Diagnosis and Treatment > Signs and Symptoms
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Summary
Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) pathways are key regulators in T-cell activation and tolerance. Nivolumab, pembrolizumab (PD-1 inhibitors), atezolizumab (PD-L1 inhibitor) and ipilimumab (CTLA-4 inhibitor) are monoclonal antibodies approved for treatment of several advanced cancers. Immune checkpoint inhibitors (ICIs)-related hypophysitis is described more frequently in patients treated with anti-CTLA-4; however, recent studies reported an increasing prevalence of anti-PD-1/PD-L1-induced hypophysitis which also exhibits slightly different clinical features. We report our experience on hypophysitis induced by anti-PD-1/anti-PD-L1 treatment. We present four cases, diagnosed in the past 12 months, of hypophysitis occurring in two patients receiving anti-PD-1, in one patient receiving anti-PD-1 and anti-CTLA-4 combined therapy and in one patient receiving anti-PD-L1. In this case series, timing, clinical presentation and association with other immune-related adverse events appeared to be extremely variable; central hypoadrenalism and hyponatremia were constantly detected although sellar magnetic resonance imaging did not reveal specific signs of pituitary inflammation. These differences highlight the complexity of ICI-related hypophysitis and the existence of different mechanisms of action leading to heterogeneity of clinical presentation in patients receiving immunotherapy.
Learning points:
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PD-1/PD-L1 blockade can induce hypophysitis with a different clinical presentation when compared to CTLA-4 blockade.
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Diagnosis of PD-1/PD-L1 induced hypophysitis is mainly made on clinical grounds and sellar MRI does not show radiological abnormalities.
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Hyponatremia due to acute secondary adrenal insufficiency is often the principal sign of PD-1/PD-L1-induced hypophysitis and can be masked by other symptoms due to oncologic disease.
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PD-1/PD-L1-induced hypophysitis can present as an isolated manifestation of irAEs or be in association with other autoimmune diseases
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Summary
A 69-year-old male was admitted for severe hyponatremia disclosed after an accidental fall. He was anticoagulated from 2 months after the implantation of a biologic aortic valve prosthesis. The work-up disclosed adrenal failure and MRI showed bilateral adrenal hemorrhage. Clinical picture and lab parameters normalized quickly after the appropriate replacement treatment. Anticoagulation excess should be added to the list of drugs potentially causing hyponatremia.
Learning points:
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Hyponatremia requires a complete and timely workup in order to start an appropriate treatment for the improvement of clinical conditions.
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History is crucial: a detailed list of drugs potentially causing hyponatremia should be collected. Anticoagulants should be added to the list, mostly in the event of excessive anticoagulation.
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Intra-adrenal hemorrhage is a rare cause of hyponatremia and adrenal failure.
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The ACTH test is still the gold standard for the diagnosis of hypoadrenalism.
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Summary
Bilateral adrenal hemorrhages rarely occur during the neonatal period and are often associated with traumatic vaginal deliveries. However, the adrenal gland has highly regenerative capabilities and adrenal insufficiency typically resolves over time. We evaluated a newborn female after experiencing fetal macrosomia and a traumatic vaginal delivery. She developed acidosis and acute renal injury. Large adrenal hemorrhages were noted bilaterally on ultrasound, and she was diagnosed with adrenal insufficiency based on characteristic electrolyte changes and a low cortisol (4.2 µg/dL). On follow-up testing, this patient was unable to be weaned off of hydrocortisone or fludrocortisone despite resolution of hemorrhages on ultrasound. Providers should consider bilateral adrenal hemorrhage when evaluating critically ill neonates after a traumatic delivery. In extreme cases, this may be a persistent process.
Learning points:
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Risk factors for adrenal hemorrhage include fetal macrosomia, traumatic vaginal delivery and critical acidemia.
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Signs of adrenal hemorrhage include jaundice, flank mass, skin discoloration or scrotal hematoma.
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Adrenal insufficiency often is a transient process when related to adrenal hemorrhage.
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Severe adrenal hemorrhages can occur in the absence of symptoms.
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Though rare, persistent adrenal insufficiency may occur in extremely severe cases of bilateral adrenal hemorrhage.
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Consider adrenal hemorrhage when evaluating a neonate for shock in the absence of an infectious etiology.
