Hypercalcemia in granulomatous diseases

INTRODUCTION — Hypercalcemia is a relatively common clinical problem. It results when the entry of calcium into the circulation exceeds the excretion of calcium into the urine or deposition in bone. This occurs when there is accelerated bone resorption, excessive gastrointestinal absorption, or decreased renal excretion of calcium. In some disorders, however, more than one mechanism may be involved.

Hypercalcemia has been described in patients with most granulomatous disorders. This topic card will review hypercalcemia associated with granulomatous diseases. Other disorders that lead to hypercalcemia are reviewed separately. (See "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)

CLINICAL FINDINGS — The signs and symptoms of hypercalcemia depend on the acuity and severity of hypercalcemia. Many patients with hypercalcemia due to granulomatous disease are asymptomatic. Symptoms and signs of chronic hypercalcemia (nephrolithiasis, nephrocalcinosis, renal insufficiency, and polyuria due to reduced responsiveness to antidiuretic hormone) may occur. (See "Clinical manifestations of hypercalcemia" and "Kidney disease in sarcoidosis".)

GRANULOMATOUS DISORDERS — Hypercalcemia has been described in patients with most granulomatous disorders [1-3]. Among them, sarcoidosis [4-10] and tuberculosis [11-15] are probably most common. Other causes include berylliosis [16], coccidioidomycosis [17], paracoccidioidomycosis [18], histoplasmosis [19,20], candidiasis [21], Crohn's disease [22,23], Langerhans-cell histiocytosis (also called histiocytosis X, and including eosinophilic granuloma) [24], leprosy [25,26], silicone-induced granulomas [27,28], methacrylate injection [29], talc granuloma [30], cat-scratch disease [31], granulomatosis with polyangiitis (GPA) [32], and Pneumocystis jirovecii pneumonia [33]. Hypercalcemia has also been described as a rare side effect of immunotherapy used for the treatment of various malignancies, with granuloma formation reported in some, but not all cases [34,35].

The diagnosis of a granulomatous disorder as the etiology of hypercalcemia may be suspected due to the finding of a low-normal or low parathyroid hormone (PTH) level (non-PTH mediated hypercalcemia). The serum 1,25-dihydroxyvitamin D level may be elevated. (See "Diagnostic approach to hypercalcemia", section on 'Determining the etiology'.)

Sarcoidosis — The mechanism responsible for the abnormal calcium metabolism in granulomatous disease has been most completely evaluated in sarcoidosis. Approximately 30 to 50 percent of patients with this disorder have hypercalciuria, and 10 to 20 percent have hypercalcemia, which is aggravated by exposure to sunlight [1,4,5]. Increased intestinal calcium absorption induced by high serum calcitriol concentrations (1,25-dihydroxyvitamin D, the most active metabolite of vitamin D) is the primary abnormality, although a calcitriol-induced increase in bone resorption may also contribute [6-9]. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis".)

In normal individuals, the conversion of 25-hydroxyvitamin D (calcidiol) to calcitriol occurs in the kidney proximal tubule via a 1-hydroxylase (CYP27B1) enzyme that is under the physiologic control of PTH, fibroblast growth factor 23 (FGF-23), and the serum phosphate concentration (see "Overview of vitamin D", section on 'Metabolism'). Hypercalcemia normally suppresses the release of PTH and therefore the production of calcitriol, but in sarcoidosis and other granulomatous diseases, activated mononuclear cells (particularly macrophages) in the lung and lymph nodes produce calcitriol from calcidiol independent of PTH [6-9].

The evidence for extrarenal calcitriol production is threefold [6-9,36]:

●Hypercalcemia and serum calcitriol concentrations have been described in an anephric patient with sarcoidosis.

●Calcidiol conversion to calcitriol can be demonstrated in vitro in alveolar macrophages or lymph node tissue obtained from hypercalcemic patients with sarcoidosis.

●Production of the messenger RNA for CYP27B1, the 1-hydroxylase, is markedly increased in alveolar macrophages isolated from hypercalcemic patients with sarcoidosis.

