Hypercalcaemia is a metabolic disorder defined by elevated serum calcium concentrations, typically exceeding 2.6 mmol/L (10.5 mg/dL), which surpasses the normal range of approximately 2.1 to 2.55 mmol/L (8.5 to 10.2 mg/dL).[1] This condition arises from disruptions in calcium homeostasis, primarily involving excessive bone resorption, increased intestinal absorption, or reduced renal excretion of calcium.[2] It is classified by severity as mild (2.6–2.97 mmol/L or 10.5–11.9 mg/dL), moderate (3.0–3.48 mmol/L or 12.0–13.9 mg/dL), or severe (above 3.5 mmol/L or 14 mg/dL), with symptomatic manifestations generally appearing above 3.0 mmol/L (12 mg/dL).[3]The most frequent etiologies of hypercalcaemia are primary hyperparathyroidism, accounting for the majority of outpatient cases due to overproduction of parathyroid hormone leading to increased bone breakdown and renal calcium reabsorption, and malignancy, the most common cause in hospitalized patients through mechanisms such as humoral factors or direct bone metastases.[4] Other notable causes include granulomatous diseases like sarcoidosis that elevate vitamin D levels, excessive vitamin D or calcium supplementation, and medications such as thiazide diuretics or lithium.[2] In cancer patients, hypercalcaemia often results from tumor-induced osteolysis or production of parathyroid hormone-related protein, making it a common paraneoplastic syndrome.[5]Clinical symptoms of hypercalcaemia are often nonspecific and correlate with the degree and acuity of elevation, including gastrointestinal effects such as nausea, vomiting, constipation, and anorexia; renal manifestations like polyuria, polydipsia, and nephrolithiasis; and neuromuscular issues including fatigue, muscle weakness, depression, and confusion.[6] Severe or acute hypercalcaemia can precipitate life-threatening complications, such as cardiac arrhythmias, acute kidney injury, pancreatitis, and altered mental status progressing to coma.[7] Bone-related effects may involve osteoporosis or fractures due to chronic mobilization of skeletal calcium stores.[2]Management of hypercalcaemia focuses on correcting the underlying cause while acutely lowering serum calcium levels, particularly in moderate to severe cases, through intravenous hydration with normal saline to promote calciuresis, followed by bisphosphonates like zoledronic acid to inhibit osteoclast activity or calcitonin for rapid but short-term reduction.[8] In malignancy-associated hypercalcaemia, denosumab may be employed as an alternative to bisphosphonates for patients with renal impairment.[5] Long-term treatment targets the etiology, such as surgical parathyroidectomy for hyperparathyroidism or glucocorticoids for granulomatous disease, with monitoring to prevent recurrence.[9]
Clinical Presentation
Symptoms
Hypercalcemia manifests through a variety of symptoms that primarily result from the effects of elevated serum calcium on neuromuscular excitability, renal function, and gastrointestinal motility. Many patients with mild elevations remain asymptomatic, but as calcium levels rise, clinical features become more prominent, often involving multiple organ systems.[1][2]Gastrointestinal symptoms are among the most common early manifestations and include constipation due to reduced smooth muscle contractility, anorexia, nausea, and vomiting. Abdominal pain may occur from ileus or direct irritation, while in more pronounced cases, hypercalcemia can precipitate acute pancreatitis through mechanisms involving premature activation of pancreatic enzymes.[3][2][10]Neurological and neuromuscular symptoms frequently develop with moderate hypercalcemia and encompass fatigue, depression, and confusion arising from altered neuronal membrane potentials. Proximal muscle weakness and lethargy are common, reflecting impaired muscle function, and in advanced stages, these can progress to profound obtundation or coma.[1][11]Renal involvement leads to polyuria and polydipsia as hypercalcemia impairs the kidneys' ability to concentrate urine by antagonizing antidiuretic hormone action. Over time, this can result in nephrolithiasis from calcium stone formation or nephrocalcinosis due to intratubular calcium deposition.[2][1]Cardiovascular effects include hypertension from vascular smooth muscle contraction and a shortened QT interval on electrocardiogram, attributable to accelerated cardiac repolarization.[4]Other symptoms may involve bone pain secondary to underlying skeletal resorption and pruritus from calcium deposition in the skin.[2][12]The severity of symptoms correlates with the degree of calcium elevation: mild hypercalcemia (typically 10.5–12 mg/dL) is often asymptomatic or subtle, moderate levels (12–14 mg/dL) predominantly feature gastrointestinal and neurological complaints, and severe hypercalcemia (>14 mg/dL) presents life-threatening manifestations such as coma or cardiac arrhythmias, potentially escalating to hypercalcaemic crisis.[4][1]
Hypercalcaemic crisis
Hypercalcaemic crisis, also known as parathyroid crisis or hyperparathyroid crisis, represents an acute and life-threatening manifestation of severe hypercalcaemia, typically defined by a total serum calcium level exceeding 14 mg/dL (3.5 mmol/L) or an ionized calcium level greater than 10 mg/dL (2.5 mmol/L), frequently accompanied by altered mental status such as confusion, lethargy, or stupor.[1][13][14] This condition arises from a rapid escalation of hypercalcaemia that overwhelms compensatory mechanisms, distinguishing it from milder forms by its potential for swift decompensation and multi-organ involvement. While general symptoms like nausea and polyuria may serve as early precursors, the crisis is marked by profound neurological and systemic derangements requiring emergent intervention.[14]Precipitating factors often include dehydration, which exacerbates hypercalcaemia through reduced renal clearance and hemoconcentration; infections such as urinary tract infections; or sudden worsening of the underlying etiology, such as parathyroid adenoma hemorrhage or malignancy-related bone resorption.[15][16] Dehydration is particularly insidious, as hypercalcaemia itself induces nephrogenic diabetes insipidus, creating a vicious cycle of fluid loss and calcium retention.[4]Clinical manifestations encompass severe dehydration leading to hypovolemia, acute kidney injury from vasoconstriction and tubular damage, cardiac arrhythmias including bradycardia, heart block, or ventricular ectopy due to altered membrane potentials, and neurological complications such as seizures or progression to coma.[17][18] These features reflect widespread cellular dysfunction, with hypercalcaemia disrupting neuromuscular excitability and electrolyte gradients across organs. If untreated, it carries a very high mortality risk, primarily from multi-organ failure, cardiac arrest, or irreversible renal damage, underscoring its status as an endocrine emergency.[19]Historically, hypercalcaemic crisis was first systematically described in the 1930s through case reports of parathyroid-related emergencies, with Frederic J. Hanes providing a seminal account in 1939 of severe hyperparathyroidism presenting as acute decompensation.[20] Earlier associations between hypercalcaemia and parathyroid pathology emerged in the 1920s, coinciding with advances in understanding calcium metabolism and the first successful parathyroidectomies, but the full syndrome of crisis was delineated later amid high-fatality surgical series.[21]
