonadism in a male patient point towards X-linked adrenal hypoplasia congenita. To date, molecular genetic testing is commercially available for the identification of several genes involved in adrenal hypoplasia syndromes. The early identification of these diseases can have important prognostic and therapeutic implications for patients with respect to surveillance for associated conditions, initiation of early treatment or screening of family members who are at risk. Adrenal insufficiency is potentially life threatening, thus treatment should be initiated as soon as the diagnosis is confirmed, or sooner if the patient presents in adrenal crisis. Therapy consists of life-long replacement therapy with glucocorticoids and mineralocorticoids. Hypogonadism or other associated disorders should be treated appropriately. Screening of family members for the disease or carrier status may also be indicated and can be critical for family planning. When a monogenic cause of adrenal failure is identified, genetic counseling is indicated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

A 46-year-old female patient was diagnosed as mixed phenotype acute leukemia with chief complaints of intermittent gingival swelling and bleeding for 1 week. The induction chemotherapy was not effective. During the second course chemotherapy, the patient had sudden convulsion and coma. She was transferred to the intensive care unit with worsened condition after transient improvement. Her final diagnosis was secondary adrenocortical insufficiency, adrenal crisis, intractable hyponatremia and cerebral edema.

Primary adrenocortical insufficiency (Addison's disease) is a potentially life-threatening endocrinological disorder caused by destruction of the adrenal cortex with consequent reduction in glucocorticoid and mineralocorticoid function. Although this is a rare condition, misdiagnosis can result in fatal consequences. Previous case reports have described the neuropsychiatric manifestations of Addison's disease which can result in misdiagnosis. Here the authors describe how a psychiatric history combined with atypical biochemical results can point towards a mistaken diagnosis of poisoning and hence disguise an Addisonian crisis.

An Addisonian crisis marks an acute adrenocortical failure which can be caused by decompensation of a chronic insufficiency due to stress, an infarct or bleeding of the adrenal cortex and also abrupt termination of a long-term glucocorticoid medication. This article reports the case of a 25-year-old patient with Crohn's disease who suffered an Addisonian crisis with hypotension, hyponatriemia and hypoglycemia during an emergency laparotomy after he had terminated prednisolone medication on his own authority. This necessitated an aggressive volume therapy in addition to an initial therapy with 100 mg hydrocortisone, 8 g glucose and a continuous administration of catecholamines. Under this treatment regimen hemodynamic stabilization was achieved. Reduction of the administration of hydrocortisone after 3 days resulted in cardiovascular insufficiency which required an escalation of the hydrocortisone substitution.

The main cause of Addison's disease is an autoimmune organ-specific destruction of the cells in the adrenal cortex by an autoreactive process of activated immune cells directed against the steroid-synthesising enzyme 21-hydroxylase. The diagnosis of Addison's disease is suspected in a patient presenting with symptoms of fatigue, bodyweight loss, anorexia, salt craving, and signs of low blood pressure and hyperpigmentation of the skin. Laboratory findings include electrolyte disturbances, and typically an elevated serum potassium level and sometimes a low serum sodium level is found together with low plasma levels of basal and corticotropin-stimulated hydrocortisone (cortisol). An aetiological diagnosis can rapidly be made using commercially available assays demonstrating the presence of autoantibodies directed against 21-hydroxylase. Determination of 21-hydroxylase autoantibodies also permits early diagnosis before a complete adrenocortical destruction has occurred. Thus, a window of opportunity for an early immunomodulatory intervention therapy may exist. Patients presenting with an acute adrenocortical crisis should be treated with 100mg of hydrocortisone and saline intravenously without awaiting laboratory results. Maintenance therapy includes substitution of glucocorticoid and mineralocorticoid steroids, using divided and lower total dosages of glucocorticoids than previously used.

