Hyponatraemia in patients on immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs), such as anti-PD-1 programmed death 1, anti- PD-L1 (PD-1 ligand) and anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) are antibodies that inhibit immune checkpoints (ICs). ¹ These agents are broadly used in the management of various patients with cancer, but they can result in various autoimmune complications as side effects.^2,3 ICIs endocrinopathies are among the most common ones. ³ - ⁵ Interestingly, recent data indicate that endocrine complications after immunotherapy with ICIs may represent a positive predictor of treatment response. Indeed, there is a recent term in the literature known as ‘beneficial autoimmunity’. ⁶

There are various mechanisms which can lead to hyponatraemia in patients on ICIs. First of all, hypovolemic hyponatraemia can be present due to hemodynamic disturbances secondary to volume depletion from autoimmune adverse effects like colitis and enteritis or due to congestive heart failure, nephrosis or cirrhosis. Second, syndrome of inappropriate antidiuretic hormone (SIADH) secretion can be also present due to an underlying lung cancer or due to neurological adverse effects like encephalitis and meningitis. Last but not least, various ICIs endocrinopathies, such as hypophysitis, primary adrenal insufficiency (PAI) and hypothyroidism may lead to euvolemic hyponatraemia.^2,3

The overall incidence of hypophysitis is up to 17% in patients treated with ICIs, with a female to male ratio of 1:4. The mean age at onset is approximately 60 years. The mean time of onset after therapy initiation is within 2–3 months. ⁷ Central adrenal insufficiency may be present with hyponatraemia, hypotension and it can be life-threatening sometimes. In fact, hypophysitis presents almost always with symptoms and signs of hypocortisolism, whereas manifestations related to pituitary enlargement are overall moderate. Central hypothyroidism as well as hypogonadotropic hypogonadism are transient and these axes recover spontaneously in most cases of ICIs induced hypophysitis. ⁴ Physicians should be aware of the distinctive features of ICIs induced hypophysitis compared with primary autoimmune hypophysitis. ³ - ⁵

PAI is a rare complication of ICIs and to date only few cases have been presented in the literature, making an estimate of incidence very difficult. An important parameter is that the exact cause of adrenal insufficiency (primary or secondary) is not always clearly reported in studies.^4,8 Symptoms and signs are non-specific and include fatigue, orthostatic hypotension and abdominal discomfort. Hyponatraemia and hyperkalemia are common, while hypoglycemia and hypercalcemia can also appear. As all zones of the adrenal cortex are usually affected, mineralocorticoid deficiency is possible, rendering an adrenal crisis in that case more dangerous. In some cases, positive 21-hydroxylase autoantibodies, the autoimmune biomarker associated with regular autoimmune adrenal insufficiency, were described as positive.^3,4,8 Hyponatraemia due to hypothyroidism is rather rare and present in severe or untreated cases. ⁴

Most current guidelines recommend that serum sodium concentrations should be measured in all patients who are on ICIs along with other electrolytes, thyroid stimulating hormone (TSH), FT4, cortisol and glucose at baseline and before every immunotherapy cycle (or every 4–6 weeks), as part of a routine monitoring.^2,4 If morning cortisol concentrations are low (<5 μg/dl), this is indicative of adrenal insufficiency. A paired cortisol and adrenocorticotropic hormone (ACTH) will provide the exact diagnosis. Low cortisol levels and ACTH values of more than 2 times the upper reference limit is indicative of primary adrenal insufficiency. If the results are equivocal, a standard 250 μg iv synacthen test can be employed. This requires a rise of cortisol levels to over 18 μg/dl at 30 or 60 min to be normal. ⁸ Adrenal CT can help in the diagnosis adrenalitis and exclude other causes, such as adrenal metastases or hemorrhage. If low cortisol is accompanied by low ACTH, other pituitary hormones should be measured. Pituitary magnetic resonance imaging (MRI) can help in the diagnosis of hypophysitis and exclude other causes of pituitary failure, such as metastatic disease. Diabetes insipidus is rare, but monitoring is sometimes important especially after starting of glucocorticoids.^2,4

When adrenal insufficiency is diagnosed, hydrocortisone at a dose of 15–25 mg divided in two or three daily doses is recommended. When the cause is primary adrenal insufficiency, replacement therapy with fludrocortisone (50–100 μg) and a diet without salt restriction is also necessary.^2,9 All patients should be provided with appropriate and regular training on managing their glucocorticoid treatment during period of illness (sick day rules) regarding recognizing symptoms and relevant dose adjustments (2–3 times). Parenteral administration of high-dose hydrocortisone (100 mg at presentation) is sometimes required, when severe symptoms are present. This should be accompanied by appropriate fluid resuscitation, as well as 100–200 mg hydrocortisone/24 h via continuous intravenous therapy or 6 hourly injections. Normal saline should be intravenously administered. When hypoglycemia is also present, intravenous dextrose is required too. After improvement of the clinical and biochemical picture, treatment can be changed to oral hydrocortisone (60 mg in 24 h), which is progressively reduced to the proper replacement dose.^2,4,9 There is no robust evidence to support the use of high-dose systemic corticosteroids in patients with ICIs hypophysitis. Such a therapeutic approach (with prednisolone 1 mg/kg/day) should be reserved only for few severe cases.^4,9

In conclusion, various endocrine complications, such as hypophysitis, PAI and hypothyroidism may lead to euvolemic hyponatraemia in patients who are on ICIs immunotherapy. Physicians who treat such patients should be aware of these conditions and screen them accordingly.