Hypercalcemia: A Practice Overview of Its Diagnosis and Causes

Abstract

Hypercalcemia is defined as a serum calcium concentration higher than 10.5 mg/gL or 2.6 mmol/L. Only 50% of serum calcium is active, presented as ionized calcium. The remaining half is bound to albumin, phosphate, and other serum anions, and their changes can affect the serum calcium concentration. Thus, to discriminate true hypercalcemia from pseudo hypercalcemia, an ionized calcium concentration higher than 1.3 mmol/L might be more appropriate. Many variables can lead to hypercalcemia, and managing them is necessary to treat this ion disorder. Indeed, it can be caused by malignancies, hematologic disorders, or genetic diseases such as familial hypocalciuric hypercalcemia, or it can be related to hormone disorders involving parathormone or vitamin D. For this condition, the correct diagnostic algorithm should be followed. In this review, we summarize the diagnostic steps to follow and detail each clinical pathway is involved in hypercalcemia.

1. Introduction

Calcium is a bivalent cation physiologically present in blood at a concentration in the range of 2.1–2.6 mmol/L. Only 1% of the total calcium amount is present in the blood, whereas most is stored in the bone. About 50% of serum calcium is bound to albumin and anions, and it represents the inactive form. Indeed, it cannot interact with the surrounding environment.

The remaining 50% (1.1–1.3 mmol/L) represents the active part in the ionized form, which freely circulates into the plasma. Hormones, bones, the gastrointestinal system, and the kidneys strictly cooperate to regulate the physiologic homeostasis of calcium.

An imbalance in this regulation can lead to hypercalcemia, characterized by serum calcium levels exceeding 2.6 mmol/L. The underlying pathophysiology involves one or more mechanisms between excessive calcium release from bones, increased calcium absorption from the gastrointestinal tract, and increased renal calcium reabsorption. Less common mechanisms involve reduced skeletal calcium deposition (as in adynamic bone disease or hypophosphatemia), redistribution (as in rhabdomyolysis), and iatrogenic causes. Parathormone (PTH) is the hormone mainly involved in this regulation, acting in bone, the GI system, and the kidneys. In detail, PTH increases calcium reabsorption in the kidneys and bowel and stimulates the release of calcium from bones into the bloodstream [1]. Calcium is filtered by the glomerulus or secreted by the calcium-sensitive receptor (CaSR), and it is reabsorbed freely or via paracellular movements in the proximal tubule and in the thick ascending limb, equaling amounts of 60–70% and 20–30%, respectively. The remaining 10% interacts in the distal tubule with specialized channels called transient receptor potential (TRP) cation channels TRPV5 and TRPV6. They allow calcium inflow and, through the calbindin, outflow in the blood compartment through the basolateral Na⁺/Ca²⁺ exchanger (NCX1) or the calcium–adenosine triphosphatase (Ca²⁺-ATPase) pump (PMCA1b) [2]. CaSR is also involved in calcium excretion in the distal tubule and the collecting duct, where it is expressed in the luminal membrane. However, this role will be further explained in the subsection titled Milk-Alkali Syndrome.

2. Hypercalcemia

Hypercalcemia is defined as a serum calcium concentration higher than 2.6 mmol/L (10.5 mg/dL). However, the serum calcium concentration also depends on the volume of depletion of the albumin concentration or other anion concentrations such as phosphate. For this, ionized calcium should be dosed, where a concentration higher than 1.3 mmol/L allows for genuine hypercalcemia and pseudohypercalcemia to be distinguished.

High ionized calcium manifests in polydipsia and polyuria, volume depletion, bone and abdominal pain, kidney stones, acute kidney injury, and QT shortening. Also, sensorium impairment can occur, often in acute cases. Some acute patients may need mechanical ventilation, intensive care hospitalization, or continuous renal replacement therapy.

Before the diagnostic management of hypercalcemia, iatrogenic causes should be excluded. Indeed, most patients affected by CKD are treated with calcium salts, vitamin D supplements in various forms, vitamin D receptor activators, thiazide diuretics, and PTH-analogues, which can increase the calcium concentration and impair calcium phosphate homeostasis [3].

In keeping with Murray et al. [4] and their diagnostic algorithm of genuine hypercalcemia, the differential diagnosis should start with the PTH dosage (Figure 1).

