Hyponatraemia secondary to nivolumab-induced primary adrenal failure

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Hyponatraemia secondary to nivolumab-induced primary adrenal failure

Summary

Checkpoint inhibitors, such as ipilimumab and pembrolizumab, have transformed the prognosis for patients with advanced malignant melanoma and squamous non-small-cell lung cancer, and their use will only expand as experience is gained in a variety of other malignancies, for instance, renal and lymphoma. As the use of checkpoint inhibitors increases, so too will the incidence of their unique side effects, termed immune-related adverse events (irAEs), which can affect dermatological, gastrointestinal, hepatic, endocrine and other systems. Nivolumab is a monoclonal antibody that blocks the human programmed death receptor-1 ligand (PD-L1) found on many cancer cells and is licensed for the treatment of advanced malignant melanoma. We describe the first case of nivolumab-induced adrenalitis resulting in primary adrenal failure presenting with hyponatraemia in a 43-year-old man with malignant melanoma. The case highlights the potentially life-threatening complications of checkpoint inhibitors and the need for patient education and awareness of irAEs among the wider clinical community because such side effects require prompt recognition and treatment.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097140/

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• Learning points:
  
  Nivolumab can cause primary adrenal insufficiency.
  
  Not all cases of hyponatraemia in patients with malignancy are due to SIADH.
  
  Any patient on a checkpoint inhibitor becoming unwell should have serum cortisol urgently measured and if in doubt hydrocortisone therapy should be initiated.
  
  Although hyponatraemia can occur in patients with ACTH deficiency, the possibility of primary adrenal failure should also be considered and investigated by measurement of renin, aldosterone and ACTH.
  
  Patients receiving checkpoint inhibitors require education on the potential risks of hypocortisolaemia.
  
  PET imaging demonstrated bilateral increased activity consistent with an autoimmune adrenalitis.

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Adrenalitis

Abstract
Inflammation of the adrenal glands is caused by autoimmunopathies or infections and can induce adrenal insufficiency. Autoimmune lymphocytic adrenalitis is often combined with other autoimmune diseases and the most frequent cause of Addison's disease; however, it only becomes clinically apparent when more than 90 % of the adrenal cortex has been destroyed. Histological features are characterized by lymphoplasmacytic inflammation leading to an increased destruction of adrenocortical tissue but less severe courses can also occur. The second most frequent form of adrenalitis is adrenal tuberculosis, showing typical granulomatous findings that are nearly always caused by spreading from a tuberculous pulmonary focus. Other bacterial as well as viral infections, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and others, generally affect the adrenal glands only in patients with immunodeficiency disorders. In these infections, the adrenal cortex and medulla are frequently involved to roughly the same extent. Although surgical specimens from inflammatory adrenal lesions are extremely rare, the various forms of adrenalitis play an important role in the post-mortem examination of the adrenal glands for clarification of unclear causes of death (e.g. death during an Addisonian crisis).

Keywords: Addison’s disease; Adrenal glands; Autoimmune adrenalitis; Immunodeficiency; Tuberculosis.

https://pubmed.ncbi.nlm.nih.gov/27099224/

Chapter 42 - Adrenalitis


Addison’s disease is the result from an adrenal cortex hypofunction or dysfunction with a deficient production of glucocorticoids, mineralocorticoids, and androgens, and with high levels of both ACTH and plasma renin activity. The prevalence of AD is 110–144 cases per million population in developed countries and about 80% of cases are related to autoimmunity.

The clinical, diagnostic, genetic, immunological, histopathological, natural history, and therapeutic aspects of autoimmune AD are taken into consideration in this chapter.

https://www.sciencedirect.com/science/a ... 9298000423

[Olga]

Ivan started to get abnormal Potassium results in his blood work first, then he felt unwell few times before the morning cortisol and aldosterone and testosterone tests were ordered and adrenal insufficiency was diagnosed. What I find misleading, the drug makers report the potassium or low sodium abnormalities as the adverse effects although they are just the signs of the underlying condition, and it has to be investigated. Instead they assume it is a separate blood work abnormalities and try to correct them without looking into the underlying cause, therefore under reporting immunotherapy related AEs. When we saw the hyperkalemia persisting and sodium at the low normal, we started investigate the possible causes for it and basically Ivan self diagnosed his autoimmune Addison disease and the additional blood work ordered just confirmed that he is deficient in both, aldosterone and cortisol. Low sodium (Hyponatraemia) is caused by the excessive fluid loss in this condition and is, again, a consequence of the adrenal failure, not the separate existing blood work abnormality.

[D.ap]

Hello Olga ,
I agree that more aggressive bloodwork should be had , as the adrenal gland is so very important .😕
How long do you think Ivan had been experiencing adrenal issues before he was tested ?
I assume the test that’s scheduled first thing in morn that detects low and or semi low cortisol levels was the gage that prompted more testing? And the ultimate diagnosis ?
It looks like as a rule the average population , outside of the ICI treated patients are statically low numbers when low sodium is found in bloodwork , to have adrenal gland /cortisol levels show low ? So to prompt further testing ?
And yes the Addison patient website sure does point out that as a rule, sodium levels are just simple “treated” rather than doing more investigative testing .😕

https://www.uptodate.com/contents/adren ... -basics#H1

[Olga]

There are some other reasons for the low sodium besides the adrenal insufficiency. Low potassium, low sodium etc have to be investigated in the context of the possible immune related adverse and not just fixed.
He had some symptoms first, mostly morning weakness and salt craving and orthostatic hypotension (when you stand up and loose the balance from this move). But we really had no idea what it means. Later the potassium was getting progressively high in a few blood works and he was just given the suspension that removes an excess K from the stomach. It helped temporarily.

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Olga
I’m sure sorry this happened to Ivan .