Hypoadrenocorticism is caused by a lack of endogenous glucocorticoid and mineralocorticoid. These deficiencies can cause a myriad of clinical signs. This disease is uncommon and its clinical presentation is similar to many much more commonly recognized diseases such as renal failure and various gastrointestinal disorders. Severely affected patients may present in a life-threatening adrenocortical crisis, which is characterized by variable degrees of volume depletion and electrolyte abnormalities. The emergency clinician should maintain a high clinical suspicion for hypoadrenocorticism, as early recognition and rapid treatment of hypovolemia and electrolyte abnormalities can be lifesaving. The approach to emergency treatment of hypoadrenocorticism should be to recognize and treat life-threatening arrhythmias, replace intravascular volume and normalize perfusion, correct electrolyte abnormalities and hypoglycemia, administer glucocorticoids, and perform the adrenocorticotrophic hormone stimulation test for definitive diagnosis. Patients with this condition should have a favorable outcome when treated appropriately.

Acute adrenocortical insufficiency is a critical care emergency characterized by hemodynamic instability, lethargy, and cardiovascular collapse. Acute adrenal insufficiency has many etiologies, from rapid withdrawal of exogenous glucocorticoids to adrenocortical destruction to poor adrenal reserve after administration of steroid synthesis inhibitors. Etomidate, a parenteral hypnotic agent, is a steroid synthesis inhibitor. Although the use of continuous etomidate infusion in the intensive care unit fell from favor secondary to reports of adrenal crisis, single-dose etomidate for induction of anesthesia is common for the hemodynamically unstable patient or in patients who may not tolerate wide variance in heart rate or blood pressure. A case is presented of acute adrenocortical insufficiency and crisis after a standard induction dose of etomidate. Acute adrenal insufficiency should be suspected in intensive care unit patients who have undergone general anesthesia with etomidate induction and present with hypotension refractory to standard vasopressor administration.

Severe acute adrenocortical insufficiency or adrenal crisis are often elusive diagnoses that may result in severe morbidity and mortality when undiagnosed or ineffectively treated. Although more than 50 steroids are produced within the adrenal cortex, cortisol and aldosterone are far the most abundant and physiologically active. In primary adrenocortical insufficiency, glucocorticoid and mineral-corticoid properties are lost; however, in secondary adrenocortical insufficiency (i.e., secondary to disease or suppression of the hypothalamic-pituitary axis), mineralocorticoid function is preserved. Every emergency physician should be familiar with adrenocortical insufficiency--a potentially life-threatening entity. The initial diagnosis and decision to treat are presumptive and are based on history, physical examination, and, occasionally, laboratory findings. Delay in treatment while attempting to confirm this diagnosis can result in poor patient outcomes. This article review data about physiology, pathophysiology of the adrenal cortex, physiologic effects of glucocorticoids, aldosterone, causes of primary and secondary adrenal insufficiency, frequency, clinical picture, laboratory and imaging studies of adrenal crisis, laboratory evaluation of adrenal function and emergency therapy, replacement therapy, mortality/morbidity of this pathology.

The adrenal cortex normally produces three principal steroid hormones: the glucocorticoid cortisol, the mineralocorticoid aldosterone, and a small quantity of sex steroids. In primary adrenocortical insufficiency, there is a deficiency of both cortisol and aldosterone with characteristic clinical and laboratory findings. In contrast, with a pituitary disorder there is isolated hypocortisolism, because its production is dependent on pituitary adrenocorticotropic hormone (ACTH), whereas aldosterone production is controlled by extracellular fluid volume, renin and serum potassium. Acute adrenocortical crisis is an absolute medical emergency and its presentation is not always typical. We describe three recent cases of acute adrenocortical crisis in our hospital who presented in three different ways in three different wards.

We present a case of fatal adrenal crisis due to isolated adrenocorticotropic hormone (ACTH) deficiency. Autopsy revealed each adrenal gland weighed 0.9 g and the adrenal cortexes were very thin and atrophic. Additionally, cortisol could not be observed in the adrenal cortex by immunohistochemical staining. Furthermore, urine cortisol and 17-OHCS concentration had decreased to a very low level, 20 mg/L and 0.8 mg/L respectively. The anterior pituitary gland was atrophic, and showed fibrosis and lymphocytosis was suspected. Immunohistochemically growth hormone (GH)-stained pituitary gland cells were observed, but there were no cells stained with anti-ACTH antibody. From the history and pathological findings, no other deficiencies of pituitary hormones were evident. Therefore, isolated ACTH deficiency was suspected. Furthermore, as the thyroid gland showed lymphocytic thyroiditis, is was considered that isolated ACTH deficiency was associated with an autoimmune cause. Generally, as patients of chronic adrenocortical insufficiency are exposed to stress and, therefore, have an increased requirement for glucocorticoids, the blood pressure falls, leading to hypovolemic shock called " an adrenal crisis." Without treatment, patients die in crisis within several hours. In our case, the deceased had drunk alcohol without sleep for 2 days. We believe that the stress of drinking and sleeplessness induced adrenal crisis and caused his death.

