Disease condition and impact on patients Cortisol is an essential hormone; it helps the body respond to stress, such as surgery and illness, and recover from infections. Cortisol also helps maintain blood pressure and cardiovascular functions and regulates the metabolism of proteins, carbohydrates and fatty acids. Aldosterone plays a key role in sodium and potassium balance. Cortisol is the main glucocorticoid hormone produced by the adrenal gland. It is secreted in response to stimulation of the adrenal gland by adrenocorticotropic hormone (ACTH), produced by the pituitary. Adrenal hypofunction describes central and primary adrenal insufficiency and is characterized by insufficient secretion of cortisol. It is caused either by insufficient secretion of ACTH (central adrenal insufficiency, usually associated with deficiency in other pituitary hormones) or by a non-functional adrenal gland (primary adrenal insufficiency, most commonly because of autoimmune destruction of the gland or Addison’s disease). Patients with adrenal insufficiency, both central and primary, often present with hypotension, anorexia, vomiting, weight loss, fatigue and recurrent abdominal pain. Reproductive complaints typically occur in women (amenorrhoea, loss of libido, decreased axillary and pubic hair). In primary adrenal insufficiency, hyperpigmentation and salt craving are also usually present. Patients may also manifest neuropsychiatric signs and symptoms. In children, weight loss with failure to thrive as well as hypoglycaemic crisis with seizures can be seen. Biochemical findings include hyponatraemia, hyperkalaemia (for primary adrenal insufficiency) and hypoglycaemia. Adrenal insufficiency is a life-threatening disorder, which, if not recognized, leads to high morbidity and mortality. Any type of stress in patients with adrenal insufficiency can precipitate an adrenal crisis; the most frequent precipitating factors are gastrointestinal and other infectious diseases. Patients with adrenal crisis usually present with unexplained shock refractory to vasopressors and fluids. Early identification and treatment of adrenal crisis significantly decrease mortality rates during these episodes (1). Treatment of adrenal insufficiency is relatively easy and affordable, using medicines included in the EML. Although treatment improves quality of life and markedly decreases morbidity, there are still challenges. Adrenal hyperfunction, or Cushing’s syndrome, is characterized by excess production of ACTH by the pituitary or by excess production of cortisol directly by the adrenal gland. Although Cushing’s syndrome is clinically unmistakable when fully blown, the spectrum of clinical presentation is broad. It affects numerous systems, such as reproductive, dermatologic, metabolic, cardiovascular, musculoskeletal, neuropsychiatric and infectious. Few, if any, features of Cushing’s syndrome are unique, but some are more discriminatory than others, including reddish-purple striae, plethora, proximal muscle weakness, easy bruising and unexplained osteoporosis. Other symptoms, such as fatigue, weight gain, depression, diabetes, hypertension and menstrual irregularity are also common in individuals without the disorder, which makes the diagnosis very challenging. In children, weight gain with decreasing growth velocity is noticeable (2). This potentially lethal disorder is associated with significant comorbidities and significantly impaired quality of life. This seems to improve after remission and appears to be significantly correlated with the degree of disease control (3, 4). Untreated, Cushing’s syndrome causes severe illness and death. The earliest reports of mortality documented a median survival of 5 years, with most deaths caused by vascular or infectious complications. With modern-day treatments, however, the standard mortality ratio after normalizing cortisol is similar to that of an age-matched population (5, 6). Does the test meet a medical need? Determining serum cortisol is required to diagnose both adrenal hypofunction and hyperfunction. It is also useful in screening for adrenal hypofunction in asymptomatic patients at high risk of developing adrenal insufficiency, including previous long-term exposure to exogenous corticosteroids, as well as pituitary tumours, pituitary surgery, and history of cranial or total body irradiation. Recommendations for testing for adrenal insufficiency and Cushing’s syndrome are based on observational evidence of a large treatment effect on morbidity and mortality in patients diagnosed with the condition. Adrenal hypofunction. In patients with adrenal insufficiency, any type of infection or stress can precipitate an adrenal crisis, leading to unexplained refractory shock with a high mortality rate (7, 8). Treatment consists of glucocorticoid replacement, with hydrocortisone being the first choice, in two to three daily doses. Prednisone can also be used. Once-daily fludrocortisone is also given to patients with primary adrenal insufficiency (9). Generally, appropriately diagnosed and treated patients