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

Abstract

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.

Introduction

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a significant global health challenge. An estimated 10.8 million new cases and 1.25 million deaths were reported in 2023. Data show that middle- and low-income countries contribute the highest to the global burden of the disease, with five countries responsible for 56% of all global tuberculosis cases: India (26%), followed by Indonesia (10%), China (6.8%), the Philippines (6.8%), and Pakistan (6.3%). Although the incidence of drug-resistant TB has stabilized in recent years, treatment remains complex and costly, and the risk of further antimicrobial resistance remains high. India alone accounted for 27% of the world’s multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) cases^[1^].

TB patients have a wide range of clinical presentations, from asymptomatic infection to disseminated disease with high risk of mortality^[2^]. TB can involve nearly every organ system, including the endocrine system. Endocrine dysfunction occurs in a significant proportion of patients and may include adrenal insufficiency, syndrome of inappropriate secretion of anti-diuretic hormone, thyroid abnormalities, and disturbances in calcium metabolism^[3^]. Among these, alterations in calcium and vitamin D metabolism are of particular interest.

HIGHLIGHTS

• Paradox prevalence – Up to 28% of tuberculosis (TB) patients may develop hypercalcemia despite concurrent vitamin D deficiency, with 88% of cases asymptomatic.

• Key mechanism – Activated macrophages within granulomas produce extrarenal 1α-hydroxylase, converting 25-hydroxyvitamin D to calcitriol independent of parathyroid hormone control.

• Geographic variation – Prevalence of TB-associated hypercalcemia varies significantly, influenced by vitamin D status, nutrition, comorbidities, and healthcare access.

• Clinical implications – This paradox can complicate management decisions, especially regarding vitamin D supplementation, which may exacerbate hypercalcemia.

• Management strategies – Treatment includes TB control, calcium and vitamin D intake restriction, hydration, loop diuretics, corticosteroids, and, in refractory cases, bisphosphonates or calcitriol synthesis inhibitors.

This review aims to synthesize the evidence on the paradoxical coexistence of hypercalcemia and vitamin D deficiency (VDD) in TB, elucidate the underlying immunometabolic mechanisms, and provide clear clinical guidance for diagnosis and management. In patients with tuberculosis, extrarenal production of 1α-hydroxylase is postulated to increase the conversion of calcidiol to calcitriol, the active form of vitamin D, resulting in hypercalcemia^[3^]. This process is driven by immune activation, particularly involving T-helper cells and macrophages^[4^]. As calcidiol levels reflect an individual’s vitamin D status ^[5^], this mechanism typically corresponds with elevated vitamin D levels. However, several studies have paradoxically reported low vitamin D levels in patients with tuberculosis. The prevalence of VDD is considerably high in certain countries, such as China (83.1%), India (68.9%), and Vietnam (34.5%)^[6–10^]. A recent study from India reports a significant difference in mean calcidiol levels in patients with TB compared to healthy controls^[11^]. In India, the prevalence of VDD is not solely attributable to nutritional inadequacies but also to population-specific factors such as darker skin phototype, sun-avoidant behaviors, and increased atmospheric pollution in several regions, all of which reduce cutaneous vitamin D synthesis^[12^]. The co-occurrence of deficiency and hypercalcemia poses a clinical dilemma, especially in deciding on vitamin D supplementation strategies.

Vitamin D upregulates the immune response against M. tuberculosis, with serum levels inversely correlated with TB susceptibility^[11^]. Studies on vitamin D supplementation in TB patients indicate promising results in terms of clinical improvement, weight gain, and faster sputum conversion times^[8,13^]. However, other studies report no significant difference in M. tuberculosis clearance or sputum conversion with vitamin D supplementation, suggesting that outcomes may depend on factors such as dosing, genetic variability, or baseline deficiency^[14,15^]. Although vitamin D supplementation in TB is associated with potential risks like hypercalcemia, hypercalciuria, and nephrolithiasis, current evidence shows no significant increase in adverse effects compared to controls^[16^].