Pathophysiology
Normal calcium regulation
Calcium homeostasis is essential for numerous physiological processes, including nerve transmission, muscle contraction, and bone integrity. Normal total serum calcium levels are maintained within 8.8 to 10.4 mg/dL (2.2 to 2.6 mmol/L), with approximately 50% existing in the physiologically active ionized form, while the remainder is bound to proteins such as albumin or complexed with anions.[22][23] The body achieves this tight regulation through coordinated actions across multiple organs and hormones, ensuring serum concentrations remain stable despite varying dietary intake or metabolic demands.[24]The primary organs involved in calcium regulation include the parathyroid glands, kidneys, intestines, and bones. The parathyroid glands sense serum calcium levels via the calcium-sensing receptor (CaSR) and secrete parathyroid hormone (PTH) in response to hypocalcemia.[24] In the kidneys, PTH stimulates the 1-alpha hydroxylase enzyme to convert 25-hydroxyvitamin D to active calcitriol (1,25-dihydroxyvitamin D), which promotes intestinal calcium absorption.[24] The intestines facilitate active transcellular calcium uptake, primarily in the duodenum and jejunum, under the influence of calcitriol.[22] Bones serve as the largest reservoir of calcium, storing over 99% of total body calcium as hydroxyapatite, and dynamically release or deposit it through osteoclast-mediated resorption and osteoblast-mediated formation.[22]Parathyroid hormone (PTH) is the central calciotropic hormone that elevates serum calcium levels through three main mechanisms: increasing bone resorption by activating osteoclasts indirectly via osteoblasts, enhancing renal tubular reabsorption of calcium in the distal nephron, and promoting the renal synthesis of calcitriol to boost intestinal absorption.[24] Calcitonin, secreted by the parafollicular cells of the thyroid gland, opposes PTH by inhibiting osteoclast activity and promoting bone deposition, thereby lowering serum calcium during hypercalcemic states.[24] Calcitriol further supports calcium homeostasis by upregulating calcium-binding proteins in enterocytes for efficient absorption and synergizing with PTH in the kidneys.[25]Fibroblast growth factor 23 (FGF23), produced primarily by osteocytes in bone, and its co-receptor klotho play key roles in phosphate regulation, which indirectly influences calcium balance. FGF23 decreases renal phosphate reabsorption by downregulating sodium-phosphate cotransporters (NaPi-2a and NaPi-2c) in the proximal tubule, promoting phosphaturia, and suppresses calcitriol synthesis by inhibiting 1-alpha hydroxylase while activating 24-hydroxylase.[25] Klotho, expressed mainly in the kidneys, is required for FGF23 signaling and helps maintain mineral homeostasis by facilitating these phosphate-lowering effects, preventing ectopic calcification.[25] These actions ensure that phosphate levels remain inversely related to calcium, supporting overall mineral equilibrium.[25]Regulation occurs via intricate negative feedback loops centered on serum calcium concentration. Hypocalcemia directly stimulates PTH release from the parathyroid glands through reduced CaSR activation, while hypercalcemia suppresses PTH secretion and triggers calcitonin release to restore balance.[24] Additionally, PTH and calcitriol levels feed back to modulate FGF23 production, with elevated PTH or calcitriol stimulating FGF23 to counteract excessive phosphate retention and indirectly fine-tune calcium levels.[25]In steady-state calcium balance, daily dietary intake of approximately 1000 mg is offset by urinary excretion of about 200 mg and fecal losses of around 800 mg, with the skeleton acting as a dynamic reservoir to buffer fluctuations and maintain homeostasis.[22] This equilibrium reflects the integrated effects of intestinal absorption (typically 200-400 mg absorbed), renal handling, and bone turnover, ensuring long-term skeletal health.[22]
Mechanisms of hypercalcaemia
Hypercalcaemia arises from disruptions in calcium homeostasis, where the influx of calcium into the extracellular fluid from bone and the gastrointestinal tract exceeds its renal excretion, leading to elevated serum levels. This imbalance can occur through parathyroid hormone (PTH)-mediated pathways or PTH-independent mechanisms, often involving enhanced bone resorption, increased intestinal absorption, or impaired renal clearance.[26][27]In PTH-mediated hypercalcaemia, excessive PTH secretion, as seen in primary hyperparathyroidism, stimulates osteoclast activity to increase bone resorption, releasing calcium into the bloodstream. PTH also enhances renal calcium reabsorption in the distal tubules while promoting phosphate excretion, thereby reducing serum phosphate levels and further elevating calcium. Additionally, PTH indirectly boosts intestinal calcium absorption by stimulating the renal production of 1,25-dihydroxyvitamin D (calcitriol).[1][27]PTH-independent hypercalcaemia, characterized by suppressed PTH levels, primarily involves excess calcitriol, which directly increases intestinal calcium absorption without PTH involvement, as occurs in granulomatous diseases or vitamin D intoxication. Another key pathway is osteolytic bone destruction, where metastatic lesions release calcium through local cytokine-mediated osteoclast activation. A critical concept in this category is humoral hypercalcaemia of malignancy (HHM), driven by tumour secretion of PTH-related peptide (PTHrP), which mimics PTH by binding to its receptor to promote bone resorption and renal calcium retention, though it less potently stimulates calcitriol production.[1][28][29]Renal impairment contributes to hypercalcaemia by reducing glomerular filtration rate, which limits calcium excretion and can lead to tertiary hyperparathyroidism in chronic kidney disease, where autonomous PTH production develops after prolonged secondary hyperparathyroidism. Extracellular volume depletion exacerbates the condition through hemoconcentration, which artificially elevates measured serum calcium, and by stimulating PTH release via reduced renal perfusion, creating a vicious cycle with hypercalcaemia-induced polyuria.[27][30]
