Hypercalcemia

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: , Omar Elshafei, MD[2] Anmol Pitliya, M.B.B.S. M.D.[3], Cafer Zorkun, M.D., Ph.D. [4] Synonyms and keywords: Increased calcium in serum, Increased calcium in blood For patient information click here

Resident Survival Guide

Overview

Hypercalcemia is an elevation of the calcium concentration in the extracellular fluid above the reference range, established on an albumin-adjusted total serum calcium or an ionized calcium measurement. Calcium homeostasis is governed by parathyroid hormone, calcitriol and the calcium-sensing receptor, acting on bone, kidney and intestine, and hypercalcemia arises whenever entry of calcium into the circulation from bone resorption or intestinal absorption exceeds the capacity of the kidney to excrete it.

The single most useful step in classification is measurement of intact parathyroid hormone, which separates parathyroid hormone dependent causes, dominated by primary hyperparathyroidism, from parathyroid hormone independent causes, dominated by malignancy. Together these two categories account for the great majority of cases. Less common causes include familial hypocalciuric hypercalcemia, granulomatous disorders such as sarcoidosis and tuberculosis, vitamin D excess, the calcium-alkali syndrome, thiazide and lithium therapy, thyrotoxicosis, prolonged immobilization, adrenal insufficiency and inherited defects of vitamin D metabolism.

Presentation ranges from an incidental biochemical finding in an asymptomatic outpatient to a life threatening metabolic emergency. Classic manifestations reflect renal, skeletal, gastrointestinal and neuropsychiatric involvement, summarized in the traditional phrase stones, bones, abdominal groans and psychic moans. Severe hypercalcemia produces dehydration, acute kidney injury, obtundation and shortening of the QT interval on the electrocardiogram.

Management follows two parallel tracks. Acute lowering of the serum calcium rests on restoration of extracellular volume with isotonic saline followed by an antiresorptive agent, either an intravenous bisphosphonate or denosumab, with calcitonin added for rapid onset in severe disease and glucocorticoid therapy reserved for calcitriol mediated hypercalcemia. Definitive management is directed at the underlying cause, which in primary hyperparathyroidism means parathyroidectomy and in malignancy means treatment of the tumor. Longer term outcomes differ sharply between the two: primary hyperparathyroidism is usually indolent and often stable for years, whereas hypercalcemia complicating malignancy carries a substantially increased short term mortality.

Historical Perspective

Recognition of hypercalcemia as a common clinical problem is a product of laboratory automation rather than of any change in disease biology. The introduction of automated multichannel serum chemistry analyzers in the 1970s produced an abrupt rise in the detected incidence of primary hyperparathyroidism, which peaked in the community of Rochester, Minnesota at 121.7 per 100,000 person-years beginning in 1974, and shifted the typical presentation from symptomatic disease with overt skeletal and renal complications to asymptomatic biochemical hypercalcemia.

A second and smaller peak of 86.2 per 100,000 person-years began in 1998, coinciding with the introduction of national osteoporosis screening guidelines, reimbursement for bone density measurement and new drugs for osteoporosis. Case ascertainment bias arising from targeted testing of patients evaluated for osteoporosis is the most likely explanation, and the median age at diagnosis rose over the same interval from 55 years in 1985 to 1997 to 60 years in 1998 to 2010.

The milk-alkali syndrome was described in the early twentieth century in patients treated for peptic ulcer disease with the Sippy regimen of milk and absorbable alkali, and was believed to have disappeared with the advent of acid suppressing therapy. It has since re-emerged in a different population, driven by over the counter calcium carbonate and vitamin D supplementation for osteoporosis, and has been renamed the calcium-alkali syndrome to reflect the changed epidemiology and the central role of the calcium-sensing receptor and the TRPV5 channel in its pathogenesis.

The epidemic of idiopathic infantile hypercalcemia observed in Britain in the 1950s during a period of high vitamin D fortification of milk products remained unexplained for more than half a century. Recessive loss of function mutations in CYP24A1, the gene encoding 25-hydroxyvitamin D 24-hydroxylase and the key enzyme of 1,25-dihydroxyvitamin D degradation, were identified in affected children in 2011 and also in infants who developed severe hypercalcemia after bolus vitamin D prophylaxis.

International consensus on the management of asymptomatic primary hyperparathyroidism has been developed through a series of international workshops. The guidelines published in 2014 were superseded in 2022 by the Fifth International Workshop, which revised the renal indications for surgery, refined the definitions of the disease phenotypes and applied formal GRADE methodology to the surgical and non-surgical management questions. A parallel guideline addressing the treatment of hypercalcemia of malignancy was issued by the Endocrine Society in 2023.

Classification

Hypercalcemia is classified in three complementary ways: by biochemical severity, by the dependence of the disorder on parathyroid hormone, and, in the case of primary hyperparathyroidism, by clinical phenotype.