This narrative review was conducted based on a comprehensive literature search across PubMed, Scopus, Web of Science, ScienceDirect, and Oxford Academic databases up to December 2024. Search terms included: (“tuberculosis” OR “TB”) AND (“hypercalcemia” OR “hypercalcaemia”) AND (“vitamin D deficiency” OR “hypovitaminosis D”) AND (“calcitriol” OR “1,25-dihydroxyvitamin D”) AND (“granuloma” OR “macrophage”). The search was limited to human studies and articles in English. All study types (case reports, series, observational, and interventional studies) were considered for inclusion. The review is structured following the Scale for the Assessment of Narrative Review Articles (SANRA) framework^[17^].

For the purposes of this review, hypercalcemia is defined as a serum total calcium concentration of >10.5 mg/dl (2.62 mmol/l) after correction for serum albumin, or as an elevated ionized calcium level when available, in accordance with standard clinical practice^[18,19^]. Albumin-corrected calcium was preferentially used in most cited studies, as ionized calcium measurements were not uniformly reported^[20–25^]. VDD was defined as a serum 25-hydroxyvitamin D [25(OH)D] level of <20 ng/ml (<50 nmol/l), while severe deficiency was considered at levels of <10 ng/ml (< 25 nmol/l), consistent with thresholds used across the referenced tuberculosis cohorts and endocrine guidelines^[6,26,27^]. All vitamin D values are reported in nanogram per milliliter unless otherwise stated.

Vitamin D and calcium homeostasis in the body

Vitamin D exhibits a dual role in regulating mineral metabolism and modulating immune responses, an interaction that becomes especially significant in granulomatous diseases such as tuberculosis^[26,28^]. Vitamin D is synthesized in the skin upon exposure to ultraviolet B light as cholecalciferol (vitamin D3). It is then transported via the bloodstream to the liver, where it is hydroxylated to form 25(OH)D, the primary circulating form and the marker of vitamin D status^[29^]. The enzyme CYP27B1 further hydroxylates this metabolite in the kidneys to produce the biologically active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], whose synthesis is regulated by the parathyroid hormone (PTH) in response to blood calcium levels^[26^].

1,25(OH)₂D enhances intestinal calcium absorption by upregulating calcium transport proteins like TRPV6 and calbindin-D9k. When hypocalcemia occurs, PTH stimulates the renal synthesis of 1,25(OH)₂D, leading to increased bone resorption and enhanced intestinal calcium absorption to maintain normal serum calcium levels^[26,30^].

However, this endocrine negative feedback loop becomes disrupted in TB, owing to the extrarenal induction of CYP27B1 by activated macrophages within granulomas^[28^]. Unlike renal CYP27B1, which remains under PTH control, macrophage-mediated extrarenal conversion of 25(OH)D to 1,25(OH)₂D occurs independent of PTH and bypasses the normal feedback inhibition. As a result, hypercalcemia can develop even in the presence of low 25(OH)D levels^[31^].

Beyond its role in mineral homeostasis, vitamin D exerts important immunomodulatory effects. It acts on both the innate and adaptive immune systems, notably by modulating T cell responses and inducing the production of antimicrobial peptides^[28,31^]. This endocrine-immune crosstalk is particularly relevant in granulomatous infections, where immune-mediated vitamin D activation may influence systemic calcium levels^[28^].

Current research also explores the impact of vitamin D receptor (VDR) polymorphisms in TB susceptibility, as well as the inconsistent outcomes of clinical trials evaluating vitamin D supplementation as an adjunctive therapy. These observations emphasize the necessity for a precision-medicine approach to vitamin D-related interventions in TB^[32,33^].

