Myxoedema coma caused by immunotherapy-related thyroiditis and enteritis

Abstract

Summary Thyroid dysfunction is among the most common immune-related adverse reactions associated with immune checkpoint inhibitors. It most commonly manifests as painless thyroiditis followed by permanent hypothyroidism. This usually causes mild toxicity that does not interfere with oncological treatment. In rare instances, however, a life-threatening form of decompensated hypothyroidism called myxoedema coma may develop. We present a case of myxoedema coma in a woman in her sixties who was treated with a combination of CTLA-4 and PD-1 immune checkpoint inhibitors; for stage four malignant melanoma. She became hypothyroid and required thyroxine replacement after an episode of painless thyroiditis. Six months after the initial diagnosis of malignant melanoma, she presented to the emergency department with abdominal pain, profuse diarrhoea, lethargy and confusion. She was drowsy, hypotensive with a BP of 60/40 mmHg, hyponatraemic and hypoglycaemic. Thyroid function tests (TFTs) indicated profound hypothyroidism with a TSH of 19 mIU/L, and undetectable fT3 and fT4, despite the patient being compliant with thyroxine. She was diagnosed with a myxoedema coma caused by immune-related enteritis and subsequent thyroxine malabsorption. The patient was treated with i.v. triiodothyronine (T3) and methylprednisolone in the ICU. While her clinical status improved with T3 replacement, her enteritis was refractory to steroid therapy. A thyroxine absorption test confirmed persistent malabsorption. Attempts to revert to oral thyroxine were unsuccessful. Unfortunately, the patient’s malignant melanoma progressed significantly and she passed away four months later. This is the first reported case of myxoedema coma that resulted from two distinct immune-related adverse reactions, namely painless thyroiditis and enterocolitis. Learning points Myxoedema coma, a severe form of decompensated hypothyroidism is a rare immunotherapy-related endocrinopathy. Myxedema coma should be treated with either i.v. triiodothyronine (T3) or i.v. thyroxine (T4). Intravenous glucocorticoids should be co-administered with thyroid hormone replacement to avoid precipitating an adrenal crisis. Thyroid function tests (TFTs) should be monitored closely in individuals with hypothyroidism and diarrhoea due to the risk of thyroxine malabsorption. A thyroxine absorption test can be used to confirm thyroxine malabsorption in individuals with persistent hypothyroidism.

Myxedema coma secondary to levothyroxine malabsorption in a patient previously submitted to bariatric surgery

“…A very recent study by Mc Donald and cols. reported a case of immune-related enteritis malabsorption in a female patient on treatment with immune checkpoint inhibitors ( 25 ). Reardon and cols.…”

Potential pitfalls in diagnosis of immunotherapy-induced hypothalamic–pituitary–adrenal axis suppression

“…endocrinology by informing clinicians about challenging cases (Mc Donald et al,2021) and stimulating discussions. Future guidelines need to address the diagnostic difficulties encountered in immunotherapy-related more comprehensively.…”

“…The potential mechanisms underlying this association are still unknown. Case reports, such as the one outlined, help to inform clinicians and stimulate discussion about challenging cases ( Mc Donald et al 2021 ) in an evolving area of endocrinology. Future guidelines need to address the diagnostic difficulties encountered in immunotherapy-related hypophysitis more comprehensively.…”

Cancer immunotherapy and the management of side effects

“…Administration of thyroxine in this circumstance can precipitate an adrenal crisis as thyroxine increases the metabolism of (already deficient) cortisol. 4 An urgent assessment of the hypothalamic-pituitaryadrenal (HPA) axis with measurement of ACTH and cortisol is mandatory in patients presenting with secondary hypothyroidism. Once confirmed, hydrocortisone replacement should be initiated followed by thyroxine replacement at least 48 hours after.…”

“…3 Training in microbiology is not accessible for those with paediatric experience, only those who have undertaken training in adult internal medicine. 4 The majority of infection diagnostic laboratories will process samples for a paediatric population, but experience in Paediatric infection for those running these laboratories is becoming increasingly limited.…”