From the Guidelines
Hypercalcemia in sarcoidosis occurs primarily due to dysregulated vitamin D metabolism, where activated macrophages and granulomas produce excess 1-alpha-hydroxylase enzyme, leading to elevated serum calcium levels. In sarcoidosis, this increased calcitriol production enhances intestinal calcium absorption and bone resorption, resulting in hypercalcemia. Approximately 10-20% of sarcoidosis patients develop hypercalcemia, while hypercalciuria is even more common, affecting up to 50% of patients 1. The condition is often exacerbated by sunlight exposure, vitamin D supplementation, or high calcium intake.
Pathophysiology
The mechanisms of abnormal calcium metabolism in sarcoidosis are likely multifactorial, including increased 1a‐hydroxylase production by granulomatous macrophages, which converts 25-(OH) vitamin D to 1,25-(OH)2 vitamin D, increased expression of parathyroid hormone–related protein in sarcoidosis macrophages, and cytokine and other growth factor production 1.
Management
Management typically involves corticosteroids (such as prednisone 20-40 mg daily for 1-2 months with gradual tapering) to suppress granuloma activity and calcitriol production 1. Patients should avoid excessive sun exposure, vitamin D supplements, and high-calcium foods during active disease. Hydration is important to prevent kidney stone formation and renal damage. In refractory cases, steroid-sparing agents like hydroxychloroquine (200-400 mg daily) may be used to inhibit 1-alpha-hydroxylase activity 1.
Screening and Monitoring
For patients with sarcoidosis who do not have symptoms or signs of hypercalcemia, baseline serum calcium testing is recommended to screen for abnormal calcium metabolism 1. If assessment of vitamin D metabolism is deemed necessary, measuring both 25- and 1,25-OH vitamin D levels before vitamin D replacement is suggested 1.
Treatment Algorithm
The proposed treatment algorithm highlights key concepts by sarcoidosis phenotype and is derived from the resulting Delphi consensus recommendations 1. The algorithm assists clinicians in making treatment decisions, including the use of corticosteroids, antimetabolites, and biologic agents. Hydroxychloroquine is considered in cases of hypercalcemia or skin disease 1.
Quality of Life and Morbidity
The treatment approach should prioritize minimizing toxicity and reducing the risk of hypercalcemia, while also considering the potential benefits of calcium and vitamin D supplementation on bone health and the anti-inflammatory effects of vitamin D supplementation 1. The goal is to improve quality of life and reduce morbidity in patients with sarcoidosis.
From the Research
Hypercalcaemia in Sarcoidosis
- Hypercalcaemia is a common complication of sarcoidosis, affecting approximately 2-63% of patients 2.
- The condition occurs due to the uncontrolled synthesis of 1,25-dihydroxyvitamin D3 by macrophages, leading to increased absorption of calcium in the intestine and resorption of calcium in the bone 2, 3, 4.
Pathophysiology
- 1,25-dihydroxyvitamin D3 plays a crucial role in the development of hypercalcaemia in sarcoidosis, and its levels are elevated in patients with the condition 2, 3, 4.
- The production of 1,25-dihydroxyvitamin D3 by macrophages is not regulated, leading to an overproduction of the hormone and subsequent hypercalcaemia 2, 4.
- Hypercalcaemia can also be exacerbated by sun exposure and phosphorus intake, such as through dietary cola drinks 3.
Treatment Options
- Treatment of hypercalcaemia in sarcoidosis depends on the severity of the condition and may include glucocorticosteroids, chloroquine, or ketoconazole 2.
- Glucocorticosteroids act by inhibiting the production of 1,25-dihydroxyvitamin D3 by macrophages, while chloroquine and ketoconazole may also be effective in reducing calcium levels 2.
- Methotrexate has also been shown to be effective in treating sarcoidosis-induced hypercalcemia in some cases 5.
- Patients with sarcoidosis should be advised to avoid sun exposure, omit fish oils rich in vitamin D, and produce more than two liters of urine per day to reduce the risk of hypercalcaemia 2.