Hypercalcemia in tuberculosis

Prevalence and reported cases of hypercalcemia in TB

Most studies evaluating tuberculosis-associated hypercalcemia were conducted in adult inpatient populations with active pulmonary or disseminated TB, although pediatric cases and outpatient cohorts have also been described^[22,25,34^]. Hospitalized patients were overrepresented in studies reporting higher calcium levels, likely reflecting more extensive granulomatous burden and systemic inflammation^[22,23^]. Important comorbidities influencing hypercalcemia risk included renal impairment, severe anemia, disseminated disease, and HIV co-infection^[22,25,35^]. Chronic corticosteroid exposure was generally excluded or adjusted for in most cohorts, given its known suppressive effect on extrarenal calcitriol synthesis^[36^]. Malignancy-related hypercalcemia was systematically excluded in case series through suppressed PTH levels and compatible clinical context^[37,38^]. These methodological differences contribute to the wide reported prevalence range of 2.3–28% across regions^[20–24^]. Although most cases involved adults, a pediatric TB-associated hypercalcemia case has been reported, often presenting symptomatically and requiring closer biochemical monitoring^[34^]. Notably, a large retrospective cohort study (n = 450) reported a prevalence of 6.4%^[22^], whereas smaller case series from Greece reported figures as high as 28%^[23^], highlighting significant geographic heterogeneity potentially linked to variations in sun exposure, dietary calcium, and genetic factors.

Several determinants for the development of hypercalcemia have been identified, with vitamin D status and dietary calcium intake being prominent. In regions where both are high, such as Greece, the prevalence is correspondingly elevated. Conversely, in countries like India, where adequate sun exposure is possible but nutritional intake is lower, the prevalence remains moderately high^[3^]. These regional variations may reflect disparities in healthcare access, diagnostic protocols, and comorbidities that influence both TB presentation and hypercalcemia detection. Furthermore, it has been seen that patients with concomitant renal failure, disseminated infection, and severe anemia have a greater risk of developing hypercalcemia^[22^]. Most cases are seen in pulmonary TB, though extrapulmonary forms have also been implicated^[25^]. Notably, most TB patients (88%) with hypercalcemia remain asymptomatic^[22^]. However, untreated hypercalcemia may lead to complications such as nephrocalcinosis and renal stones. Therefore, routine calcium monitoring is advisable in TB patients, especially those with severe forms or multiple risk factors^[22^].

Several case reports and small clinical series have documented calcitriol-mediated hypercalcemia occurring concurrently with VDD in patients with tuberculosis (Table 1). This phenomenon has been described in both pulmonary and extrapulmonary diseases. For example, a recent Indian case of tubercular lymphadenitis demonstrated severe hypercalcemia despite 25(OH)D insufficiency, with increased 1,25(OH)₂D and suppressed PTH levels, supporting macrophage-mediated extrarenal conversion as the primary mechanism^[37^]. Similarly, other reports from diverse geographic settings describe low 25(OH)D, elevated or inappropriately normal 1,25(OH)₂D concentrations, and PTH suppression, reinforcing that VDD does not preclude granuloma-driven hypercalcemia.

Table 1.

Reported cases of tuberculosis-associated hypercalcemia occurring in the setting of vitamin D deficiency.

Type of TB	Serum calcium	25(OH)D	1,25(OH)₂D	PTH	Study design and key findings	Reference
Extrapulmonary TB (lymphadenitis)	High	Low	High	Suppressed	Case report; confirmed granuloma-driven calcitriol production.	[37]
Pulmonary TB	High	Low	High	Suppressed	Case series (n = 3); demonstrated PTH-independent mechanism.	[38]
Pulmonary TB	High	Low	High	Suppressed	Observational study; linked cytokine levels to calcitriol.	[39]
TB pleuritis	High	Low	High (pleural > plasma)	Suppressed	Case-control study; showed local calcitriol synthesis in pleura.	[40]
Pulmonary TB	High	Low	High	Suppressed	Large retrospective cohort (n = 450); prevalence: 6.4%; asymptomatic: 88%.	[22]
TB with anemia/renal impairment	High	Low	High	Suppressed	Prospective cohort; identified renal failure as a risk factor.	[25]
Pediatric TB	High	Low	High	Suppressed	Case series; highlighted symptomatic presentation in children.	[34]
Disseminated TB	High	Low	High	Suppressed	Case report; illustrated severe hypercalcemia in disseminated disease.	[41]

Mechanisms of TB-induced hypercalcemia

The primary mechanism for hypercalcemia in TB is the extrarenal production of 1,25-dihydroxyvitamin D (calcitriol) by activated macrophages within granulomas^[3,41^]. The granuloma, a cluster of immune cells formed in response to mycobacterial infection, features macrophages stimulated by Th1 cell-derived cytokines like interferon-γ (IFN-γ), which promote the upregulation of 1-α-hydroxylase (CYP27B1). This results in the unregulated conversion of 25(OH)D to calcitriol^[4,41^], leading to increased intestinal calcium absorption and bone resorption. Experimental studies, including one measuring calcitriol production by alveolar macrophages, have confirmed this pathway^[42^]. Calcitriol binding to VDR on macrophages also modulates the inflammatory response, enhancing antimicrobial peptide (e.g., cathelicidin) release and nitric oxide synthesis while upregulating Treg cells to limit tissue damage^[43–45^].