Normally, monocytic/macrophage synthesis of calcitriol is self-regulated by negative feedback to prevent excess production. In comparison, monocytes in patients with granulomatous disease both produce more calcitriol and are resistant to the normal feedback control of calcitriol production. These effects appear to be mediated by interferon-gamma [37].

Although only 30 to 50 percent of patients with active sarcoidosis are hypercalciuric, abnormal calcitriol metabolism can be demonstrated in some who are normocalciuric and normocalcemic [38]. As an example, increasing calcium intake appropriately lowers serum calcitriol concentrations in normal subjects but not in patients with sarcoidosis.

Parathyroid hormone-related protein (PTHrP), the usual etiologic agent of humoral hypercalcemia of malignancy, may also contribute to the hypercalcemia in some patients with sarcoidosis. In one series, PTHrP was found in 85 percent (17 of 20) of biopsies of granulomatous tissue from patients with sarcoidosis, and a few patients with both sarcoidosis and hypercalcemia had high serum PTHrP concentrations [39].

Tuberculosis — Hypercalcemia in association with high serum calcitriol concentrations has also been described in patients with tuberculosis [13,14,40]. Activated macrophages in granulomas are the most likely source of the high calcitriol levels. As in sarcoidosis, hypercalciuria due to hyperabsorption of dietary calcium is more common than overt hypercalcemia [41].

The frequency of tuberculosis as a cause of hypercalcemia in such patients will vary with the population studied. In some reports, the incidence of hypercalcemia has been reported to be as high as 28 percent [11,14], whereas other studies suggest a much lower incidence (2.3 percent or less) [42,43]. In a series of hospitalized hypercalcemic patients in Hong Kong, tuberculosis was thought to be the cause of hypercalcemia in 6 percent [15].

A possible explanation for the discrepancy in incidence may lie in regional differences in vitamin D status and calcium intake. Patients who live in areas with low rates of hypercalcemia have either low dietary calcium intake or low vitamin D intake, while those who live in regions with high rates have relatively high levels of dietary calcium and vitamin D [44].

Coccidioidomycosis — The mechanism of hypercalcemia in patients with coccidioidomycosis is unclear. In one study of 13 patients, there was no evidence of increased production of 1,25-dihydroxyvitamin D in the seven patients in whom it was measured [45]. In addition, PTH levels, which were assessed in nine individuals, were normal in six and suppressed in three. One study suggested that PTHrP overexpression may contribute to hypercalcemia in disseminated coccidiomycosis [46]. (See "Primary pulmonary coccidioidal infection".)

TREATMENT

Goals — Treatment of the hypercalcemia or hypercalciuria in granulomatous disorders is aimed at treatment of the underlying disorder. In addition, treatment of hypercalcemia or hypercalciuria includes reducing intestinal calcium absorption and calcitriol synthesis. These can be achieved by:

●Reducing calcium intake (no more than 400 mg/day)

●Reducing oxalate intake

●Elimination of dietary vitamin D supplements

●Avoidance of sun exposure

Glucocorticoids and bisphosphonates have also been used successfully to treat hypercalcemia in granulomatous diseases. (See 'Pharmacologic therapy' below and "Treatment of hypercalcemia".)

Dietary interventions — Reducing calcium intake (no more than 400 mg/day) may improve hypercalcemia and hypercalciuria [38].

Concurrent restriction of dietary oxalate (eg, avoid spinach, rhubarb, potatoes) is required to prevent a marked increase in oxalate absorption and hyperoxaluria; the latter may increase the risk of kidney stone formation even though urinary calcium excretion is reduced [47]. Oxalate absorption is normally limited by the formation of insoluble calcium oxalate salts in the intestinal lumen. Dietary calcium restriction leads to more free oxalate in the gut lumen that can then be absorbed if oxalate intake is unchanged. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'Limit oxalate intake'.)

Thiazide diuretics, an accepted treatment for recurrent calcium stones due to hypercalciuria, can sequentially lead to reduced calcium excretion, calcium retention, and result in or worsen hypercalcemia. In patients with sarcoidosis, thiazide diuretics should be avoided in those with hypercalcemia and used judiciously and with close monitoring of serum and urine calcium in those with hypercalciuria. (See "Kidney stones in adults: Prevention of recurrent kidney stones", section on 'High urine calcium' and "Kidney disease in sarcoidosis", section on 'Kidney stones'.)