Etiology
Endocrine causes
Endocrine causes of hypercalcaemia primarily involve dysregulation of parathyroid hormone (PTH) secretion or other hormonal influences on calcium homeostasis, with primary hyperparathyroidism being the most prevalent etiology in outpatient settings.[31] This condition accounts for the majority of cases among ambulatory patients, particularly affecting postmenopausal women over 50 years of age, with an incidence of approximately 25 to 76 per 100,000 person-years in this demographic.[32] In primary hyperparathyroidism, autonomous overproduction of PTH by the parathyroid glands leads to increased bone resorption, renal calcium reabsorption, and enhanced intestinal calcium absorption, resulting in elevated serum calcium levels.[31] It is often discovered incidentally through routine blood tests, as many patients remain asymptomatic or present with mild symptoms like fatigue or kidney stones.[33]The underlying pathology in primary hyperparathyroidism typically involves a single parathyroid adenoma in 80-85% of cases, four-gland hyperplasia in about 15%, and parathyroid carcinoma in fewer than 1%.[31] Serum PTH levels are invariably elevated or inappropriately normal in the presence of hypercalcaemia, distinguishing it from PTH-independent causes.[33] Surgical parathyroidectomy is curative in most instances, particularly for adenomas, while hyperplasia may require subtotal gland removal.[31]Familial hypocalciuric hypercalcaemia (FHH) represents a benign genetic variant of hypercalcaemia due to inactivating heterozygous mutations in the calcium-sensing receptor (CaSR) gene on chromosome 11, which encodes the CaSR protein expressed in parathyroid and renal tissues.[34] These mutations reduce the receptor's sensitivity to extracellular calcium, leading to mild, lifelong hypercalcaemia (typically 10.2-12.0 mg/dL) with normal or slightly elevated PTH and notably low urinary calcium excretion (fractional excretion <1%).[34] Unlike primary hyperparathyroidism, FHH does not require intervention, as it rarely causes complications, and genetic testing confirms the diagnosis to avoid unnecessary surgery.[34]Chronic lithium therapy, commonly used in bipolar disorder, can induce hypercalcaemia in up to 10-26% of long-term users by altering the parathyroid set-point, resulting in elevated PTH and calcium levels through mechanisms that include reduced sensitivity to calcium feedback and direct stimulation of parathyroid proliferation.[35] This effect is reversible in some cases upon discontinuation, but persistent hyperparathyroidism may develop, necessitating monitoring of serum calcium annually.[35]Thyrotoxicosis, characterized by excess thyroid hormone production, contributes to hypercalcaemia, occurring in approximately 15–20% of patients with thyrotoxicosis through direct stimulation of osteoclast activity and bone resorption, independent of PTH.[36] Elevated levels of triiodothyronine (T3) and thyroxine (T4) increase bone turnover, often manifesting as mild hypercalcaemia that resolves with antithyroid treatment.[36]Adrenal insufficiency rarely causes hypercalcaemia, occurring in approximately 7% of patients with adrenal insufficiency, primarily through volume depletion, reduced glomerular filtration rate, and increased proximal tubular calcium reabsorption, leading to PTH-independent elevations in serum calcium.[37] This association is more common in acute crises and underscores the need for cortisol assessment in unexplained hypercalcaemia.[37]
Neoplastic causes
Neoplastic causes, also known as hypercalcemia of malignancy (HCM), account for the majority of hypercalcemia cases in hospitalized patients, comprising up to 30% of instances and serving as the leading etiology in this setting.[38] HCM is recognized as a paraneoplastic syndrome, driven by tumor-secreted factors that dysregulate calcium balance independently of direct glandular involvement.[39] Patients with HCM face a grave prognosis, with median survival typically ranging from 1 to 3 months following diagnosis.[39]The primary mechanisms of HCM involve excessive bone resorption or enhanced calcium absorption, often through local or systemic tumor effects. Local osteolytic hypercalcemia arises from skeletal metastases where tumor cells release cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF-α), stimulating osteoclasts to erode bone matrix and liberate calcium. This pathway predominates in breast cancer with bone involvement, accounting for approximately 20% of HCM cases, and is also prominent in multiple myeloma due to similar cytokine-mediated lytic lesions.[39][40]Humoral hypercalcemia of malignancy (HHM) results from tumor production of parathyroid hormone-related protein (PTHrP), which binds PTH receptors to promote renal calcium retention, phosphaturia, and osteoclast activation, thereby elevating serum calcium without bone metastases. HHM accounts for approximately 80% of HCM occurrences and is frequently linked to solid tumors, including squamous cell lung carcinoma and renal cell carcinoma.[39][40]A less common but distinct mechanism is 1,25-dihydroxyvitamin D (calcitriol)-mediated hypercalcemia, where malignancies ectopically express 1α-hydroxylase to generate excess calcitriol, boosting intestinal calcium uptake and bone resorption. This is particularly associated with lymphomas, driving about 60% of hypercalcemia episodes in these patients, including both Hodgkin and non-Hodgkin subtypes.[39]In multiple myeloma, hypercalcemia often stems from cytokine-driven processes, with myeloma cells secreting factors like receptor activator of nuclear factor kappa-B ligand (RANKL) and macrophage inflammatory protein-1α (MIP-1α) to induce osteoclastogenesis and focal bone destruction, affecting a notable fraction of advanced cases.[40]
Granulomatous and vitamin D-related causes
