A 65-year-old man is evaluated in the clinic for severe, progressive fatigue, generalized … — USMLE Step 2 CK

A $65$ -year-old man is evaluated in the clinic for severe, progressive fatigue, generalized weakness, and loss of appetite over the past $3$ weeks. He also reports a mild, constant, diffuse headache. The patient has a history of metastatic melanoma and has been receiving combination immunotherapy with nivolumab and ipilimumab for the past $4$ months. Blood pressure is $96/60$ mmHg while supine and $82/50$ mmHg while standing. Heart rate is $92$ /min. Physical examination reveals vitiligo over the upper extremities. The thyroid gland is not palpable.

Laboratory studies show the following:

Laboratory Test	Result	Reference Range
Serum sodium	$131$ mEq/L	$136-145$ mEq/L
Serum potassium	$4.1$ mEq/L	$3.5-5.0$ mEq/L
Thyroid-stimulating hormone (TSH)	$0.2$ $\mu$ U/mL	$0.5-5.0$ $\mu$ U/mL
Free thyroxine (T4)	$0.5$ ng/dL	$0.9-1.7$ ng/dL

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

Measurement of serum early-morning cortisolCevap
B
Initiation of oral levothyroxine therapy
C
Measurement of anti-thyroid peroxidase antibodies
D
Magnetic resonance imaging of the brain
E
Intravenous administration of $3\%$ sodium chloride

Cevap

Measurement of serum early-morning cortisol

The correct answer is measurement of serum early-morning cortisol. This patient is presenting with headache, profound fatigue, orthostatic hypotension, hyponatremia, and central hypothyroidism (low free T4 with an inappropriately low TSH) after receiving combination immune checkpoint inhibitor therapy (nivolumab and ipilimumab). This clinical constellation is highly characteristic of immune checkpoint inhibitor-induced hypophysitis. Hypophysitis causes inflammation and destruction of the anterior pituitary, frequently leading to deficiencies in multiple axes, most notably ACTH (secondary adrenal insufficiency) and TSH (secondary hypothyroidism). When a patient has central hypothyroidism, it is a critical rule in endocrinology to evaluate the adrenal axis before initiating thyroid hormone replacement. Administering levothyroxine increases the basal metabolic rate and hepatic clearance of cortisol. If the patient has an undiagnosed concomitant cortisol deficiency, starting levothyroxine can precipitate a sudden, life-threatening acute adrenal crisis. Therefore, assessing the adrenal axis with an early-morning serum cortisol level is the most urgent and appropriate next step.

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Analyze the clinical presentation and medication history.

The patient has fatigue, headache, orthostatic hypotension, and is taking immune checkpoint inhibitors (ipilimumab and nivolumab).

Immune checkpoint inhibitors are well known to cause immune-related adverse events, particularly endocrinopathies such as hypophysitis.

Interpret the laboratory findings.

Low free T4 (

0.5

ng/dL) with an inappropriately low TSH (

0.2

\mu

U/mL) indicates central (secondary) hypothyroidism. Mild hyponatremia with normal potassium is also present.

Primary hypothyroidism would feature an elevated TSH. The combination of central hypothyroidism, hyponatremia, and orthostasis strongly suggests concomitant secondary adrenal insufficiency.

Determine the safest sequence of management.

The adrenal axis must be evaluated (via early-morning cortisol) before treating the thyroid axis.

Administering levothyroxine accelerates basal metabolism and hepatic clearance of cortisol. In a patient with untreated adrenal insufficiency, this can precipitate a fatal adrenal crisis.

Anahtar Kavram

In patients with suspected central hypothyroidism and panhypopituitarism (e.g., due to immune checkpoint inhibitor-induced hypophysitis), evaluation and treatment of the adrenal axis (glucocorticoids) MUST precede the administration of thyroid hormone (levothyroxine) to avoid precipitating an adrenal crisis.

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