However, corticosteroids, commonly used in severe TB, may mitigate hypercalcemia by suppressing macrophage activity and calcitriol production^[36^]. It is important to note that some studies from various geographical regions have not found a consistent association between calcitriol and hypercalcemia in TB, suggesting alternative or contributing mechanisms in certain populations, such as PTH-related protein (PTHrP) secretion or altered calcium set-point^[25^]. Furthermore, Figure 1 illustrates the role of granulomas and macrophages in the pathogenesis of hypercalcemia in TB patients.

Figure 1.

Mechanism of hypercalcemia in TB. This figure illustrates the pathogenesis of hypercalcemia in TB. Activated macrophages within granulomas, stimulated by Th1 cytokines (IFN-γ and TNF-α), express 1-α-hydroxylase, converting 25(OH)D to calcitriol. Calcitriol increases intestinal calcium absorption (via TRPV6/Calbindin) and bone resorption, leading to hypercalcemia, independent of PTH regulation.

In summary, hypercalcemia in tuberculosis arises through a complex interaction of granulomatous inflammation, macrophage activation, and dysregulation of calcium metabolism. Its prevalence differs across regions, influenced by environmental conditions, nutritional status, and healthcare disparities. As many cases are asymptomatic, regular calcium level monitoring is advisable for high-risk patients, including those with renal failure, disseminated disease, or severe anemia. Enhancing clinical awareness and initiating timely treatment can reduce the risk of serious complications.

In addition to calcitriol-mediated mechanisms, adrenal insufficiency itself may precipitate hypercalcemia in patients with chronic granulomatous diseases, including tuberculosis. This form of hypercalcemia is typically characterized by low or normal 1,25(OH)₂D concentrations and resolves with glucocorticoid and mineralocorticoid replacement therapy, distinguishing it from calcitriol-driven pathways^[46,47^].

Vitamin D deficiency in TB

VDD is a well-documented comorbidity in TB, often existing before diagnosis and potentially increasing disease susceptibility. A meta-analysis of case-control studies confirmed significantly lower serum 25(OH)D levels in patients with active pulmonary TB compared to healthy controls (pooled mean difference: −6.63 ng/ml, 95% CI: −8.60 to −4.66)^[48^]. This association persists worldwide, with systematic reviews demonstrating links between low vitamin D levels and increased TB risk, disease severity, and radiological burden^[48,49^].

The active form of vitamin D, 1,25(OH)₂D, plays a critical role in host defense against M. tuberculosis by enhancing macrophage autophagy and upregulating cathelicidin^[50^]. Importantly, deficiency may precede infection, impairing these immune responses. During active TB, vitamin D metabolism undergoes dysregulation. While macrophage activation can elevate plasma 1,25(OH)₂D levels, concurrent downregulation of the VDR suggests impaired downstream signaling^[51^]. This paradox results in a functional deficiency. Therefore, VDD in TB demonstrates clear immunological mechanisms beyond traditional causes like malnutrition.

The interplay between innate immunity and vitamin D depletion is further evidenced by toll-like receptor (TLR) signaling. TLR1/2 activation in infected macrophages induces local 1,25(OH)₂D production via upregulation of CYP27B1^[52^]. However, chronic immune activation can deplete circulating 25(OH)D stores, particularly in populations with low nutritional reserves^[53^]. This immune-mediated consumption may perpetuate deficiency.

Additionally, first-line TB therapy exacerbates VDD. Rifampin accelerates vitamin D catabolism by inducing hepatic cytochrome P450 enzymes, reducing plasma levels by up to 70% during short-term use^[54^]. Such drug-induced depletion compounds pre-existing deficiency.