Hypercalcaemia in granulomatous diseases arises primarily from dysregulated vitamin D metabolism, where activated macrophages within granulomas express 1α-hydroxylase, an enzyme that converts 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D (calcitriol). This excess calcitriol enhances intestinal calcium absorption and bone resorption, leading to elevated serum calcium levels.[41][42]Sarcoidosis, a multisystem granulomatous disorder, is the most common cause in this category, with hypercalcaemia occurring in approximately 5-11% of patients with sarcoidosis, though clinically significant cases occur in a minority. In sarcoidosis, pulmonary or extrapulmonary granulomas produce calcitriol independently of renal regulation, often resulting in hypercalciuria even without overt hypercalcaemia.[41][43] This mechanism is substrate-dependent, exacerbated by vitamin D supplementation, and linked to an adaptive immune response involving cathelicidin expression.[41]Other granulomatous conditions, such as tuberculosis, histoplasmosis, and berylliosis, follow a similar pathway but are less frequently associated with hypercalcaemia. In tuberculosis, extra-renal 1α-hydroxylase activity in granulomas can cause hypercalcaemia in up to 16% of cases, though symptomatic presentations are rare and often resolve with antitubercular therapy.[42][44] Fungal infections like histoplasmosis and occupational exposures leading to berylliosis have been reported in isolated cases, with hypercalcaemia mediated by granuloma-driven calcitriol overproduction.[45][46]Vitamin D intoxication, or hypervitaminosis D, results from excessive exogenous intake, typically from supplements exceeding 50,000 IU daily or chronic doses over 10,000 IU, leading to elevated 25-hydroxyvitamin D levels that promote hypercalcaemia through increased gastrointestinal absorption and bone mobilization.[47] This is distinct from granulomatous causes but shares the feature of suppressed parathyroid hormone (PTH) and normal parathyroid hormone-related protein (PTHrP). Serum 25-hydroxyvitamin D levels above 150 ng/mL confirm toxicity.[47]Idiopathic hypercalcaemia of infancy represents a genetic form linked to vitamin D hypersensitivity, primarily due to biallelic mutations in CYP24A1, which encodes the enzyme responsible for calcitriol catabolism, or heterozygous variants in SLC34A1/SLC34A3 affecting renal phosphate handling in milder cases. Symptoms, including failure to thrive and nephrocalcinosis, often emerge after standard vitamin D prophylaxis (e.g., 400-500 IU daily), highlighting impaired 1,25-dihydroxyvitamin D degradation.[48][49]Characteristic laboratory findings across these causes include suppressed PTH, elevated calcitriol (in granulomatous and idiopathic cases), and normal PTHrP, distinguishing them from primary hyperparathyroidism or malignancy-associated hypercalcaemia. In vitamin D intoxication, 25-hydroxyvitamin D is markedly elevated, while calcitriol may be normal or high.[41][47] Treatment emphasizes avoiding vitamin D and calcium supplementation to prevent exacerbation, alongside hydration, glucocorticoids for granulomatous cases, and specific therapies like antifungals or genetic counseling for idiopathic forms.[41][47]
Other causes
Other causes of hypercalcaemia encompass a diverse group of less common etiologies, including iatrogenic factors, metabolic disturbances, and recovery states from certain acute conditions. These miscellaneous causes collectively account for less than 10% of hypercalcaemia cases, with many being iatrogenic in origin.[50]Immobilization represents one such cause, particularly in individuals with high bone turnover states, where prolonged bed rest or limited mobility leads to rapid bone resorption. This process is driven by uncoupling of bone formation and resorption, resulting in net calcium release from the skeleton that exceeds renal clearance capacity. Conditions predisposing to immobilization-related hypercalcaemia include Paget's disease of bone, multiple fractures, or spinal cord injuries, where mechanical unloading of the skeleton enhances osteoclastic activity. In critical care settings, such as prolonged ICU stays, this can manifest within days to weeks, especially in younger patients or those with underlying skeletal disorders.[51][52][53]Milk-alkali syndrome arises from excessive intake of calcium and absorbable alkali, such as calcium carbonate antacids, leading to the classic triad of hypercalcaemia, metabolic alkalosis, and acute kidney injury. The hypercalcaemia stems from increased gastrointestinal calcium absorption and reduced renal excretion due to volume contraction and suppressed parathyroid hormone levels. Historically linked to milk and bicarbonate consumption for peptic ulcer treatment, it has resurged with widespread use of calcium supplements for osteoporosis prevention. Renal impairment exacerbates the condition by impairing calcium clearance, creating a vicious cycle; discontinuation of the offending agents typically resolves the hypercalcaemia.[54][55]Certain medications can induce hypercalcaemia through effects on renal calcium handling or bone metabolism. Thiazide diuretics, commonly used for hypertension, reduce urinary calcium excretion by enhancing distal tubular reabsorption via sodium-calcium exchange mechanisms, potentially unmasking underlying hyperparathyroidism or causing mild hypercalcaemia in susceptible individuals. Theophylline, a phosphodiesterase inhibitor used in asthma management, has been associated with hypercalcaemia, possibly through beta-adrenergic stimulation that promotes bone resorption or alters calcium homeostasis, with levels normalizing upon drug withdrawal.[56][57][58]Rhabdomyolysis contributes to hypercalcaemia primarily during the recovery phase, following an initial period of hypocalcaemia due to calcium deposition in damaged muscle. As muscle repair occurs and acute kidney injury resolves, mobilized calcium from soft tissues enters the circulation, overwhelming renal excretory capacity and leading to hypercalcaemia in up to 30% of cases with associated renal failure. Similarly, recovery from acute pancreatitis can precipitate hypercalcaemia in select patients, particularly those with prior hypocalcaemia from saponification or renal complications, though this is less frequently documented. These recovery-phase shifts highlight the importance of monitoring serum calcium during convalescence from such insults.[59][60]Hypervitaminosis A, resulting from chronic excessive intake of vitamin A (retinol), is a rare cause of hypercalcaemia mediated by direct stimulation of osteoclast activity and bone resorption. This toxicity, often seen in individuals consuming high-dose supplements for purported health benefits, leads to periosteal hyperostosis and elevated serum calcium levels independent of parathyroid hormone. Diagnosis involves measuring serum retinol levels, and cessation of supplementation is curative, underscoring the need to consider nutritional excesses in unexplained cases.[61][62]