The causes of hypercalcemia can be split into two groups:

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PTH-mediated hypercalcemia with normal–high PTH;

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Non-PTH-mediated hypercalcemia with low PTH.

PTH-mediated hypercalcemia includes primary hyperparathyroidism (HPT), tertiary HPT, familial hypocalciuric hypercalcemia (FHH), and lithium-related adverse events.

Non-PTH-mediated hypercalcemia includes hypercalcemia caused by the overproduction of PTH-related peptide (PTHrP), a higher vitamin D concentration (both 1.25OH vitamin D and 25OH vitamin D), malignancies, milk-alkali syndrome, and William’s syndrome.

After detecting PTH-mediated or non-PTH-mediated hypercalcemia, PTHrP, vitamin D in two forms, and oncological screening should be performed.

3. PTH-Mediated Hypercalcemia

PTH-mediated hypercalcemia is a set of diseases characterized by a calcium concentration higher than 10.5 mg/dL (>1.3 mmol/L) caused by normal–high PTH levels. The impaired effectiveness of hypercalcemic negative feedback on both PTH regulation (normal PTH) and PTH overproduction (high PTH) can occur.

3.1. Primary Hyperparathyroidism

As previously reported, PTH measurement should be the first step in the differential diagnosis of hypercalcemia [5]. Primary HPT is a calcium phosphate endocrine disorder caused by inappropriate PTH production, affecting 1–2 patients in every 1000 people, and occurs more in females than in males. It occurs for adenomas (85%) or hyperplasia (15%). In rare cases, it is caused by adenomas of more than one gland or parathyroid carcinoma [6,7]. Correctly diagnosing HPT is important to treat it before it progresses to hypercalcemia. Indeed, as reported by Egli H et al. [8] in an observational study evaluating 1200 transplanted patients, mortality is significantly increased in patients without PTH normalization.

Furthermore, it is often related to normal–low serum phosphate levels in contrast to secondary hyperparathyroidism, which is related to high serum phosphate and low vitamin D levels. Indeed, both phosphate and vitamin D regulate the PTH concentration. In detail, the negative feedback on PTH that results from vitamin D and FGF23 is lacking in the case of vitamin D deficiency. Conversely, high serum phosphate levels stimulate PTH synthesis with the intention of improving the excretion of serum phosphate.

3.2. Familial Hypocalciuric Hypercalcemia

FHH is a class of genetic diseases characterized by mild hypercalcemia associated with low urinary calcium excretion and partial responsiveness only to loop diuretics [9]. It is considered a benign disease and does not require specific treatment, except for rare severe hypercalcemia. Genetic mutations are related to the CaSR gene on chromosome 3, the G-protein subunit α11 gene (GNA11) on chromosome 19, and the sigma 1 subunit of the adaptor-related protein complex 2 (AP2S1) on chromosome 10. These mutations classify the three groups of FHH, namely FHH1, FHH2, and FHH3 (Figure 2). FHH1 is the most frequent, and it occurs due to heterozygous inactivating mutations in CaSR on chromosome 3. More than 200 mutations in CaSR exist, but there are no strong genotype–phenotype correlations [10]. FHH2, the less frequent (about 10%) type, is caused by a deletion or transversion in chromosome 19p13.3 inactivating the GNA11, implicated in the CaSR signal transduction through the C phospholipase (PLC) pathway [11]. Furthermore, the inactivating mutations in the AP2S1 gene of FHH3 are involved in the clathrin-mediated endocytosis of the CaSR [12] and cause about 20% of FHH cases. To summarize, FHH1 involves receptor anomalies, and FHH2 involves transduction inhibition, whereas FHH3 involves the blocking of CaSR receptor endocytosis.

3.3. Lithium

The impact of lithium on sodium–water equilibrium through its interaction with epithelial sodium channels (ENaCs) [13] is well known, as well as the high prevalence of nephrogenic diabetes insipidus (NDI), which has been reported in 85% of cases [14]. Furthermore, as reported by Bovin E. et al., kidney function decline is strongly and directly related to both lithium dose and time of exposure [15]. The impact of lithium on hypercalcemia and hyperparathyroidism can be explained by two different physiopathologic pathways, causing acute and chronic effects, respectively. Acute damage occurs through a reversible effect of lithium on the calcium-sensing receptor and glycogen synthase kinase 3 pathway. It develops in a biochemical process that simulates familial hypocalciuric hypercalcemia [16]. Conversely, the chronic effect is mediated by permanent changes in the parathyroid glands.