In summary, VDD in TB arises from a complex interplay of nutritional insufficiency, immune-driven metabolic shifts, receptor dysregulation, and treatment-related effects. Addressing this modifiable factor may improve clinical outcomes.

It should be noted that in the majority of cited studies, serum 25(OH)D levels were measured at TB diagnosis, prior to anti-tuberculosis therapy^[6,9,11^]. However, levels can decline further during treatment, especially with rifampin^[54,55^].

The paradox: hypercalcemia with VDD in TB

The paradoxical coexistence of hypercalcemia and VDD in tuberculosis arises primarily from unregulated extrarenal conversion of 25(OH)D to calcitriol within granulomatous macrophages^[39,40,56,57^]. This process bypasses normal PTH regulation and may occur even when circulating 25(OH)D levels are low^[31,41^].

The key mechanism is the excess extrarenal 1α-hydroxylase activity within granulomas (Fig. 2). Activated pulmonary alveolar and pleural fluid macrophages express 1α-hydroxylase, converting 25(OH)D to calcitriol^[39,40^]. TLR and interferon-γ-mediated activation further upregulate this enzyme and the VDR^[52,56^]. This conversion occurs independently of PTH^[57^], leading to elevated calcitriol, which enhances intestinal calcium absorption and bone resorption, causing hypercalcemia. Simultaneously, serum 25(OH)D levels may appear low due to consumption by this extrarenal pathway and sequestration within granulomatous tissue.

Figure 2.

Hypercalcemia due to 1α-Hydroxylase activity in activated macrophages in TB. Schematic depicting the paradox: low circulating 25(OH)D levels are consumed by granuloma-based macrophages expressing 1α-hydroxylase, leading to high local and systemic calcitriol, which drives hypercalcemia via intestinal and bone effects. Pulmonary tuberculosis activates macrophages through Toll-like receptor signaling and interferon-γ (IFN-γ) stimulation, leading to increased expression of extrarenal 1α-hydroxylase. This enzyme enhances the conversion of 25-hydroxyvitamin D₃ [25(OH)D₃] to its active form, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], resulting in dysregulated calcium homeostasis and potential hypercalcemia.

However, not all TB patients develop hypercalcemia despite similar immunopathological mechanisms. Several factors may account for this variability, including granuloma burden, renal calcium excretion capacity, baseline dietary calcium intake, genetic polymorphisms in the vitamin D receptor, and concurrent corticosteroid exposure^[25,36,58^]. Additionally, downregulation of vitamin D receptor expression during chronic inflammation may limit calcitriol bioactivity in some patients, resulting in normocalcemia despite elevated synthesis^[51^].

Discussion

Comparison with previous evidence

Prior studies on patients with pulmonary and extrapulmonary TB denoted that there was an increase in 1,25(OH)₂D levels with suppressed PTH values with either low or variable 25(OH)D concentrations^[39,40,56,57^]. This has been reiterated in recent studies that confirm macrophage-induced CYP27B1 activity as the leading cause of hypercalcemia. However, some studies have reported normal calcitriol levels in TB patients with hypercalcemia^[22,25^], implicating secondary causes like increased calcium load, renal injury, or PTHrP expression. This highlights the complex, multifactorial etiology and the need for individualized evaluation^[25,46,47^].

Clinical implication and diagnostic approach

TB-associated hypercalcemia is fundamentally a PTH-independent process. In the differential diagnosis, granulomatous disease must be considered even when 25(OH)D is low. Measurement of calcitriol is essential in any TB patient presenting with hypercalcemia, as elevated 1,25(OH)₂D may still be the primary driver. Recognizing this paradox is critical, as approximately 88% of patients are asymptomatic^[22^]. Symptomatic patients can present with nausea, constipation, polyuria, renal stones, and in severe cases, acute kidney injury or cognitive changes^[18^].

We propose the following diagnostic protocol (Fig. 3):

1. Suspect: Unexplained hypercalcemia (corrected Ca >10.5 mg/dl) in a patient with active or suspected TB.

2. Initial work-up: Measure serum PTH, 25(OH)D, creatinine, albumin. A suppressed PTH with low/normal 25(OH)D is suggestive.