Diagnostic Approach
Laboratory evaluation
Laboratory evaluation of hypercalcaemia begins with measurement of serum calcium levels to confirm the diagnosis. Total serum calcium is commonly assessed, with normal ranges typically 8.5 to 10.5 mg/dL (2.1 to 2.6 mmol/L), though laboratory-specific variations exist.[4] Ionized calcium, representing the physiologically active free fraction (normal 4.5 to 5.6 mg/dL or 1.1 to 1.4 mmol/L), is preferred in critically ill patients or when albumin binding is altered, as it avoids the need for correction.[63] Since approximately 40-45% of total calcium is bound to albumin, hypoalbuminaemia can artifactually lower measured total calcium; thus, an albumin-corrected value is calculated using the formula:\text{Corrected calcium (mg/dL)} = \text{measured total calcium (mg/dL)} + 0.8 \times (4 - \text{serum albumin (g/dL)}).This adjustment ensures accurate assessment of hypercalcaemia, defined as corrected total calcium >10.5 mg/dL or ionized >5.3 mg/dL.[64]The next critical test is serum intact parathyroid hormone (PTH) assay, which distinguishes PTH-dependent (inappropriately normal or elevated PTH) from PTH-independent hypercalcaemia (suppressed PTH).[30] In PTH-dependent cases, such as primary hyperparathyroidism, PTH is elevated or inappropriately normal despite high calcium, promoting bone resorption and renal calcium reabsorption.[9] PTH-independent hypercalcaemia, often due to malignancy or vitamin D excess, shows low PTH levels as feedback suppression occurs.[9]Additional serum electrolytes provide diagnostic clues. Phosphate levels are typically low (hypophosphataemia) in PTH-mediated hypercalcaemia due to PTH-induced renal phosphate excretion.[4] Conversely, hyperphosphataemia may accompany hypercalcaemia in renal failure, where impaired phosphate clearance exacerbates the imbalance.[3] Serum magnesium is often measured, as hypomagnesaemia can coexist and impair PTH secretion or action.[65] Renal function is evaluated via creatinine, since hypercalcaemia can induce acute kidney injury through vasoconstriction and dehydration, elevating creatinine levels.[65]Vitamin D metabolites are assessed to identify intoxication or granulomatous causes. Serum 25-hydroxyvitamin D (25-OH D) reflects overall vitamin D status and stores, while 1,25-dihydroxyvitamin D (1,25-OH D, calcitriol) is the active form; elevated 1,25-OH D with normal or low 25-OH D suggests ectopic production, as in sarcoidosis.[66] These levels help differentiate vitamin D-mediated hypercalcaemia from other etiologies.[65]Urinary calcium excretion aids in distinguishing familial hypocalciuric hypercalcaemia (FHH) from primary hyperparathyroidism (HPT), both featuring PTH-dependent hypercalcaemia. A 24-hour urine calcium <100 mg/day or a calcium-to-creatinine clearance ratio (UCCR = [urine Ca/serum Ca] / [urine Cr/serum Cr]) <0.01 supports FHH, indicating reduced renal calcium clearance due to calcium-sensing receptor mutations, whereas higher values (>200 mg/day or UCCR >0.02) favor primary HPT.[67] Spot urine calcium-to-creatinine ratio can approximate this when 24-hour collection is impractical.[68] Severe hypercalcaemia (>12 mg/dL) may warrant electrocardiographic evaluation for associated changes.[4]
Electrocardiographic findings
Hypercalcaemia commonly manifests on electrocardiography (ECG) as a shortened QT interval, resulting from accelerated phase 2 repolarization of the cardiac action potential due to elevated extracellular calcium levels.[69] This shortening primarily affects the ST segment, leading to a reduced QTc interval, often below 350 ms when serum calcium exceeds 12 mg/dL (3.0 mmol/L).[70] The degree of QT shortening correlates directly with the severity of hypercalcaemia, serving as a useful indicator of elevated ionized calcium concentrations, and typically resolves upon normalization of calcium levels.[71]In more severe cases, additional ECG abnormalities may occur, including bradycardia, prolonged PR and QRS intervals, atrioventricular (AV) block, and bundle branch blocks, reflecting impaired cardiac conduction.[72] Osborn waves (J waves), characterized by a positive deflection at the J-point, are rarely observed but have been reported in profound hypercalcaemia, mimicking findings seen in hypothermia.[73] These changes can occasionally simulate acute myocardial infarction with ST-segment elevation, underscoring the need for clinical correlation with laboratory calcium measurements.[74]The clinical significance of these ECG findings lies in their association with increased risk of arrhythmias, including progression to complete heart block or cardiac arrest when serum calcium surpasses 15-20 mg/dL (3.75-5.0 mmol/L).[72] Monitoring ECG is essential in hypercalcaemic crises to detect conduction disturbances and guide urgent interventions. Historically, the link between hypercalcaemia and ECG alterations, particularly QT shortening and J-point changes, was first noted in studies from the 1930s, establishing the foundational understanding of calcium's influence on cardiac electrophysiology.[75]
Imaging and advanced tests