Pharmacologic therapy

●Sarcoid

•Glucocorticoid therapy – In addition to dietary measures, moderate-dose glucocorticoid therapy (20 to 40 mg/day of prednisone) is typically used to treat pulmonary sarcoidosis [48,49]. If the lung involvement is not severe enough to warrant therapy, glucocorticoids may be necessary to treat hypercalcemia that is severe (eg, ≥12 mg/dL) or symptomatic. The serum calcium concentration begins to fall in two days, but the full hypocalcemic response may take 7 to 10 days depending upon the prednisone dose. Inhibition of calcitriol synthesis by the activated mononuclear cells is thought to play a major role in this response [48,50], although inhibition of intestinal calcium absorption and of osteoclast activity also may contribute. (See "Treatment of pulmonary sarcoidosis: Initial approach", section on 'Adverse effects'.)

•Glucocorticoid-refractory hypercalcemia – Patients who are intolerant of or refractory to glucocorticoid therapy warrant referral to a specialist. Ketoconazole, a general inhibitor of P450 enzymes, may be used to decrease calcitriol production [51-53]. Some reports describe a series of patients treated with the anti-tumor necrosis factor (TNF) monoclonal antibody infliximab with promising results [54], including one case of refractory hypercalcemia that responded to infliximab [55]. (See "Treatment of pulmonary sarcoidosis refractory to initial therapy", section on 'Tumor necrosis factor-alpha antagonists'.)

Alternative therapies for hypercalcemia in sarcoidosis include bisphosphonates, such as pamidronate or zoledronic acid, or an antimalarial drug such as chloroquine, or perhaps the less toxic hydroxychloroquine [10,56-59]. The latter two drugs act by decreasing the inflammatory activity of the disease. (See "Kidney disease in sarcoidosis", section on 'Impaired kidney function'.)

●Other granulomatous disorders – For patients with tuberculosis, coccidioidomycosis, or other underlying infectious etiology, hypercalcemia generally resolves with effective treatment (eg, antibiotics, antifungal agents) of the underlying etiology. Glucocorticoids and bisphosphonates have also been used successfully in such patients [45,60,61]. (See "Treatment of hypercalcemia".)

Rifampin, an antimicrobial commonly used in the treatment of tuberculosis and leprosy, can also directly lower calcitriol concentration by inducing the expression of enzymes that degrade calcidiol (including CYP24A1, CYP3A4, UGT1A4, and UGT1A3) [62-64].

In patients with paraffin oil-induced granulomatous hypercalcemia, the addition of the calcineurin-inhibitor tacrolimus enabled the reduction of doses of oral glucocorticoids used to treat hypercalcemia, whereas ketoconazole and hydroxychloroquine had no significant impact on serum calcium or glucocorticoid therapy [65].

SUMMARY AND RECOMMENDATIONS

●Granulomatous disorders associated with hypercalcemia – Hypercalcemia has been described in patients with granulomatous disorders, most commonly sarcoidosis and tuberculosis. (See 'Introduction' above and 'Granulomatous disorders' above.)

●Mechanism of hypercalcemia – Hypercalcemia in sarcoidosis and other granulomatous diseases is due to parathyroid hormone (PTH)-independent extrarenal production of calcitriol from calcidiol by activated mononuclear cells (particularly macrophages) in the lung and lymph nodes. (See 'Sarcoidosis' above.)

●Treatment – In addition to treatment of the underlying disorder, treatment of hypercalcemia or hypercalciuria is aimed at reducing intestinal calcium absorption and calcitriol synthesis. These can be achieved by reducing calcium intake (no more than 400 mg/day), reducing oxalate intake, elimination of dietary vitamin D supplements, and avoidance of sun exposure. Glucocorticoids and bisphosphonates have also been used successfully to treat hypercalcemia in granulomatous diseases. (See 'Treatment' above and "Treatment of hypercalcemia".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Zalman Agus, MD, who contributed to an earlier version of this topic review.