Paradoxical hypercalcemia in tuberculosis with concurrent vitamin D deficiency: mechanisms, clinical implications, and management strategies

Calcium and vitamin D play a critical role in maintaining skeletal integrity and regulating immune responses, particularly in tuberculosis (TB). Vitamin D facilitates intestinal calcium absorption by upregulating calcium transport proteins and modulates immunity by regulating Th1 responses and enhancing macrophage-mediated bactericidal activity against Mycobacterium tuberculosis . Despite these protective roles, a paradoxical association of vitamin D deficiency with hypercalcemia is commonly observed in active TB, reported in up to 40% of cases. This hypercalcemia is primarily attributed to extrarenal production of 1,25-dihydroxyvitamin D (calcitriol) by activated macrophages within granulomatous lesions, leading to increased calcium levels independent of circulating 25-hydroxyvitamin D concentrations. This phenomenon is particularly prevalent in TB-endemic regions with extensive granulomatous disease and high mycobacterial burden. Globally, more than half of TB patients exhibit vitamin D deficiency, linked to severe disease manifestations and higher bacillary loads. The interplay between vitamin D metabolism, calcium homeostasis, and immune activation in TB highlights the importance of routine biochemical monitoring. Further studies are needed to elucidate molecular mechanisms and guide individualized therapeutic strategies.