The diagnostic approach to hypercalcemia relies on initial laboratory assessment of serum parathyroid hormone (PTH) levels to guide subsequent imaging and advanced testing. When PTH is elevated or inappropriately normal in the setting of hypercalcemia, parathyroid imaging is indicated to localize potential adenomas or hyperplasia as the underlying cause. Neck ultrasound serves as a first-line, non-invasive modality for detecting parathyroid adenomas, offering real-time visualization of glandular enlargement or nodules, often with a sensitivity of 70-80% in experienced hands. Technetium-99m (99mTc) sestamibi scintigraphy, particularly when enhanced with single-photon emission computed tomography (SPECT), is another primary tool for preoperative localization, achieving a sensitivity of 80-90% for solitary parathyroid adenomas by exploiting differential uptake and washout patterns between parathyroid and thyroid tissue.[76][77][78]In cases where PTH is suppressed, non-parathyroid etiologies such as malignancy must be investigated promptly, as hypercalcemia of malignancy accounts for up to 30% of cases and often requires urgent oncologic evaluation. Computed tomography (CT) and magnetic resonance imaging (MRI) are essential for staging known or suspected malignancies and identifying bone metastases, which contribute to hypercalcemia through local osteolysis; contrast-enhanced CT of the chest, abdomen, and pelvis can detect primary tumors or metastatic spread with high specificity, while MRI provides superior soft-tissue resolution for evaluating spinal or pelvic involvement. Bone scintigraphy using 99mTc-labeled diphosphonates is the standard for detecting osteolytic or mixed lytic-sclerotic lesions in cancers such as breast, lung, or multiple myeloma, with a sensitivity exceeding 90% for metastatic disease but potentially limited by superscans in severe hypercalcemia.[30][79][80]Advanced biochemical assays complement imaging in specific scenarios. Measurement of serum parathyroid hormone-related peptide (PTHrP) is crucial for confirming humoral hypercalcemia of malignancy (HHM), the most common paraneoplastic form, where elevated PTHrP levels (often >2 pmol/L) mimic PTH actions on bone and kidney despite suppressed endogenous PTH. Genetic testing for inactivating mutations in the calcium-sensing receptor (CASR) gene is recommended when familial hypocalciuric hypercalcemia (FHH) is suspected, particularly in mild, asymptomatic hypercalcemia with low urinary calcium excretion; sequencing identifies pathogenic variants in approximately 70% of FHH type 1 cases, distinguishing it from primary hyperparathyroidism to avoid unnecessary surgery.[5][28][34]
Treatment
Hydration and bisphosphonates
The initial management of hypercalcemia focuses on correcting dehydration and promoting renal calcium excretion through intravenous (IV) hydration with normal saline. Typically, 0.9% sodium chloride solution is administered at a rate of 200-300 mL per hour, adjusted to achieve a urine output of 100-150 mL per hour, which helps restore intravascular volume and enhance calciuresis.[81][82] This approach can lower serum calcium levels by 1-3 mg/dL over 24-48 hours, depending on the severity of dehydration and baseline renal function.[83]Once euvolemia is achieved, loop diuretics such as furosemide may be added to further augment urinary calcium excretion. Furosemide is given at 20-40 mg IV every 1-4 hours, but only after adequate hydration to avoid exacerbating volume depletion, which could worsen renal perfusion.[82][84] This combination of hydration and diuresis is particularly useful in moderate to severe cases, though monitoring for electrolyte imbalances, such as hypokalemia or hypomagnesemia, is essential.Bisphosphonates represent the cornerstone therapy for inhibiting osteoclast-mediated bone resorption in hypercalcemia, particularly when associated with malignancy. Zoledronic acid, administered as a 4 mg IV infusion over 15 minutes, is the preferred agent due to its rapid onset (within 24-48 hours) and prolonged duration of action (up to 4 weeks).[85][86] Pamidronate serves as an alternative, typically dosed at 60-90 mg IV over 2-4 hours. Treatment with bisphosphonates achieves normocalcemia in approximately 70-75% of patients, with an average reduction of 1-2 mg/dL in serum calcium levels.[87][88]For zoledronic acid in the treatment of hypercalcemia of malignancy, no dose adjustment is required for mild to moderate renal impairment prior to initiation (CrCl ≥30 mL/min); use with caution if CrCl <30 mL/min and consider alternatives like denosumab. For pamidronate, dose reduction is required: 60 mg if CrCl 30-60 mL/min, 30 mg if <30 mL/min.[89] Calcitonin may be used briefly as an adjunct for faster initial calcium lowering in severe cases.[88]
Calcitonin and other acute therapies
Calcitonin serves as a rapid-onset therapy for severe hypercalcemia, particularly in acute settings where immediate calcium reduction is needed. Administered as salmon calcitonin subcutaneously or intramuscularly at an initial dose of 4 international units per kilogram every 12 hours, it can be escalated to 8 international units per kilogram if the response is inadequate after 1 to 2 doses. The mechanism involves direct inhibition of osteoclast-mediated bone resorption and promotion of renal calcium excretion, leading to a decrease in serum calcium levels of approximately 0.5 to 2 mg/dL. Onset of action occurs within 4 to 6 hours, with peak effects at 24 to 48 hours, making it suitable for bridging to longer-acting treatments. However, tachyphylaxis typically develops within 48 to 72 hours due to osteoclast adaptation, necessitating its use as short-term adjunctive therapy rather than monotherapy.[90][91]Denosumab is recommended for refractory hypercalcemia, especially in cases of bisphosphonate failure or significant renal impairment where alternatives are limited. As a human monoclonal antibody targeting receptor activator of nuclear factor kappa-B ligand (RANKL), it potently inhibits osteoclast differentiation and bone resorption, thereby reducing calcium mobilization from bone. The standard regimen for hypercalcemia of malignancy is 120 mg subcutaneously every 4 weeks, with supplemental 120 mg doses on days 8 and 15 during the first month to achieve rapid control. Clinical response begins within 3 days, with normocalcemia attained in about 64% of patients by day 10 and a median duration of response exceeding 100 days in responsive cases. Supplementation with calcium and vitamin D is essential to mitigate the risk of hypocalcemia post-treatment.[92][91]Hemodialysis is indicated in hypercalcemic crises complicated by acute renal failure, sodium-resistant hypercalcemia, or severe symptoms such as coma, arrhythmias, or oliguria unresponsive to medical measures. Using a dialysate with low or zero calcium concentration, sessions typically last 3 to 4 hours and can lower serum calcium by 3 to 5 mg/dL immediately, providing life-saving stabilization. This modality is particularly valuable when volume overload precludes aggressive hydration, though it requires vascular access and monitoring for complications like hypotension.[91]Glucocorticoids are targeted for hypercalcemia driven by excess 1,25-dihydroxyvitamin D production, as seen in granulomatous disorders like sarcoidosis or certain lymphomas. These agents suppress extrarenal 1-alpha-hydroxylase activity in macrophages, reduce intestinal calcium absorption, and accelerate vitamin D catabolism. For acute management, prednisone is dosed at 40 to 60 mg orally daily, or hydrocortisone at 200 to 400 mg intravenously daily for 3 to 5 days, followed by taper; this yields a serum calcium reduction exceeding 3 mg/dL within 7 days in most cases. Therapy duration is typically 1 to 2 weeks, with close monitoring for steroid-related adverse effects. Adequate hydration remains a prerequisite for all these interventions to support renal calcium excretion.[91][93]