Specifically, lithium stimulates the Wnt/beta-catenin pathway stimulating parathyroid cell proliferation [17]. The similarity between ionized calcium and lithium causes the latter to act as an antagonist of CaSR receptors, thus giving a hypocalcemic stimulus that favors PTH secretion. When this stimulus lasts long, the parathyroid glands develop hyperplasia, functionally escaping the physiological regulation mechanism of calcium changes. Why some patients undergoing lithium therapy develop hypercalcemia and others do not is not clear. Differences in receptors and vitamin D status are probably involved. However, patients at the greatest risk and therefore need to be monitored the most closely are patients with long-term exposure to lithium and patients with pre-existing alterations in parathyroids. Indeed, lithium can unmask subclinical hyperparathyroidism in patients with parathyroid adenoma and can act as a trigger of multiglandular hyperparathyroidism [18].

4. Non-PTH-Mediated Hypercalcemia

Conversely to PTH-mediated hypercalcemia, non-PTH-mediated hypercalcemia is a set of diseases characterized by a calcium concentration higher than 10.5 mg/dL (>1.3 mmol/L) and low PTH levels.

Indeed, the efficient negative feedback of hypercalcemia on PTH regulation reduces PTH levels, but the production of PTHrP, vitamin D, and local osteolysis result in an augmented calcium concentration.

4.1. Malignancies

The most prevalent type of non-PTH-mediated hypercalcemia is caused by malignancies. They can act through different pathways, including the following:

• Ectopic tumor production of PTH-related peptide (PTHrP) or 1.25(OH)2D;
• Local osteolytic hypercalcemia (LOH);
• MEN or pheocromocitoma [19].

PTHrP is a peptide with the first 13 amino acid residues similar to the first 13 amino acids of PTH. It is secreted by various kinds of malignancies. Indeed, a high level of PTHrP was reported in solid organ malignancies, squamous cell carcinoma, squamous cell carcinoma of the lung, and adenocarcinomas. More rare causes are myxoid sarcoma, plasma cell leukemia, duodenal adenocarcinoma, and metastatic Merkel cell carcinoma [20].

PTHrP mimics the effect of PTH and mediates bone reabsorption and renal calcium reabsorption via the type 1 PTH receptor [21]. It includes three different peptides: the N-terminal, mild region, and C-terminal. Among these, the C-terminal form has been reported in the urine of patients with oncological hypercalcemia [22]. LOH causes about 20% of the hypercalcemia cases related to malignancies. It includes breast, prostate, and hematologic cancers, which increase the osteoclastic action of the NF-κB ligand (RANKL) and downregulate osteoprotegerin (OPG) [23].

Furthermore, B cell lymphoma and ovarian germ cell tumors are able to increase 1-alpha-hydroxylase activity which improves the 1.25-OH vitamin D. Indeed, it is this form of vitamin D which has a greater impact on calcium reabsorption than 25-OH vitamin D or cholecalciferol [24,25].

4.2. William’s Syndrome

William’s syndrome is a genetic disease caused by a deletion or duplication of gene 7q11.23, coding for elastin and the general transcription factor 2I, GTF2I (protein TFII-I). It affects about 1 in 10,000 people [26]. Patients affected by this mutation manifest anasarca, macrocephaly, hypoplasia of the mandible, fullness of the midface, wide mouth, malformed external ears, and a hypertrophied tongue. Furthermore, an increased heart weight and great cardiac vessel anomalies are described, with consequent increased cardiovascular complications [27]. TFII-I plays a role in the cytoplasmatic regulation of intracellular calcium through phospholipase C (PLC) γ-isoforms [28]. Specifically, it competes with transient receptor potential (TRP) channel TRPC3 for PLC binding, with an inhibition of calcium entry.

4.3. Milk-Alkali Syndrome (MAS)

MAS is a syndrome that was described for the first time in 1915 [29]. It consists of hypercalcemia, renal failure, and metabolic alkalosis after the ingestion of large amounts of calcium and alkali [30]. However, a retrospective study by McGee LC et al. in 1939 presented the hypothesis that hypochloremia and dehydration are needed to manifest MAS [31,32].