Acute adrenal crisis in patients with unrecognized chronic adrenocortical failure is difficult to diagnose and potentially fatal. We describe 2 patients with acute adrenal crisis whose diagnoses were hindered because of concomitant glucocorticoid treatment. Acute adrenal insufficiency is primarily a state of mineralocorticoid deficiency. Prednisolone and prednisone, the most frequently prescribed anti-inflammatory corticosteroid agents, have minimal mineralocorticoid activity. Several conditions that may be treated with pharmacological glucocorticoids are associated with an increased risk of Addison disease. An acute adrenal crisis, against which concurrent glucocorticoid therapy does not confer adequate protection, may develop in such patients.

In developing countries tuberculosis is a common cause of constrictive pericarditis and its involvement of other organs may sometimes complicate the surgical management of such patients. A case is reported of constrictive pericarditis in which the patient developed protracted hypotension which was unresponsive to inotropic therapy, following pericardiectomy. On investigation the cause of hypotension was diagnosed as acute adrenocortical insufficiency, secondary to adrenal tuberculosis. The patient was successfully treated with corticosteroids. Low cardiac output after pericardiectomy, which is not uncommon, should not necessarily be attributed to a 'myocardial factor'. Patients with tuberculous pericarditis may have co-existent Addison's disease.

We present a patient with Cushing's syndrome due to adrenocortical adenoma who developed acute adrenal insufficiency one month after unilateral adrenalectomy. She had received lithium carbonate for five years for manic-depressive psychosis. Drug administration was interrupted for 2 weeks postoperatively and was resumed thereafter. At the adrenal crisis, her serum free T4 and T3 levels were both high and serum TSH was subnormal. The thyrotoxicosis subsided spontaneously within 2 weeks. Serum thyroglobulin was markedly increased during the thyrotoxic state. Tests for antimicrosomal antibodies and antithyroglobulin antibodies remained negative. Examination of an open-biopsy specimen of the thyroid gland showed no evidence of thyroiditis. We considered the transient thyrotoxicosis to be due to lithium-induced thyrotoxicosis. Caution should therefore be exercised in administering lithium carbonate, especially when the patient's adrenal reserve is low, since even a mild degree of thyrotoxicosis can precipitate an acute adrenal crisis.

Natural and synthetic glucocorticoids have been used not merely to manage chronic and acute adrenocortical insufficiency as replacement therapy, but to manage a wide variety of conditions as pharmacological agents. In endocrine disease, they are also used to achieve pharmacological effects, not necessarily related to normal physiological roles. In general, the desired effects is suppression of immune reactivity or inflammatory process. According to these effects, they are used to manage Graves' ophthalmopathy and subacute thyroiditis. They are also given to manage thyroid storm and hyperparathyroid crisis.

Three dogs with gastrointestinal tract bleeding of sufficient severity to necessitate blood transfusion were determined to have hypoadrenocorticism on the basis of adrenocortical response to exogenous adrenocorticotropic hormone. All dogs survived the acute crisis and are being managed with fludrocortisone acetate. Hypoadrenocorticism should be considered in the differential diagnosis of acute severe gastrointestinal tract hemorrhage.

We describe a patient with type I diabetes mellitus and hypothyroidism who developed frank adrenocortical insufficiency while receiving a high-dose ketoconazole therapy for keratitis caused by Acanthamoeba species. While impaired cortisol responses to corticotropin and mildly symptomatic hypoadrenalism have been described previously with ketoconazole therapy, to our knowledge, this case represents the first documented article of an actual adrenal crisis associated with this drug. Two reasons are postulated for the development of this complication in our patient: high-dose ketoconazole therapy given in divided doses during the day, and a possibly impaired central response to stress because of hypothyroidism. Our article points to the need to monitor patients treated with high-dose ketoconazole for adrenal insufficiency, particularly if associated illnesses are present that may impair an adequate stress response.