Long-term and specific interventions
For primary hyperparathyroidism, the definitive long-term intervention is parathyroidectomy, which involves surgical removal of one or more overactive parathyroid glands and achieves normocalcemia in approximately 95-98% of cases when performed by experienced surgeons.[94] Minimally invasive parathyroidectomy techniques, guided by preoperative imaging such as sestamibi scans or four-dimensional computed tomography, allow for targeted excision through smaller incisions, reducing operative time and recovery compared to traditional bilateral neck exploration while maintaining comparable cure rates.In patients with inoperable primary hyperparathyroidism or parathyroid carcinoma, cinacalcet, a calcimimetic agent that sensitizes the calcium-sensing receptor on parathyroid cells, serves as a medical alternative by lowering serum parathyroid hormone (PTH) and calcium levels.[95] Typical dosing begins at 30 mg twice daily, titrated up to 60 mg twice daily or higher based on response, with studies showing normalization of serum calcium in up to 70% of patients within weeks.[96]Long-term management must address the underlying etiology to prevent recurrence; for hypercalcemia of malignancy, this includes antitumor therapies such as chemotherapy, targeted agents, or radiation, which can resolve elevated calcium by controlling tumor burden.[82] In granulomatous diseases like sarcoidosis, corticosteroids such as prednisone at moderate doses (e.g., 20-40 mg daily) suppress extrarenal 1,25-dihydroxyvitamin D production and inflammation, effectively normalizing calcium levels in most cases.[97]Ongoing monitoring is essential for all patients, involving serial measurements of serum calcium and PTH every 3-6 months to detect persistence or recurrence, alongside dual-energy X-ray absorptiometry (DEXA) scans every 1-2 years to assess bone mineral density and prevent complications like osteoporosis.[98]The 2022 Endocrine Society clinical practice guideline emphasizes denosumab—a monoclonal antibody inhibiting RANKL—as a key option for refractory hypercalcemia of malignancy, particularly after bisphosphonate failure, with subcutaneous doses of 120 mg every 4 weeks achieving calcium normalization in over 60% of cases.[99]
Prognosis and Epidemiology
Clinical outcomes and complications
Hypercalcaemia can lead to significant short- and long-term morbidity, with outcomes varying widely based on severity, underlying etiology, and timeliness of intervention. In severe cases, defined by serum calcium levels exceeding 3.5 mmol/L, in-hospital mortality rates range from 30% to 50%, often due to acute complications such as cardiac arrhythmias or renal failure.[38] For hypercalcaemia associated with malignancy, which accounts for a substantial proportion of severe presentations, prognosis is particularly dismal, with median survival typically 1 to 3 months and 6-month mortality rates exceeding 70-80% in advanced disease.[100] These poor outcomes reflect the advanced stage of underlying cancers and the metabolic burden imposed by persistent hypercalcaemia.Common sequelae include renal and skeletal complications that may persist even after acute resolution. Chronic kidney disease frequently arises from nephrocalcinosis, where calcium deposits in the renal parenchyma impair glomerular filtration and lead to progressive tubular damage.[6] Osteoporosis can develop due to accelerated bone resorption driven by elevated parathyroid hormone or related peptides, increasing fracture risk over time. Recurrent nephrolithiasis is another frequent long-term issue, as sustained hypercalciuria promotes stone formation and urinary tract obstruction.[1]Prognosis differs markedly by cause. In primary hyperparathyroidism, the most common benign etiology, surgical parathyroidectomy yields excellent results, with calcium normalization rates exceeding 95% in experienced centers and low recurrence.[101] Conversely, malignancy-related hypercalcaemia carries a grave outlook, with survival heavily influenced by tumor response to oncologic therapy rather than hypercalcaemia correction alone.[102] Key prognostic factors include patient age, with older individuals facing higher risks due to reduced physiologic reserve; comorbidities such as preexisting renal or cardiac disease, which exacerbate organ damage; and delays in treatment, which allow for irreversible complications like dehydration-induced acute kidney injury.[1]
Incidence and risk factors
Hypercalcaemia has a prevalence of approximately 1% to 2% in the general population, with higher rates observed in hospitalized patients ranging from 0.6% to 2%.[1][103] The condition is often detected incidentally through routine laboratory testing rather than symptomatic presentation.[1]Demographically, primary hyperparathyroidism (PHPT), the most common cause accounting for about 90% of cases alongside malignancy, predominantly affects postmenopausal women, with an incidence roughly two to three times higher in females than males and peaking in those over 60 years old.[1][104] In contrast, hypercalcaemia of malignancy occurs in 2% to 30% of patients with advanced cancers, particularly those with solid tumors like breast or lung cancer or hematologic malignancies.[99][105]Key risk factors include advanced age, female sex, excessive vitamin D supplementation, and chronic kidney disease, which can exacerbate calcium retention and parathyroid dysfunction.[106][107] Malignancy itself serves as a major risk, especially in patients with known metastatic disease.[5]Geographic variations influence incidence, with higher rates in regions of elevated calcium intake through diet or water sources, as well as areas endemic for tuberculosis, where granulomatous inflammation can trigger vitamin D-mediated hypercalcaemia. Differences in screening practices and sunlight exposure also contribute to regional disparities in PHPT presentation.[108]Trends indicate an increasing detection of hypercalcaemia due to widespread routine serum calcium testing.
