What is the mechanism by which sarcoidosis causes hypercalcemia?

Mechanism of Hypercalcemia in Sarcoidosis

The primary mechanism of hypercalcemia in sarcoidosis is increased 1α-hydroxylase production by granulomatous macrophages, which converts 25-(OH) vitamin D to 1,25-(OH)2 vitamin D, leading to increased calcium absorption in the intestine and increased bone resorption. 1

Pathophysiological Mechanisms

• Granulomatous macrophages in sarcoidosis produce excessive amounts of 1α-hydroxylase enzyme, which converts 25-hydroxyvitamin D to the active form 1,25-dihydroxyvitamin D (calcitriol) 1
• This dysregulated production occurs outside normal renal control mechanisms, leading to inappropriate calcitriol synthesis 2
• Increased expression of parathyroid hormone-related protein (PTHrP) in sarcoidosis macrophages contributes to the hypercalcemia 1, 3
• Various cytokines and growth factors produced by granulomas further influence calcium metabolism 1
• Gamma-interferon produced by activated lymphocytes and macrophages plays a major role in stimulating 1,25-(OH)2 vitamin D synthesis 3

Clinical Manifestations and Prevalence

• Hypercalcemia is detected in approximately 6% (95% CI, 4-8%) of patients with sarcoidosis 1
• Hypercalciuria appears to be twice as prevalent as hypercalcemia and should be screened for in all sarcoidosis patients 2
• Untreated hypercalcemia can lead to renal failure in 42% (95% CI, 33-52%) of patients 1, 4
• The prevalence of hypercalcemia varies widely (2-63%) in different studies, possibly due to the undulating course of sarcoidosis 2

Vitamin D Profile in Sarcoidosis

• Most sarcoidosis patients (84%) have low 25-(OH) vitamin D levels 1
• Despite low 25-(OH) vitamin D, approximately 11% have high 1,25-(OH)2 vitamin D levels 1
• Patients with a history of hypercalcemia typically have relatively higher 1,25-(OH)2 vitamin D levels compared to their 25-(OH) vitamin D levels 1
• Serum vitamin D levels may not accurately reflect tissue-level vitamin D activity in sarcoidosis 5

Unique Aspects of Vitamin D Metabolism in Sarcoidosis

• Tissue-level conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D can occur locally within granulomas 5
• This local conversion may explain why some patients develop hypercalcemia despite having low serum 25-hydroxyvitamin D levels 5
• Hypovitaminosis D may actually be associated with increased disease activity in sarcoidosis 6

Clinical Implications and Management

• Baseline serum calcium testing is strongly recommended for all sarcoidosis patients, even without symptoms of hypercalcemia 1
• If vitamin D assessment is needed, both 25-(OH) and 1,25-(OH)2 vitamin D levels should be measured before any supplementation 1, 7
• Patients should be advised to avoid excessive sun exposure to reduce vitamin D synthesis in the skin 2
• Adequate hydration (>2 liters of urine daily) is recommended for all sarcoidosis patients 2
• Glucocorticoids (prednisone 15-25 mg/day) are the treatment of choice for hypercalcemia, as they inhibit the excessive 1α-hydroxylase activity 3

Pitfalls and Caveats

• Vitamin D supplementation without measuring both 25-(OH) and 1,25-(OH)2 vitamin D levels can worsen hypercalcemia in sarcoidosis patients 7
• Low serum 25-(OH) vitamin D levels may not indicate true vitamin D deficiency at the tissue level in sarcoidosis 5
• Some patients may develop hypercalcemia with vitamin D replacement despite having low serum 25-(OH) vitamin D levels 5
• Careful monitoring of calcium levels is essential when considering vitamin D supplementation in sarcoidosis patients 7, 6