A 59-year-old man with metastatic melanoma is brought to the emergency department by his w… — USMLE Step 2 CK

A $59$ -year-old man with metastatic melanoma is brought to the emergency department by his wife due to profound fatigue, generalized weakness, and nausea that have progressively worsened over the past two weeks. He has been receiving immunotherapy with ipilimumab and nivolumab for the past four months. His temperature is $36.8^\circ\text{C}$ ( $98.2^\circ\text{F}$ ), blood pressure is $88/56\text{ mm Hg}$ , and pulse is $98/\text{min}$ . When he stands, his blood pressure drops to $76/45\text{ mm Hg}$ and he feels dizzy. Physical examination shows a lethargic man. Mucous membranes are dry, and there is no abnormal skin pigmentation.

Laboratory studies show:

Test	Result	Reference Range
Sodium	$128\text{ mEq/L}$	$136-145\text{ mEq/L}$
Potassium	$4.1\text{ mEq/L}$	$3.5-5.0\text{ mEq/L}$
Chloride	$95\text{ mEq/L}$	$98-106\text{ mEq/L}$
Bicarbonate	$22\text{ mEq/L}$	$22-28\text{ mEq/L}$
Blood urea nitrogen (BUN)	$24\text{ mg/dL}$	$7-18\text{ mg/dL}$
Creatinine	$1.1\text{ mg/dL}$	$0.7-1.3\text{ mg/dL}$
Glucose	$62\text{ mg/dL}$	$70-100\text{ mg/dL}$
Thyroid-stimulating hormone (TSH)	$0.8\text{ mIU/L}$	$0.4-4.0\text{ mIU/L}$
Free thyroxine (T4)	$0.4\text{ ng/dL}$	$0.9-1.7\text{ ng/dL}$

Which of the following additional laboratory findings is most likely to be present in this patient?

Decreased serum adrenocorticotropic hormone (ACTH) concentrationAnswer
B
Elevated serum thyroid peroxidase (TPO) antibody titer
C
Decreased serum aldosterone concentration
D
Elevated serum prolactin concentration
E
Elevated serum luteinizing hormone (LH) concentration

Answer

Decreased serum adrenocorticotropic hormone (ACTH) concentration

The correct answer is decreased serum adrenocorticotropic hormone (ACTH) concentration. This patient's presentation of profound fatigue, hypotension, orthostasis, hyponatremia, and hypoglycemia in the setting of recent immune checkpoint inhibitor therapy (ipilimumab and nivolumab) is highly suspicious for immune-mediated hypophysitis. Hypophysitis is a known, potentially life-threatening adverse effect of CTLA-4 inhibitors. It causes destructive inflammation of the anterior pituitary gland, leading to multiple endocrinopathies (panhypopituitarism).

The laboratory findings confirm central hypothyroidism, characterized by a low free T4 with an inappropriately normal TSH. This pituitary localization indicates that the patient's adrenal crisis is due to central adrenal insufficiency. Therefore, the damaged pituitary gland cannot produce adequate ACTH to stimulate the adrenal cortex, resulting in a simultaneously decreased serum ACTH concentration. The patient's normal serum potassium concentration and absence of hyperpigmentation further confirm a central etiology, as aldosterone production (which prevents hyperkalemia and is RAAS-dependent) is preserved, and excess ACTH precursor peptides (which cause hyperpigmentation) are not present.

Step-by-Step Solution

Analyze the thyroid laboratory panel.

The patient has a low free T4 with an inappropriately normal TSH.

This specific combination localizes the endocrine defect to the pituitary gland or hypothalamus, indicating central hypothyroidism rather than a primary thyroid gland issue.

Evaluate the clinical presentation and metabolic derangements.

The patient exhibits severe fatigue, hypotension, orthostasis, hypoglycemia, and hyponatremia with a normal potassium level.

These findings are classic for adrenal insufficiency. The normal potassium level provides a critical clue that the mineralocorticoid axis (aldosterone) is preserved.

Synthesize the laboratory data with the patient's medication history.

The combination of central hypothyroidism and likely central adrenal insufficiency in a patient taking ipilimumab points to immune checkpoint inhibitor-induced hypophysitis.

CTLA-4 inhibitors are well known to cause destructive inflammation of the anterior pituitary gland, leading to panhypopituitarism.

Determine the expected ACTH level based on the etiology.

ACTH will be decreased.

Because the destruction is at the level of the anterior pituitary (central adrenal insufficiency), the gland cannot produce ACTH to stimulate the adrenal cortex, distinguishing this from primary Addison's disease where ACTH is highly elevated.

Key Concept

Immune checkpoint inhibitor-induced hypophysitis causes panhypopituitarism, classically presenting with central hypothyroidism (low T4, normal/low TSH) and central adrenal insufficiency (low cortisol, low ACTH, preserved aldosterone).

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