A 35-year-old woman comes to the clinic to discuss recent laboratory results. A basic meta… — USMLE Step 3

A 35-year-old woman comes to the clinic to discuss recent laboratory results. A basic metabolic panel obtained during a pre-employment physical examination showed an elevated serum calcium level. The patient feels completely well and has no fatigue, abdominal pain, bone pain, or changes in bowel habits. She has no significant past medical history and takes no medications or over-the-counter supplements. She exercises vigorously four times a week. Vital signs are within normal limits. Physical examination is unremarkable.

Laboratory studies reveal the following:

Test	Result	Reference Range
Serum calcium	$11.1\text{ mg/dL}$	$8.4-10.2\text{ mg/dL}$
Serum phosphorus	$2.5\text{ mg/dL}$	$2.5-4.5\text{ mg/dL}$
Serum albumin	$4.0\text{ g/dL}$	$3.5-5.0\text{ g/dL}$
Serum creatinine	$0.8\text{ mg/dL}$	$0.6-1.2\text{ mg/dL}$
Intact parathyroid hormone	$58\text{ pg/mL}$	$15-65\text{ pg/mL}$
25-hydroxyvitamin D	$35\text{ ng/mL}$	$20-50\text{ ng/mL}$
24-hour urine calcium	$75\text{ mg/day}$	$100-300\text{ mg/day}$
24-hour urine creatinine	$1200\text{ mg/day}$	$800-1800\text{ mg/day}$

Which of the following is the most likely underlying mechanism for this patient's laboratory findings?

Reduced sensitivity of transmembrane receptors in the parathyroid glands and kidneysAnswer
B
Autonomous overproduction of a peptide hormone by a monoclonal glandular proliferation
C
Enhanced extrarenal 1-alpha-hydroxylase activity by activated macrophages
D
Ectopic secretion of a protein structurally homologous to a physiologic hormone
E
Increased calcium reabsorption in the distal convoluted tubule due to pharmacologic blockade of sodium-chloride cotransporters

Answer

Reduced sensitivity of transmembrane receptors in the parathyroid glands and kidneys

The patient has asymptomatic hypercalcemia with an inappropriately normal intact parathyroid hormone (PTH) level. In a healthy individual, a serum calcium of

11.1\text{ mg/dL}

would suppress PTH to near zero. A normal or elevated PTH in this setting indicates a PTH-dependent hypercalcemia, which is primarily caused by either primary hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH). The key differentiating laboratory test is the 24-hour urine calcium or the urine calcium-to-creatinine clearance ratio (UCCR). This patient's 24-hour urine calcium is remarkably low (

75\text{ mg/day}

), and her UCCR is

< 0.01

. This profile is classic for FHH. FHH is an autosomal dominant disorder caused by an inactivating mutation in the calcium-sensing receptor (CaSR), a G-protein-coupled receptor found primarily in the parathyroid glands and renal tubules. The mutation causes a decreased sensitivity to serum calcium, requiring a higher-than-normal calcium level to suppress PTH secretion, while also maximizing renal calcium reabsorption.

Step-by-Step Solution

Analyze the serum calcium and parathyroid hormone (PTH) relationship.

The patient has hypercalcemia (

11.1\text{ mg/dL}

) with an inappropriately normal intact PTH (

58\text{ pg/mL}

Normal physiological feedback should completely suppress PTH in the presence of hypercalcemia. An unsuppressed PTH indicates a PTH-dependent process, narrowing the differential to primary hyperparathyroidism or familial hypocalciuric hypercalcemia (FHH).

Evaluate the 24-hour urinary calcium excretion and calculate the urine calcium-to-creatinine clearance ratio (UCCR).

The 24-hour urine calcium is abnormally low (

75\text{ mg/day}

). The calculated UCCR is

< 0.01

UCCR is calculated as

(U_{Ca} \times S_{Cr}) / (S_{Ca} \times U_{Cr})

. Here,

(75 \times 0.8) / (11.1 \times 1200) = 60 / 13320 \approx 0.0045

. A UCCR

< 0.01

and a 24-hour urine calcium

< 100\text{ mg/day}

reliably differentiate FHH from primary hyperparathyroidism.

Identify the pathophysiologic mechanism of the underlying condition.

The correct mechanism is an inactivating mutation of the calcium-sensing receptor (CaSR).

FHH is an autosomal dominant condition caused by decreased sensitivity of the CaSR in the parathyroid gland (requiring higher calcium levels to suppress PTH) and the kidneys (increasing tubular calcium reabsorption).

Key Concept

Familial hypocalciuric hypercalcemia (FHH) presents with mild hypercalcemia, inappropriately normal-to-elevated parathyroid hormone, and marked hypocalciuria (UCCR < 0.01) due to a defective calcium-sensing receptor.

Estimated Time:2m 30s

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