3. Confirm mechanism: Measure serum 1,25(OH)₂D. An elevated or inappropriately normal level confirms granuloma-driven pathology.

4. Exclude other causes and image: Evaluate for other causes of hypercalcemia (e.g., malignancy). Perform imaging (CXR/CT) to assess pulmonary/extrapulmonary granulomatous burden.

5. Diagnose and manage: Confirm TB diagnosis microbiologically/histologically. Initiate anti-TB therapy and specific management for hypercalcemia as outlined below.

Figure 3.

Stepwise diagnostic protocol for TB-associated hypercalcemia. This algorithm outlines a structured approach to evaluating hypercalcemia in the context of tuberculosis. After confirming elevated serum calcium (Step 1), parathyroid hormone (PTH) and 25-hydroxyvitamin D levels are assessed (Step 2). If PTH is suppressed, measurement of 1,25-dihydroxyvitamin D and imaging studies for tuberculosis are performed (Step 3). Management includes initiating anti-tuberculous therapy alongside appropriate treatment of hypercalcemia (Step 4).

Management of paradoxical hypercalcemia in TB

Management should target suppressing extrarenal calcitriol production while treating the underlying infection. Outlined below are the management guidelines for hypercalcemia in TB:

1. General Measures: Restrict dietary vitamin D and calcium. Initiate aggressive hydration with isotonic saline to promote calciuresis.

2. First-line Pharmacotherapy: Glucocorticoids (e.g., prednisone 20–40 mg/day) are the cornerstone, as they inhibit macrophage 1α-hydroxylase. They typically reduce calcium within 3–5 days^[36,59,60^].

3. Second-line Agents: For refractory cases, bisphosphonates (inhibit bone resorption) or agents that inhibit calcitriol synthesis (ketoconazole and hydroxychloroquine) may be used^[61^].

4. Special Considerations in HIV/TB: Monitor closely for Immune Reconstitution Inflammatory Syndrome, which can exacerbate hypercalcemia^[35,62^].

5. Vitamin D Supplementation: CRITICAL GUIDANCE – Supplementation should be avoided during active hypercalcemia due to risk of exacerbation. In patients with severe deficiency (<10 ng/ml), consider cautious repletion only after hypercalcemia has resolved and inflammatory activity is controlled, under close biochemical surveillance (calcium, 25(OH)D, 1,25(OH)₂D)^[6,63–66^]. Instances of hypercalcemia post-repletion have been reported^[67^] (Table 2).

Table 2.

Comparative overview of vitamin D and calcium homeostasis in normal, deficient, and TB conditions.

Condition	Vitamin D levels (25[OH]D)	Calcium levels	Primary mechanism	Key differentiating features	References
Normal physiology	Normal	Normal	Homeostatic regulation by PTH and renal CYP27B1.	PTH and calcitriol are in a tight feedback loop.	[6,26]
Vitamin d deficiency	Low	Low/normal	↓ Intestinal calcium absorption, ↓ 1,25(OH)₂D synthesis.	PTH is typically elevated (secondary hyperparathyroidism).	[6,26,27]
TB with vitamin D deficiency and hypercalcemia	Low	High	Macrophage-driven extrarenal CYP27B1 → ↑ 1,25(OH)₂D → unregulated calcium absorption.	PTH is suppressed. Calcitirol is high/normal despite low 25(OH)D.	[26,27,55,68]
Granulomatous disease	Variable (often low)	High	Same extrarenal CYP27B1 mechanism.	Identical biochemical profile to TB; diagnosis relies on etiology.	[63,65,69]
Hypercalcemia of malignancy	Variable	High	PTHrP secretion or bony metastases.	PTH is suppressed, PTHrP may be elevated, calcitriol is usually low.	[18]

