A 47-year-old woman comes to the clinic reporting worsening fatigue, increased thirst, and frequent urination over the past three months. She has a history of chronic cough and was told she had "enlarged lymph nodes" in her chest a year ago, but she did not follow up. Her temperature is 37.0°C (98.6°F), blood pressure is 128/82 mmHg, and pulse is 78/min. Physical examination reveals a few erythematous nodules on her anterior lower legs. Laboratory studies show:
| Laboratory Parameter | Result | Reference Range |
|---|---|---|
| Calcium, serum | 12.8 mg/dL | 8.4-10.2 mg/dL |
| Phosphorus, serum | 4.6 mg/dL | 2.5-4.5 mg/dL |
| Parathyroid hormone (PTH) | 9 pg/mL | 10-65 pg/mL |
| Creatinine, serum | 1.1 mg/dL | 0.6-1.1 mg/dL |
Which of the following cellular mechanisms best explains this patient's current laboratory abnormalities?
- ASecretion of a peptide homologous to the amino-terminal portion of parathyroid hormone
- BDecreased sensitivity of calcium-sensing receptors leading to a blunted suppression of parathyroid hormone
- Unregulated conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by activated macrophagesCevap
- DEnhanced calcium reabsorption in the distal convoluted tubule due to an unlisted diuretic medication
- EIncreased bone resorption mediated by osteoclast-activating factors and inflammatory cytokines
Cevap
Unregulated conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by activated macrophages
The correct answer is the unregulated conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D by activated macrophages. This patient's presentation of hypercalcemia, suppressed parathyroid hormone (PTH), polyuria, and constitutional symptoms, along with a history of bilateral hilar lymphadenopathy and erythema nodosum, is highly suspicious for sarcoidosis. In sarcoidosis and other granulomatous diseases, disease-associated macrophages ectopically express the enzyme 1-alpha-hydroxylase. This enzyme converts 25-hydroxyvitamin D into the active form, 1,25-dihydroxyvitamin D (calcitriol), independent of normal physiologic feedback mechanisms. The excess calcitriol increases intestinal absorption of both calcium and phosphorus, leading to hypercalcemia and normal-to-elevated serum phosphorus. The resultant hypercalcemia suppresses endogenous PTH secretion from the parathyroid glands via negative feedback.
Adım Adım Çözüm
Anahtar Kavram
The primary mechanism of hypercalcemia in sarcoidosis and other granulomatous diseases is the unregulated, ectopic production of 1,25-dihydroxyvitamin D (calcitriol) by 1-alpha-hydroxylase expressed in activated macrophages.