Thanks to Sahar for presenting the interesting case of a middle-aged woman with metastatic melanoma recently started on ipilimumab who presented with a headache and fatigue, found to have hypothyroidism and adrenal insufficiency with work up consistent with hypopituitarism related to an adverse effect of ipilimumab: lymphocytic hypophysitis!
Clinical Pearls
- Remember that adrenal insufficiency and hypothyroidism are causes of elevated ADH levels.
- Red flags for obtaining head imaging for headache include age >55, sudden onset, positional, onset after trauma or exercise, fever, focal neuro findings, and immunosuppression.
- Pituitary adenomas can have three manifestations: mass effect, hormonal hypersecretion, and hypopituitarism. When imaging shows a pituitary mass, your work up should address each of these categories.
- The most sensitive test to assess hypothalamic-pituitary access function is LH/FSH!
- Immunotherapies are commonly associated with a flare of autoimmune diseases. A more rare side effect of CTLA-4 inhibitors (like ipilimumab) is lymphocytic hypophysitis (inflammation of the pituitary gland)
- This condition commonly presents with headache out of proportion to neurologic findings and preferential decline in ACTH and TSH though other hormones can also be impacted.
- For hypopituitarism, remember to always treat adrenal insufficiency first before replacing thyroid hormone. Failure to do so can precipitate adrenal crisis!
Indications for imaging a patient with headache:
- Age >55
- Sudden onset
- Worse with lying down or wakes patient from sleep
- Rapid onset after trauma or exercise
- Fever
- Focal neurologic findings
- New headache in immunosuppressed patient
Pituitary adenoma:
- Evaluate for the following
- Mass effect: visual field deficit, headache
- Hormonal hypersecretion
- Prolactin ⇒ galactorrhea, amenorrhea, infertility
- GH ⇒ Acromegaly
- TSH ⇒ hyperthyroidism
- ACTH ⇒ Cushing disease
- ADH ⇒ SIADH
- Hyposecretion:
Hypophysitis:
- Inflammation of the pituitary
- Four categories based on histologic findings:
- Lymphocytic
- Most common form
- Seen in late pregnancy and post-partum period
- Also associated with ipilimumab as our patient here!
- Granulomatous
- Idiopathic or secondary to GPA, sarcoid, TB
- Plasmacytic (IgG4-related)
- Xanthomatous (most rare)
- Lymphocytic
- Clinical presentation
- Headache out of proportion to exam findings
- Preferential decrease in ACTH and TSH ⇒ adrenal insufficiency and hypothyroidism
- Prognosis:
- Pituitary size eventually normalizes but pituitary loss of function is often permanent.
Hyponatremia:
Lastly, refer to this algorithm from our recent morning report to help you think through hyponatremia.
SCVMC IM Chief Resident Blog 
nice case. you probably saw it already, but a decent reference for immune related adverse events (from 1/2018) was this article in NEJM. The mechanism of hypophysitis here is interesting (figure 1, bottom right): CTLA4 inhibits T cells and dendritic cells. CTLA4 is expressed on normal pituitary tissue which normally protects it from the immune system, but probably mediates the hypophysitis when CTLA4 inhibitor is applied (ipilimumab) (source: Iwama S et al. Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody. Sci Transl Med 2014)
On Wed, Oct 3, 2018 at 1:55 PM Santa Clara Valley Medical Center Internal Medicine Residency wrote:
> vmcimchiefs posted: “Thanks to Sahar for presenting the interesting case > of a middle-aged woman with metastatic melanoma recently started on > ipilimumab who presented with a headache and fatigue, found to have > hypothyroidism and adrenal insufficiency with work up consistent wi” >
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