have a good prognosis and can have a normal lifespan, compared with the high mortality rate seen in untreated patients (10). The benefits of using steroids to treat patients with adrenal insufficiency have long been proven. In the 1930s, many case reports documented miraculous recovery in patients with Addison’s disease who were treated with hydrocortisone. When congenital adrenal hyperplasia was discovered, chronic administration of hydrocortisone to these infants was found to dramatically reverse hypotension, hypoglycaemia and salt wasting (11). Current research is focused on finding different steroid formulations that can mimic the physiological circadian pattern of cortisol secretion, with less frequent dosing, in order to improve quality of life as well as compliance (12). Preventing adrenal crisis, which has a mortality rate of 0.5 per 100 patient years, is important (13). It requires timely diagnosis of at-risk patients as well as education of both patients and health professionals (1, 14). Early treatment with parenteral hydrocortisone is life-saving and is recommended for any patient with even suspected adrenal crisis by all expert guidelines (9). Adrenal hyperfunction. Patients with active Cushing’s syndrome have a mortality rate that is 1.7–4.8 times greater than the general population. It is associated with significant comorbidities, including hypertension, diabetes, coagulopathy, cardiovascular disease, infections and fractures (15, 16). Treating patients with moderate to severe Cushing’s syndrome clearly reduces illness and death. Because Cushing’s syndrome tends to progress and severe hypercortisolism is probably associated with a worse outcome, it is likely that early recognition and treatment of mild disease would also reduce the risk of residual morbidity (17). Even though morbidity and mortality rates decrease with treatment, these may still be higher than the general population, even after hypercortisolism is cured. A recent meta-analysis of seven studies showed that patients with Cushing’s disease in whom initial surgical cure was not obtained had higher death rates than the general population, while patients with initial remission did not (6). But a multicentre, retrospective cohort study showed that patients in remission for more than 10 years still had a higher risk of overall mortality compared with the general population, particularly from circulatory disease; median survival from cure was still found to be excellent at about 40 years of remission (5). How the test is used Adrenal hypofunction. A morning cortisol 140 nmol/L is used as a preliminary test suggestive of adrenal insufficiency. A morning cortisol > 400–500 nmol/L rules out adrenal insufficiency. When corticotropin is available (uncommon in many low-resource settings), intravenous (IV) administration of high dose (250 mcg of cosyntropin in adults, 125 mcg in children > 2 years and 15 mcg/kg of body weight in infants and children < 2 years) or low dose (1 mcg of cosyntropin), followed by determination of serum cortisol 30 or 60 min after the injection should be performed. A peak cortisol level of less than 500 nmol/L (or 250 nmol/L in infants) at this time is commonly used to diagnose adrenal insufficiency (assay dependent) (9). In HICs, the ACTH stimulation test is commonly used because it is independent of the time of the day, cosyntropin is usually readily available and there is no limit on the number of cortisol samples to be assessed. In LMICs, early morning cortisol determination is preferred. Adrenal hyperfunction. The first step in evaluating patients for hypercortisolism is to exclude any exogenous causes, such as administration of corticosteroid medications. After ruling these out, the two most common options for screening are: • The so-called low-dose dexamethasone test, which can be performed as an outpatient test. 1 mg dexamethasone per os is administered between 23:00 and 24:00 h, and serum cortisol is then determined between 08:00 and 09:00 h the next morning. A post-dexamethasone serum cortisol of less than 50 nmol/L rules out Cushing’s syndrome with a sensitivity rate of greater than 95%. This test is easy to perform and is not expensive; dexamethasone is also listed in the EML, albeit for use in palliative care. • Midnight cortisol (2). Overall, the evidence in adults indicates that both tests have similar performance, so choosing which one to use depends on feasibility and technical aspects (2). This application includes cortisol to diagnose both adrenal hypo- and hyperfunction. In low-resource settings, implementing one test for both conditions will be beneficial in terms of training, quality control, etc. Given the low incidence of Cushing’s disease and the fact that it can be properly diagnosed by measuring cortisol after a dexamethasone suppression test or overnight, we would not recommend including other tests to the EDL at the present time. Urinary free and salivary cortisol are also mentioned as alternative tests to diagnose Cushing’s; but these are not usually readily available in LMICs.