Steroid responsive idiopathic calcitriol induced hypercalcemia: a case report and review of the literature

The patient described has a long history of symptomatic hypercalcemia and recurrent nephrolithiasis. A broad work-up was pursued eliminating common etiologies of hypercalcemia, starting with primary hyperparathyroidism. Intact PTH was found to be suppressed and neck ultrasound was unremarkable, making this diagnosis unlikely. Vitamin D testing demonstrated elevated calcitriol levels, which is seen in the clinical context of lymphoma and chronic granulomatosis disease [1, 2, 7]. These conditions were unlikely in our patient given lack of constitutional and inflammatory systemic symptoms, unremarkable bone scan, and chest CT and X-ray follow up ruled out the possibility of primary lung malignancy and active granulomatous diseases.

While hypercalcemia is seen in 10–20% of patients with Sarcoidosis, [3, 7] the diagnosis is unlikely in the absence of any physical exam, laboratory, or radiologic evidence of Sarcoidosis [2, 7]. Furthermore, low ACE levels make this diagnosis even less likely seeing that ACE levels are elevated in 60% of patients with Sarcoidosis [3]. Active tuberculosis infection is also associated with hypercalcemia [2] and was explored given our patient’s history of tuberculosis, but workup was negative. The patient denied taking vitamin D or A, silicon, or paraffin oil, ruling out external causes of hypercalcemia. One consideration is that while this patient underwent a broad workup, an underlying pathology explaining the observed hypercalcemia may reveal itself with time. This is a possibility so the authors will remain vigilant moving forward.

The first report discussing idiopathic calcitriol induced hypercalcemia emerged in 1994, where Kreisberg [1] explored all the possible etiologies of hypercalcemia and appropriate workups through clinical problem-solving. He never found a definitive diagnosis, and his patient improved on low dose prednisone that was continued long-term. Evron et al. [6] subsequently coined the term idiopathic calcitriol induced hypercalcemia suggesting it as a possible diagnosis for three patients they treated. Their patients presented with low iPTH, high calcitriol and high ACE levels. After finding no evidence of Sarcoidosis and normalization of calcium levels post prednisone treatment, they suggested term idiopathic calcitriol induced hypercalcemia as a separate disease entity. Rijckborst et al. [7] consolidated the diagnosis further describing one patient with low iPTH, high calcitriol and high ACE levels. Their patient also underwent a robust investigative workup demonstrating no clear etiology that could explain the observed hypercalcemia. Their patient also responded to prednisone but required a low maintenance dose to prevent disease recurrence. Our patient’s presentation and treatment course differ from those previously reported in respect to ACE levels. Elevated ACE levels in previous case reports [6, 7] lead them to postulate alternation in macrophage function as a possible underlying mechanism for idiopathic calcitriol induced hypercalcemia. Low ACE levels in our patient might emphasize the need to look for alternative causes that could explain elevated calcitriol and calcium levels. Additionally, our case report outlines a case of specific recurrent nephrolithiasis from a young age. Although idiopathic calcitriol induced hypercalcemia is not generally associated with nephrolithiasis, previous history of kidney stone can explain the susceptibility of nephrolithiasis in the setting of hypercalcemia and hypercalciuria.

Calcitriol plays a key role in calcium homeostasis. Systemically, calcitriol binds to vitamin-D receptors in the kidneys, parathyroid glands, intestines, and bones to raise serum blood calcium levels by facilitating intestinal absorption, renal tubular reabsorption, and bone release. The calcium-binding protein encoded by the transcription factor calcitriol carries both calcium and phosphate ions concurrently through intestinal epithelial cells [8]. By stimulating osteoclasts via the release of receptor activator of nuclear factor kappa-B ligand (RANKL) from osteoblasts, calcitriol promotes bone resorption. By causing apoptosis, calcitriol dramatically reduces the growth of T lymphocytes and normal human epidermal keratinocytes. Through this distinct array of self-regulatory mechanisms, calcitriol increases serum calcium levels. Therefore, elevated calcitriol levels idiopathically will lead to hypercalcemia that is resistant to feedback pathways that usually reduce parathyroid hormone production and decreases calcium levels. Corticosteroids inhibit the production of calcitriol in macrophages, which reduces gut absorption of calcium, RANKL expression, and would theoretically promote bone retention reducing calcium levels overall [9]. However, in reality, long term use of glucocorticoids can result in a variety of side effects including bone weakening. Glucocorticoid can activate osteoclast first, later can inhibit osteoblast, which can cause osteoporosis, fractures and osteonecrosis [10]. Long term medium or high dose glucocorticoid use can cause cushingoid facial features, buffalo hump, induce refractory hyperglycemia or worsen existing diabetes, increase risk of infection, and cause a variety of other harmful effects [11]. Titrating the steroid dosage to ensure symptoms do not return, while minimizing the overall steroid burden can be difficult. Yet, this down titration process is necessary to ensure appropriate treatment of Idiopathic Calcitriol Induced Hypercalcemia while minimizing unintended consequences. While the patient continues steroid therapy, it is necessary to monitor for long-term toxicity associated with this treatment. For instance, bone mineral density (BMD) will need to be monitored one year after steroid initiation with appropriate follow-up screening every two years if BMD is stable [10]. In addition to BMD, other parameters that require surveillance with long-term steroid use include lipids, glucose parameters, and intraocular pressures. Authors are considering alternative management in the future. One such alternative is to trial Mycophenolate mofetil, an immunosuppressive agent that has been effective in the treatment of Sarcoidosis [12].

In summary, this case report discusses the case of a 51-year-old male with symptomatic hypercalcemia in the setting of Idiopathic Calcitriol Induced Hypercalcemia. Treatment with prednisone showed marked improvement of symptoms and long-term management continues to be optimized. This report builds on previous literature unifying evidence supporting Idiopathic Calcitriol Induced Hypercalcemia as a distinct disease entity while simultaneously reinforcing the need to explore alternative hypotheses for disease pathogenesis.

While identifying information was not included in this report, written informed consent was obtained from the patient to share this report in an online open-access publication.

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