Cox Conference: Ipilimumab-Induced Hypophysitis

In this week’s Ambulatory Cox’s Conference, Dr. Namrah Siddiq presented a case of a man with history of malignant melanoma on ipilimumab who presented with nausea, vomiting, and altered mentation. Further evaluation discovered that the patient had severe hyponatremia. Our expert discussant, Dr. Jessica Abramowitz guided us through immune checkpoint inhibitor related endocrinopathies.

Our differential diagnosis for an elderly patient with nausea, vomiting, and altered mental status initially included commonly encountered illnesses including viral gastroenteritis, urinary tract infection, dehydration, small bowel obstruction, malignancy (gastrointestinal tract tumor or metastatic disease), medication side effects, and metabolic disturbances. After we discovered the patient had a history of melanoma and was on ipilimumab, an immune checkpoint inhibitor that targets CTLA-4, our differential broadened to include ipilimumab-related enterocolitis, hepatitis, and hypophysitis. In the setting of severe hyponatremia, the patient was found to have an AM cortisol of 1 mcg/dL, undetectable TSH, and low free T4. Findings were consistent with hypophysitis, a known adverse effect of immune checkpoint inhibitors.

Immune Checkpoint Inhibitor Induced Hypophysitis Pearls:

  • Immune checkpoint inhibitors are a type of immunotherapy that use a patient’s immune system to fight their disease. They have provided significant benefit for a range of different cancer types and in patients who may not have had good treatment options in the past.
  • A number of immune-mediated adverse reactions have been described including enterocolitis, hepatitis, dermatitis, pneumonitis, nephritis, encephalitis/aseptic meningitis, myocarditis, and endocrinopathies (thyroid disease, diabetes, hypophysitis, and adrenal insufficiency). – NEJM paper.1
  • Hypophysitis is an inflammation of the pituitary gland with varying effects on pituitary hormone function. Most commonly presents with central adrenal insufficiency but may have central hypothyroidism, diabetes insipidus, or hypogonadism.
  • Hypophysitis has been described in 11-17% patients on ipilimumab. Ipilimumab in particular appears to most commonly be associated with hypophysitis.2

Clinical Presentation:

  • Patients will typically present with a constellation of symptoms including headache and vision changes along with symptoms of the various hormone deficiencies:
    • ACTH Deficiency – More mild symptoms ranging from fatigue, anorexia, weight loss, nausea/vomiting, postural hypotension, and tachycardia to severe symptoms including vascular collapse or death. Patients may have hyponatremia due to inappropriate secretion of antidiuretic hormone.
    • TSH Deficiency – Fatigue, cold intolerance, decreased appetite, constipation, dry skin, bradycardia, menstrual irregularies, and anemia.
    • FSH/LH Deficiency – Amenorrhea, infertility, hot flashes, and low libido.

Diagnosis:

  • Tests to order include electrolytes (BMP), morning cortisol, TSH and free T4, and ACTH.
  • Can consider ordering LH, FSH, and testosterone levels in males or premenopausal females with complaints of fatigue, loss of libido, and mood changes.
  • Consider MRI of brain with pituitary/sellar cuts in patients with multiple endocrine abnormalities.3
  • Patients with hypophysitis will have low ACTH and low cortisol, low or normal TSH with a low free T4, and low testosterone or estradiol with low LH and FSH.
  • Metabolic abnormalities can occur. In the case of central adrenal insufficiency and hypothyroidism, will have hyponatremia. With central diabetes insipidus, patients can have hypernatremia and volume depletion.

Treatment:

  • Temporarily withhold ipilimumab for symptomatic endocrinopathies.
  • Initiate appropriate hormone replacement therapy. In this case, the patient was started on stress dose steroids, hydrocortisone 150mg per day divided into 3-4 doses. He was also started on IV levothyroxine for thyroid hormone replacement.
  • It is important to use steroids with both glucocorticoid and mineralocorticoid effects such as hydrocortisone.
  • When a patient has hypophysitis with adrenal insufficiency and hypothyroidism, it is important to give the corticosteroids prior to thyroid hormone to prevent precipitating adrenal crisis.
  • After the endocrinopathies are stabilized on replacement hormones, patients can be restarted on ipilimumab with close monitoring by an endocrinologist.
  • Educate patients on increasing steroids during times of illness or surgery. They should also be told to get a medical alert bracelet for adrenal insufficiency. 3

References:

  1. Postow MA, Sidlow R, Hellman MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. NEJM 2018.
  2. Faje A. Immunotherapy and hypophysitis: clinical presentation, treatment, and biologic insights. Pituitary 2016; 19:82.
  3. Brahmer JR, et al. Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 2018.