A 58-year-old man comes to the physician due to a 2-week history of worsening fatigue, gen… — USMLE Step 2 CK

A $58$ -year-old man comes to the physician due to a $2$ -week history of worsening fatigue, generalized weakness, nausea, and decreased libido. He was diagnosed with metastatic melanoma $12$ weeks ago and has been receiving treatment with nivolumab and ipilimumab. Temperature is $37.0^\circ\text{C}$ ( $98.6^\circ\text{F}$ ), blood pressure is $102/64$ mm Hg, and pulse is $68$ /min. Physical examination shows a mildly delayed relaxation phase of the deep tendon reflexes. There is no abnormal skin hyperpigmentation. Laboratory studies show:

Laboratory Test	Result	Reference Range
Sodium	$131$ mEq/L	$136-145$ mEq/L
Potassium	$4.1$ mEq/L	$3.5-5.0$ mEq/L
Free T4	$0.4$ ng/dL	$0.9-1.7$ ng/dL
TSH	$1.1$ $\mu$ U/mL	$0.5-5.0$ $\mu$ U/mL

Which of the following is the most appropriate next step in management?

Measure serum morning cortisol levelAnswer
B
Initiate levothyroxine therapy
C
Reassure the patient and repeat laboratory tests in $6$ weeks
D
Measure serum thyroid peroxidase antibodies
E
Obtain an MRI of the brain

Answer

Measure serum morning cortisol level

The correct next step is to measure serum morning cortisol level. This patient presents with fatigue, hyponatremia, and hypotension

12

weeks after starting ipilimumab and nivolumab. His labs reveal a low free T4 with an inappropriately normal TSH, which is the hallmark of central hypothyroidism. Given his immunotherapy regimen, he has likely developed immune-related hypophysitis, a known adverse effect of checkpoint inhibitors (particularly anti-CTLA-4 agents). Hypophysitis often causes multiple anterior pituitary hormone deficiencies, including central adrenal insufficiency (decreased ACTH). It is a critical principle in endocrinology that before initiating thyroid hormone replacement for central hypothyroidism, concurrent adrenal insufficiency MUST be ruled out or treated. Administering levothyroxine increases the basal metabolic rate and accelerates the hepatic clearance of glucocorticoids. In a patient with unrecognized adrenal insufficiency, this rapid depletion of cortisol can precipitate a life-threatening adrenal crisis.

Step-by-Step Solution

Interpret the patient's thyroid laboratory results.

The free T4 is low, and the TSH is inappropriately normal, indicating central (secondary) hypothyroidism.

Primary hypothyroidism would present with an elevated TSH. A normal TSH in the setting of low free T4 points to a pituitary or hypothalamic defect.

Identify the most likely underlying etiology based on the patient's history.

The patient's recent treatment with ipilimumab and nivolumab points to immune checkpoint inhibitor-induced hypophysitis.

Immune checkpoint inhibitors (especially CTLA-4 inhibitors like ipilimumab) are strongly associated with autoimmune inflammation of the pituitary gland, causing multiple anterior pituitary hormone deficiencies.

Determine the appropriate management sequence for suspected panhypopituitarism.

Evaluation for central adrenal insufficiency must precede thyroid hormone replacement.

Starting levothyroxine increases the metabolic clearance of cortisol; in a patient with undiagnosed adrenal insufficiency (suggested here by fatigue, nausea, hyponatremia, and hypotension), this can precipitate a fatal adrenal crisis.

Key Concept

In patients with suspected central hypothyroidism (especially due to hypophysitis), the adrenal axis must be evaluated (e.g., morning cortisol) and treated if necessary BEFORE initiating levothyroxine to avoid precipitating an adrenal crisis.

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