Indeed, hypochloremia can inhibit the efficacy of basal CaSR through the inefficacy of NKCC and sodium chloride reabsorption, causing reduced calcium excretion in the thick ascending limb of the loop of Henle. In the distal convoluted tubule, a high luminal calcium concentration links to luminal CaSR, increasing the apical expression of the TRPV5 and calcium reabsorption, exacerbating hypercalcemia. Furthermore, a high pH increases the affinity of calcium to CaSR, which reduces aquaporin 2 expression in the collecting duct, worsening volume depletion [33,34,35].

4.4. Granulomatous Disease: Sarcoidosis

Sarcoidosis is an inflammatory rare disease with an incidence of 2.3/22 in 100,000 people per year, with a prevalence of 2.2/160 per 100,000 people [36]. Hypercalcemia is reported with a sarcoidosis frequency of 4–18%. Baughman et al. reported an incidence rate of 6% in a retrospective study enrolling 1606 patients with sarcoidosis [37], whereas the ACCESS Study [38], a multicentric case–control study, detected an incidence rate of about 3.7%. In sarcoidosis, activated macrophages within granulomas overproduce 1.25(OH)2D3, causing hypercalcemia [39].

4.5. Infections

Hypercalcemia is often reported in some infectious diseases or as an adverse event in patients who use antimicrobic agents. Although no large studies are available, it is mostly reported in pulmonary tuberculosis, related to higher vitamin D levels [40,41], but some cases have also been reported in pneumocystis pneumonia in transplanted patients [42], sepsis [43], and in fluconazole use [44].

Furthermore, the hyperexpression of 1-alpha-hydroxylase has been found in monocytes of patients affected by tuberculosis [45].

5. Complications of Hypercalcemia

Although some acute manifestations of hypercalcemia attract attention, such as sensorium alterations or arrhythmia, it is manifested with very high calcium levels. Conversely, low hypercalcemia can also cause silent but fatal damage.

Indeed, although acute complications of hypercalcemia involve intensive care management and mortality in about 9–33% of patients, chronic hypercalcemia silently increases the risk of vascular calcification [46]. Vascular calcification occurs in two sites: in the subintima, which improves atherosclerosis, and in the media, where it increases systolic hypertension.

Furthermore, uremia accelerates the switch of vascular smooth muscle cells to osteoblastic cells. These ectopic osteoblasts produce alkaline phosphatase, osteocalcin, collagen, and the proteic matrix, including bone morphogenic protein-2 (BMP-2), which worsens both atheromatous plaques and Mönkeberg calcification [47].

Other pathophysiologic pathways involve the linkage between calcium and phosphate. Indeed, elevated serum calcium phosphate (Ca X P) products and calcium loading seem to be independent causes of vascular calcification and early vascular aging. In patients with CKD, who often consume vitamin D with the aims of reducing PTH and managing calcium equilibrium, active vitamin D can paradoxically enhance calcium and phosphate balance, increasing the CV risk if not well managed [48]. The role of relative hypercalcemia on CaXP has been documented. Specifically, hyperphosphatemia plays a major role in promoting vascular calcification and shifting the balances of vascular smooth muscle cells into the osteoblast lineage, and increased arterial stiffness, pulse pressure, pulse wave velocity, and left ventricular mass are reported with increased mortality and morbidity [49,50,51,52,53]. Therefore, hypercalcemia increases liver drug toxicity, and some therapies should be weaned early on, like sedatives and digoxin [54].

6. Treatment

The first step of hypercalcemia treatment should be based on addressing the causes. Indeed, pathogenetic causes have to be treated to manage the serum calcium concentration. Specifically, CaSR agonists (cinacalcet or etelcalcetide) or parathyroidectomy are used to treat primary PTH (evidence 2B) [55,56]; calcimimetics, a diuretic loop, and calcium restriction are used for FHH [57]; other types of therapy are used for lithium or iatrogenic vitamin D-related hypercalcemia; oncological treatment is used for malignancies; and immunosuppressive therapy is used for granulomatosis (even though no univocal consensus exists) [58,59]. The true management of hypercalcemia is indeed based on the restriction of vitamin D supplementation or calcium intake (evidence 1B), hydration (until 200 mL/h of positive balance is reached), biphosphonate, denosumab, or dialysis [60]. Specifically, saline solution administration acts in two ways. Indeed, it is able to increase the volume and reduce calcium, plasma, and sodium chloride concentrations. Similarly to primary aldosteronism, sodium and calcium reabsorption is reduced in aldosterone-insensitive proximal tubular sites and atrial-natriuretic peptide in the distal tubule [61,62].

