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Difficulty: HardEndocrine and Metabolic Mechanisms

A 3232-year-old man comes to the clinic to establish care. He feels well and has no medical problems. He takes no medications. Vital signs are within normal limits. Routine laboratory testing reveals a serum calcium level of 11.211.2 mg/dL (N: 8.48.4-10.210.2 mg/dL) and a serum intact parathyroid hormone level of 5555 pg/mL (N: 1515-6565 pg/mL). A 2424-hour urine collection shows a calcium excretion of 4545 mg/day (N: 100100-300300 mg/day). The urine calcium-to-creatinine clearance ratio is calculated to be 0.0050.005 (normal >0.02>0.02). His mother also has a history of mild, asymptomatic hypercalcemia that was treated with a parathyroidectomy in her 3030 s without resolution of the hypercalcemia. Which of the following best describes the cellular mechanism underlying this patient's laboratory findings?

  1. Decreased sensitivity of a G protein-coupled receptor to extracellular cationsAnswer
  2. B
    Monoclonal proliferation of parathyroid chief cells leading to autonomous hormone secretion
  3. C
    Pharmacologic inhibition of the sodium-chloride cotransporter leading to enhanced tubular calcium reabsorption
  4. D
    Ectopic secretion of a peptide that activates osteoblast and renal tubule receptors
  5. E
    Aberrant extrarenal activation of a vitamin D precursor by mononuclear phagocytes

Answer

Decreased sensitivity of a G protein-coupled receptor to extracellular cations
The correct answer accurately describes the pathophysiology of familial hypocalciuric hypercalcemia (FHH). FHH is an autosomal dominant disorder caused by an inactivating mutation in the calcium-sensing receptor (CaSR) gene. The CaSR is a G protein-coupled receptor located on the chief cells of the parathyroid gland and the basolateral membrane of the thick ascending limb of the loop of Henle. In FHH, the mutated CaSR requires higher concentrations of extracellular calcium to activate its intracellular Gq signaling cascade. This decreased sensitivity raises the set-point for calcium homeostasis, resulting in mild hypercalcemia with an inappropriately normal or slightly elevated PTH level. In the kidneys, the defective CaSR leads to increased calcium reabsorption, causing marked hypocalciuria and a characteristic urine calcium-to-creatinine clearance ratio of less than 0.01. Parathyroidectomy is generally ineffective and not indicated.

Step-by-Step Solution

1
Analyze the initial serum laboratory results.
The patient has hypercalcemia with an inappropriately normal intact PTH level.
Normal physiological feedback dictates that hypercalcemia should suppress PTH secretion. An unsuppressed PTH narrows the differential to PTH-dependent causes, primarily primary hyperparathyroidism and familial hypocalciuric hypercalcemia (FHH).
2
Evaluate the urine calcium indices and family history to differentiate the diagnosis.
The 24-hour urine calcium is low, the clearance ratio is less than 0.01, and there is a family history of failed parathyroidectomy.
Primary hyperparathyroidism typically presents with increased urinary calcium excretion and a clearance ratio >0.02. The combination of hypocalciuria, a low clearance ratio, and surgical failure in a first-degree relative strongly establishes the diagnosis of FHH.
3
Identify the underlying cellular mechanism of the diagnosed condition.
FHH is caused by an inactivating mutation of the calcium-sensing receptor (CaSR), which is a G protein-coupled receptor.
The mutated CaSR has decreased sensitivity to extracellular calcium, requiring higher serum calcium levels to suppress PTH secretion and leading to increased renal tubular calcium reabsorption.

Key Concept

Familial hypocalciuric hypercalcemia (FHH) is caused by an inactivating mutation of the calcium-sensing receptor (CaSR), a G protein-coupled receptor, leading to a higher set-point for calcium homeostasis.
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Topics

Endocrine and Metabolic Mechanisms

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