Classification by Severity

Severity thresholds are not uniform across the literature, and the values below represent the strata in most common clinical use. Severity correlates only loosely with symptoms, because the rate of rise of the serum calcium is often more important than the absolute value.

Category	Albumin-adjusted serum calcium	Typical clinical correlate
Mild	Up to 3.00 mmol/L (12.0 mg/dL)	Usually asymptomatic; often an incidental finding on a routine chemistry panel
Moderate	3.00 to 3.50 mmol/L (12.0 to 14.0 mg/dL)	Polyuria, polydipsia, constipation, fatigue, impaired concentration
Severe	Above 3.50 mmol/L (14.0 mg/dL)	Volume depletion, acute kidney injury, vomiting, obtundation; treated as a metabolic emergency

For orientation to the trial literature, the two pivotal randomized trials of intravenous bisphosphonate therapy in hypercalcemia of malignancy enrolled patients with a corrected serum calcium of 3.00 mmol/L (12.0 mg/dL) or above, and the registration study of denosumab in bisphosphonate refractory disease required a corrected serum calcium above 12.5 mg/dL (3.1 mmol/L).

Classification by Parathyroid Hormone Dependence

Category	Intact parathyroid hormone	Representative causes
Parathyroid hormone dependent	Elevated or inappropriately within the reference range	Primary hyperparathyroidism, tertiary hyperparathyroidism, familial hypocalciuric hypercalcemia, lithium-associated hyperparathyroidism, parathyroid carcinoma, multiple endocrine neoplasia type 1 and related syndromes
Parathyroid hormone independent	Suppressed	Hypercalcemia of malignancy, granulomatous disease, vitamin D intoxication, calcium-alkali syndrome, thyrotoxicosis, immobilization, adrenal insufficiency, CYP24A1 and SLC34A1 defects, vitamin A excess

Classification of Primary Hyperparathyroidism

The Fifth International Workshop defines three phenotypes and proposes that asymptomatic disease be further separated according to whether evaluation demonstrates target organ involvement.

Phenotype	Defining features
Symptomatic	Overt skeletal or renal complications, which may include osteitis fibrosa cystica, fragility fracture, chronic kidney disease, nephrolithiasis or nephrocalcinosis
Asymptomatic	No overt symptoms or signs, typically detected by biochemical testing; subdivided into disease with and without evidence of target organ involvement after standard evaluation
Normocalcemic	Normal albumin-adjusted total calcium and normal ionized calcium with elevated intact parathyroid hormone on at least two occasions over three to six months, after all alternative causes of secondary hyperparathyroidism have been excluded

Normocalcemic disease is frequently diagnosed without rigorous application of these criteria. Patients meeting the definition more often have negative preoperative localization studies and multiglandular disease, and the natural history and optimal management remain unsettled.

Pathophysiology

Normal Calcium Homeostasis

Extracellular calcium concentration is held within narrow limits by parathyroid hormone, 1,25-dihydroxyvitamin D and the calcium-sensing receptor. Parathyroid cells express the calcium-sensing receptor and detect small changes in extracellular ionized calcium, adjusting parathyroid hormone secretion accordingly. Parathyroid hormone increases osteoclastic bone resorption, increases distal tubular calcium reabsorption, reduces tubular phosphate reabsorption and stimulates renal 1-alpha-hydroxylase, thereby raising 1,25-dihydroxyvitamin D and increasing intestinal calcium absorption.

Mechanisms Producing Hypercalcemia

Hypercalcemia develops when one or more of the following exceed renal excretory capacity: accelerated osteoclastic bone resorption, increased intestinal calcium absorption, and increased renal tubular calcium reabsorption. Reduced glomerular filtration, whether from intrinsic renal disease or from hypercalcemia induced volume depletion, lowers the filtered load of calcium and amplifies any of these mechanisms.

Hypercalcemia itself impairs urinary concentrating ability by antagonizing the action of antidiuretic hormone in the collecting duct, producing a nephrogenic diabetes insipidus. The resulting polyuria, compounded by anorexia and vomiting, causes extracellular volume contraction, which reduces glomerular filtration and further raises the serum calcium. This self-reinforcing cycle underlies the rapid deterioration seen in severe hypercalcemia and is the reason that volume repletion is the first therapeutic step.

Primary Hyperparathyroidism

The fundamental lesion is clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of the calcium-sensing receptor, which shifts the set point for calcium regulated parathyroid hormone secretion so that secretion persists despite hypercalcemia. Intestinal calcium hyperabsorption together with increased bone resorption raises the filtered calcium load and, with other metabolic factors, predisposes to calcium containing kidney stones. The skeletal picture reflects varying degrees of dysregulated bone remodeling, classically with preferential loss of cortical bone at the distal one third radius.

