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Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs.

With nephrotic syndrome, cortisol levels may be falsely lowered by loss of cortisol-binding globulin (CBG) in the urine. An incorrect diagnosis of adrenal insufficiency could therefore be made.We describe the case of a 52-year-old female with nephrotic syndrome that did not sufficiently respond to medication. Treatment management was complicated by symptomatic hypotension, which was thought to be caused by adrenal insufficiency. The cortisol levels in the blood were low and a clinical cause could not be identified. However, free cortisol in the saliva appeared normal and serum CBG levels were low; this therefore precluded adrenal insufficiency. After complete remission of the nephrotic syndrome, cortisol levels normalised.The reduced cortisol level in this patient was caused by the reduced CBG level due to loss associated with nephrotic syndrome. First and foremost it is important to indicate an abnormal laboratory result within an existing disease, before making a new diagnosis of concomitant disease.

Adrenal insufficiency is a rare but fatal disease if left unrecognized. Symptoms often mimic more prevalent diseases. We discuss three patients with primary adrenal insufficiency. These cases illustrate that presenting symptoms such as syncope, nausea, vomiting, weight loss and hypoglycemia are often non-specific and, therefore, often not immediately recognized. When an adrenal crisis is suspected, glucocorticoids should be given promptly. The symptoms are caused by insufficient production of adrenal hormones due to destruction of the adrenal glands by auto-immune adrenalitis. An ACTH stimulation test should confirm the diagnosis when primary adrenal insufficiency is suspected. Treatment consists of glucocorticoid and mineralocorticoid replacement. Primary adrenal insufficiency is a 'master of disguise'. Unexplained syncope, vomiting, weight loss or hypoglycemia should prompt suspicion of this disease.

The famous and beautifully illustrated monograph "On the Constitutional and Local Effects of Disease of the Suprarenal Capsules" was published by Thomas Addison in 1855. This was the first description of the disease that now bears his name. Thomas Addison provided the first real contribution to the knowledge of adrenal function after three centuries of non-productive speculation and is one of the founders of modern endocrinology.

In patients known to have adrenal insufficiency, inadequate adjustment of the glucocorticoid dosage during intercurrent illness can be life threatening. We describe two patients with adrenal insufficiency who died after their glucocorticoid dosage was insufficiently increased during an episode of gastroenteritis and pneumonia, respectively. Another patient died after a few days of fever and vomiting of unknown origin, after a period of refusing her medication. To prevent unnecessary death from Addisonian crisis, we have developed a protocol. Patients with known adrenal insufficiency, as well as their relatives and general practitioners, should repeatedly receive verbal and written instructions on how to deal with physical and severe psychic stress. We teach the patients and their relatives how to use an emergency injection of hydrocortisone, and the patients can consult the on-call endocrinologist by telephone 24 hours a day.

A 50-year-old woman complained of nausea, diarrhoea, tiredness and dizziness five weeks after a visit to Egypt. She was deeply tanned with hyperpigmentation on the metacarpophalangeal joints, palm of hand creases and buccal mucosa, due to Addison's disease.

Three boys, aged 5, 11 and 14 years, were admitted due to vomiting, fatigue and dehydration, and a 10-year-old boy was admitted due to circulatory and respiratory insufficiency. Two had Addison's disease, one had a late presentation of congenital adrenal hypoplasia due to a DAX-1 mutation and in one adrenal insufficiency was the first manifestation ofadrenoleukodystrophia. The boys recovered after treatment. It is important to recognise the symptoms of adrenal insufficiency, because treatment can be life-saving. After the initial diagnosis the underlying pathology should be sought.

An 88-year-old man presented with nausea and vomiting. Recently a cutaneous B-cell lymphoma had been diagnosed on his right cheek. Laboratory investigation showed hyponatraemia. Fluid restriction was started, based on the diagnosis of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). However the hyponatraemia persisted and a diagnosis of 'reset osmostat' was made. CT of the abdomen revealed slight bilateral adrenal enlargement, which was interpreted as adrenal incidentaloma. No other localisation of the lymphoma, besides that on the right cheek, was seen. Although the symptoms initially disappeared, they recurred and were quickly followed by hypotension. The patient died. Post-mortem examination showed bilateral destruction of the adrenal glands due to lymphoma. The correct diagnosis was Addison's disease. This case shows that diseases do not always present with all the classical symptoms, and that it is important to consider test characteristics of diagnostic tests and to judge investigations in the context of the other clinical findings.

Most symptoms and signs of adrenocortical insufficiency are aspecific. For a definitive diagnosis a stimulation test is often needed. In case of secondary adrenocortical insufficiency glucocorticoid substitution nearly always suffices. Patients with primary adrenocortical insufficiency need substitution not only with glucocorticoids but also with mineralocorticoids. A standard daily dose of 30 mg hydrocortisone as glucocorticoid substitution is too high for many patients, while for some a standard daily dose of 0.1 mg fludrocortisone as mineralocorticoid substitution is too low. Patients with adrenocortical insufficiency need adequate instructions about what to do in case of stress, such as a (febrile) illness or trauma. Duration and severity of the suppression of the pituitary-adrenal axis by the use of pharmacological amounts of glucocorticoids are highly variable. When pharmacological amounts of glucocorticoids (7.5 mg prednisone daily) are used for 3 weeks or longer, a clinically relevant suppression of the pituitary-adrenal axis is possible, and this may persist for one year after discontinuing the use of glucocorticoids.

In three patients, two women aged 71 and 59 years and a man aged 49 who had been living in the Netherlands for a long time and who were admitted because of vague symptoms, extrapulmonary manifestations of tuberculosis were diagnosed: tuberculosis of the lumbar spine with psoas abscess, tuberculous peritonitis and adrenal tuberculosis with Addison's disease in a patient with open pulmonary tuberculosis. All three recovered with tuberculostatic therapy (isoniazid, streptomycin, pyrazinamide and rifampicin).