Veterinary Aspects
Companion animals
Hypercalcaemia in companion animals, primarily dogs and cats, arises from disruptions in calcium homeostasis similar to human pathophysiology but influenced by species-specific factors such as diet, renal function, and toxin exposure.[109] In cats, it is frequently linked to chronic kidney disease (CKD), with ionized hypercalcaemia observed in approximately 20% of cats at the time of azotemic CKD diagnosis.[110] Overall incidence of hypercalcaemia in feline populations from referral hospitals is around 3.2%.[111] In dogs, prevalence is higher at about 10.7% in similar settings, often associated with endocrine disorders.[111]Common causes in cats include idiopathic hypercalcaemia (IHC), CKD, and neoplasia, with a 2023 study of 238 cats identifying kidney diseases, IHC, and cancer as the primary associations, affecting over half of cases with a defined pathological basis.[112] Vitamin D toxicity is less common but notable in cats exposed to rodenticides. In dogs, primary hyperparathyroidism is the leading naturally occurring cause, followed by hypoadrenocorticism (Addison's disease) and vitamin D rodenticide toxicity, which can induce acute, severe elevations.[109] Neoplasia accounts for up to 50% of cases in dogs and up to 30% in cats.[113][114]Clinical symptoms overlap with human presentations but manifest prominently as polyuria, polydipsia, vomiting, and weakness; in cats, anorexia is a particularly salient sign, often leading to rapid weight loss.[115] Gastrointestinal effects like constipation and cardiac arrhythmias may occur in severe cases (>4 mmol/L ionized calcium).[116]Diagnosis relies on measuring ionized calcium levels, which is more accurate than total calcium in veterinary patients due to protein binding variations.[113] Parathyroid hormone (PTH) assays distinguish primary hyperparathyroidism (elevated PTH with high calcium) from other causes, while parathyroid hormone-related peptide (PTHrP) testing identifies paraneoplastic syndromes; abdominal ultrasound evaluates parathyroid glands and kidneys.[109]Treatment begins with aggressive intravenous fluid therapy using 0.9% saline to promote calciuresis, often combined with diuretics like furosemide once hydrated.[117] Bisphosphonates such as pamidronate (1-2 mg/kg IV) effectively lower calcium in non-malignant cases, with onset within 24-48 hours.[113] Calcitonin provides rapid but short-term relief (4-8 IU/kg SC q12h), useful in acute toxicity. Surgical parathyroidectomy is curative for primary hyperparathyroidism in dogs, resolving hypercalcaemia in most within 48 hours.[118] For feline IHC or CKD-associated cases, 2023 research highlights nutritional modifications with low-calcium diets (<200 mg/100 kcal) resolving ionized hypercalcaemia in many without additional therapy.[119]Prognosis is favorable for non-malignant etiologies, with survival times exceeding 1-2 years post-treatment in idiopathic or endocrine cases, though CKD-complicated hypercalcaemia in cats carries a guarded outlook due to progressive renal decline.[112] Early intervention prevents complications like nephrocalcinosis.[120]
Livestock and wildlife
In livestock, hypercalcaemia frequently arises from nutritional excesses, particularly vitamin D toxicity in cattle due to over-supplementation in dairy herds. Large parenteral doses of vitamin D3, such as 15 to 17.5 million IU, induce prolonged hypercalcaemia and hyperphosphataemia, leading to increased bone resorption and soft tissue mineralization.[121] In horses, chronic renal failure commonly presents with hypercalcaemia, often exceeding 20 mg/dL, resulting from decreased calcium excretion and excessive dietary absorption rather than elevated parathyroid hormone activity.[122][123]Plant toxicities also contribute to hypercalcaemia in ruminants, notably from Solanum species like S. malacoxylon and S. glaucophyllum, which contain calcinogenic glycosides that mimic vitamin D activity, causing hypercalcaemia, hyperphosphataemia, and metastatic calcification in soft tissues.[124][125] In zoo and wildlife settings, granulomatous diseases, such as fungal infections, can trigger hypercalcaemia through macrophage-mediated production of active vitamin D (1,25-dihydroxyvitamin D), exacerbating mineral imbalances in exotic species.[23]Common symptoms across affected livestock include weakness, lameness, tachycardia, shallow breathing, and recumbency, which can progress to death if untreated; these manifestations stem from neuromuscular dysfunction and dehydration induced by hypercalcaemia.[126] In farming operations, such cases lead to economic losses through reduced productivity, treatment costs, and mortality, particularly from toxic plant ingestion or supplementation errors that affect herd health and meat or milk output.[127]Management focuses on addressing the underlying cause, such as immediate cessation of vitamin D supplementation and dietary correction to lower calcium intake, alongside fluid therapy to promote calciuresis.[113] Calcitonin administration can rapidly lower serum calcium by inhibiting bone resorption, though its effects are transient and it is used adjunctively in severe cases.[113] Prevention relies on balanced feeds with appropriate calcium-to-phosphorus ratios and vigilant monitoring of supplements to avoid toxicity.[126]In wildlife and captive non-livestock species, hypercalcaemia often links to reproductive or environmental factors. Egg-laying birds experience physiological hypercalcaemia during ovulation, with total calcium levels exceeding 5.0 mmol/L due to estrogen-induced increases in protein-bound calcium to support eggshell formation.[128] In captive reptiles, vitamin D toxicity from excessive supplementation or prolonged UVB exposure can cause hypercalcaemia, leading to renal damage and mineralization, though such cases are less common than deficiencies.[129] Treatment parallels that in livestock, with dietary adjustments and supportive care, similar to approaches in companion animals for acute stabilization.[113]