1,25(OH)₂D, 1,25-dihydroxyvitamin D (calcitriol); 25(OH)D, 25-hydroxyvitamin D; CYP27B1, 1-alpha hydroxylase; PTH, parathyroid hormone. Bold significance indicates the 'The combination of “high” calcium levels despite low 25(OH)D in tuberculosis reflects a paradoxical mechanism driven by extrarenal macrophage expression of CYP27B1, leading to increased production of calcitriol independent of normal renal and parathyroid hormone (PTH) regulation. This results in unregulated intestinal calcium absorption and hypercalcemia. The accompanying finding that “PTH is suppressed” is clinically significant, as it distinguishes this condition from secondary hyperparathyroidism seen in isolated vitamin D deficiency, where PTH is elevated. Together, these features help differentiate granulomatous causes of hypercalcemia, such as tuberculosis, from other etiologies including primary hyperparathyroidism and malignancy-associated hypercalcemia.'

Future directions and research gaps

1. Mechanisms: Further research is needed to clarify the role of non-calcitriol mediators (e.g., PTHrP) and the impact of genetic polymorphisms (VDR and CYP27B1) on hypercalcemia risk in TB.

2. Vitamin D therapy: Future trials should stratify participants by baseline 25(OH)D, VDR genotype, and disease severity to better define who benefits from adjunctive vitamin D supplementation^[58,70,71^].

3. Screening and management: Prospective studies are needed to validate the cost-effectiveness of routine calcium/vitamin D metabolite screening in high-risk TB patients and to establish standardized protocols for safe vitamin D repletion in the context of granulomatous disease.

Pediatric considerations

Hypercalcemia in pediatric TB, though less common, often presents with more pronounced symptoms (e.g., failure to thrive and vomiting) and may require more aggressive monitoring and management^[34^]. The principles of pathophysiology and treatment are similar to adults.

Limitations

This review is based primarily on observational studies and case reports. The heterogeneity in diagnostic protocols and definitions across studies limits direct comparability. Prospective longitudinal studies are needed to track calcium and vitamin D metabolite dynamics throughout TB treatment.

Conclusion

Tuberculosis presents a unique paradox in mineral metabolism, wherein VDD often coexists with hypercalcemia due to unregulated, granuloma-driven calcitriol production. Awareness of this dysregulation is essential for correct diagnosis and to avoid the mismanagement of supplementing vitamin D during active hypercalcemia. A personalized approach, involving cautious management of supplementation and measurement of PTH, 25(OH)D, and 1,25(OH)₂D, is warranted. Future research should focus on establishing safe, individualized protocols for vitamin D repletion in TB.

This narrative review adheres to the Transparency in the Reporting of Artificial Intelligence in Research (TITAN) guideline^[72^]. During the preparation of this manuscript, generative AI tools (DeepSeek, DeepSeek Inc., June 2025 version: temperature parameter = 0.7) were used only as auxiliary aids to assist in formatting, standardization, organization of background information, and language consistency checks. Furthermore, all AI-assisted text was thoroughly reviewed, edited, and refined by the authors. The conceptualization, literature interpretation, synthesis of ideas, and manuscript writing were performed entirely by the authors, ensuring the academic rigor, accuracy, and originality of the review.

Ethical approval

No approval was required from the ethics committee for this review article.

Consent

Not applicable. No consent is needed as this article is a narrative review.

Sources of funding

The authors received no financial support for the publication of this article.

Conflicts of interest disclosure

The authors declare no potential conflicts of interest.

Author contributions

S.S.B.: conceptualization, methodology, writing – original draft, data curation; S.G.: literature review, writing – original draft, validation; T.B.: visualization, writing – review & editing, writing – original draft; Y.C.: investigation, resources, writing – review & editing; R.E.A.R.C.: investigation, resources, writing – review & editing, writing – original draft; C.M.: data curation, writing – review & editing; A.R.: literature review, resources, writing – review & editing; A.K.: literature review, resources, writing – review & editing, writing – original draft; J.M.: investigation, writing – review & editing; J.K: supervision, resources, project administration, writing – review & editing, and submission.

Guarantor

Shreya Singh Beniwal.

Research registration unique identifying number (UIN)

Not applicable, as this study is a narrative review.

Provenance and peer review

Not applicable.

Data availability statement

All data pertaining to this study are included within the article. If requested, additional literature sources used in the synthesis of the article can be provided.