Also, glucocorticoids can be helpful when hypercalcemia occurs due to granulomatous diseases or hematological malignancies, and they have to be used with caution in myopathies [63].

Once hypercalcemia is confirmed, treatment will depend on the severity, duration, and presence of symptoms. In moderate (calcium < 14 mg/dL) cases or long-standing, asymptomatic hypercalcemia, immediate treatment is unnecessary. Management focuses on avoiding exacerbating factors such as dehydration, excessive calcium intake, prolonged immobilization, thiazide diuretics, and vitamin D supplementation until the underlying cause is identified and treated [64]. A significant proportion of patients with chronic mild hypercalcemia have primary hyperparathyroidism (PHPT). In such cases, parathyroidectomy is indicated for patients meeting specific criteria associated with an increased risk of developing PHPT [65]. When parathyroidectomy is not possible, calcimimetics such as cinacalcet may be used [66].

In the case of calcium levels > 14 mg/dL, acute hypercalcemia, or symptomatic hypercalcemia, initial treatment includes isotonic saline administration with intravenous bisphosphonates, with or without calcitonin, depending on renal function and clinical presentation. Dehydration is the primary cause of severe hypercalcemia, and the initial treatment includes hydration with saline at a rate of 200–300 mL/h to achieve a urine output of 100–150 mL/h [64]. Diuretics should be avoided until euvolemia is reached unless there is a high risk of fluid overload. In cases where the cause is known and easily reversible, hydration alone may resolve hypercalcemia.

In cases with increased bone resorption, commonly associated with dehydration, intravenous bisphosphonates and/or calcitonin should be used. Studies in patients with malignant hypercalcemia have shown that zoledronic acid (4 mg IV over 15 min) is more effective than pamidronate (90 mg over 2 h), with similar efficacy and lower renal toxicity compared to zoledronic acid at a dose of 8 mg [67]. Results from small RCTs and case series support the use of bisphosphonates for treating PHPT, immobilization, vitamin D intoxication, and sarcoidosis [68,69,70,71].

In cases of persistent hypercalcemia, zoledronic acid and pamidronate can be repeated after one week. Patients with pre-existing renal insufficiency are at a higher risk for nephrotoxicity from bisphosphonates. To minimize the risk, adequate hydration should be ensured, nephrotoxic substances should be avoided, and bisphosphonates should be administered at lower doses or with a slower infusion rate [64]. Bisphosphonates typically take 24–36 h to improve calcium levels. During this window, calcitonin, which has a rapid onset of action within hours, can lower calcium levels quickly by inhibiting bone resorption and increasing urinary calcium excretion. Calcitonin can be started alongside hydration and bisphosphonates and discontinued after 48 h when tachyphylaxis develops [72].

In cases of bisphosphonate-refractory malignant hypercalcemia, denosumab (120 mg subcutaneously) can be considered. While there is limited evidence, denosumab (60 mg or 0.3 mg/kg) may be preferred over bisphosphonates in patients with renal disease as the kidneys do not eliminate them. However, caution is needed due to the risk of hypocalcemia [73].

For vitamin D toxicity, granulomatous disorders, and certain lymphomas causing increased intestinal calcium absorption, glucocorticoids can be used due to their ability to inhibit gastrointestinal calcium absorption, stimulate urinary calcium excretion, and inhibit 1α-hydroxylase. Typically, prednisone doses range from 20 mg/day to 40 mg/day and may sometimes be higher. Ketoconazole can be an alternative to glucocorticoids or used in conjunction with lower doses in patients with sarcoidosis, tuberculosis, or silicone-related granulomatous disease and in individuals with CYP24A1 variants as it inhibits calcitriol production [64].

In cases of severe refractory hypercalcemia, symptomatic patients, or those with heart failure unable to tolerate hydration, hemodialysis with low-calcium dialysate may be an option [64].

7. Conclusions

To summarize, hypercalcemia can be related to various diseases with different pathogenesis, each of which has an impact on mortality and morbidity. Indeed, this review aims to highlight the correct diagnostic algorithm to correctly diagnose and manage the causes of hypercalcemia beyond the serum calcium concentration to help in reducing the complications of hypercalcemia and its underlying causes.