A genetic basis can be identified in approximately 10% of all cases of primary hyperparathyroidism. These occur as part of the multiple endocrine neoplasia syndromes MEN1 through MEN4 or the hyperparathyroidism jaw tumor syndrome, or as non-syndromic isolated endocrinopathy such as familial isolated hyperparathyroidism and neonatal severe hyperparathyroidism.

Hypercalcemia of Malignancy

Four mechanisms operate, sometimes in combination in the same patient.

Mechanism	Mediator	Typical tumors
Humoral hypercalcemia of malignancy	Parathyroid hormone-related protein	Squamous carcinoma of the lung, head and neck, oesophagus, cervix; renal cell carcinoma; breast cancer
Local osteolytic hypercalcemia	Cytokines and RANK ligand released within bone marrow	Multiple myeloma, breast cancer with extensive skeletal metastases, lymphoma
Calcitriol mediated	Extrarenal 1-alpha-hydroxylase activity raising 1,25-dihydroxyvitamin D	Lymphoma, including Hodgkin and non-Hodgkin subtypes
Ectopic parathyroid hormone secretion	Authentic parathyroid hormone produced by tumor tissue	Rare; described with ovarian, lung, thymic and neuroendocrine tumors

Vitamin D Mediated and Genetic Mechanisms

Ingestion of excessive vitamin D2 or vitamin D3 produces hypercalcemia and hypercalciuria through supraphysiological concentrations of 25-hydroxyvitamin D, which binds the vitamin D receptor with lower affinity than 1,25-dihydroxyvitamin D, and through formation of 5,6-trans 25-hydroxyvitamin D, which binds the receptor more tightly. In granulomatous disease such as sarcoidosis and tuberculosis, and in tumors such as lymphoma, hypercalcemia arises from ectopic CYP27B1 activity in macrophages or tumor cells with excessive formation of 1,25-dihydroxyvitamin D. Biallelic and in some instances monoallelic CYP24A1 mutations impair degradation of 1,25-dihydroxyvitamin D, producing elevated 1,25-dihydroxyvitamin D with suppressed parathyroid hormone, hypercalciuria, nephrocalcinosis and nephrolithiasis.

Causes

Category	Specific causes	Dominant mechanism
Parathyroid disease	Primary hyperparathyroidism due to single adenoma, multiglandular disease or hyperplasia; parathyroid carcinoma; tertiary hyperparathyroidism in chronic kidney disease and after renal transplantation	Autonomous parathyroid hormone secretion with bone resorption, renal calcium retention and intestinal hyperabsorption
Inherited disorders	Familial hypocalciuric hypercalcemia due to inactivating CASR mutations; multiple endocrine neoplasia type 1, MEN2A, MEN4; hyperparathyroidism jaw tumor syndrome (CDC73); neonatal severe hyperparathyroidism; CYP24A1 and SLC34A1 defects	Altered calcium sensing, tumor predisposition or impaired vitamin D catabolism
Malignancy	Squamous carcinomas, breast cancer, renal cell carcinoma, multiple myeloma, lymphoma, leukemia	Parathyroid hormone-related protein, local osteolysis, extrarenal calcitriol production, rarely ectopic parathyroid hormone
Granulomatous disease	Sarcoidosis, tuberculosis, fungal infection, berylliosis, granulomatosis with polyangiitis	Macrophage 1-alpha-hydroxylase activity raising 1,25-dihydroxyvitamin D
Drugs and supplements	Thiazide diuretics, lithium, excessive calcium and vitamin D supplementation (calcium-alkali syndrome), vitamin A and retinoids, teriparatide, theophylline toxicity	Reduced renal calcium excretion, shifted calcium set point, increased intestinal absorption with metabolic alkalosis
Endocrine disorders	Thyrotoxicosis, adrenal insufficiency, pheochromocytoma, acromegaly	Increased bone turnover or reduced calcium clearance
Other	Prolonged immobilization, especially after spinal cord injury or in high bone turnover states; total parenteral nutrition; rhabdomyolysis with recovering acute kidney injury; Williams syndrome; subcutaneous fat necrosis of the newborn	Uncoupling of bone resorption from formation and reduced renal excretion

Two drug related causes deserve emphasis because their management is commonly misunderstood. In a population-based cohort of 221 residents with thiazide-associated hypercalcemia, primary hyperparathyroidism was diagnosed in 53 patients (24%), and among those who discontinued the thiazide, 71% remained hypercalcemic; hypercalcemia appeared on average 5.2 years after the drug was started and severe hypercalcemia was not observed despite continuation of treatment in 62.4%. Withdrawal of the thiazide therefore does not exclude underlying parathyroid disease. In a systematic review and meta-analysis of 385 studies, lithium treatment was associated with an increase in blood calcium of 0.09 mmol/L (95% confidence interval 0.02 to 0.17, p=0.009) and in parathyroid hormone of 7.32 pg/mL (95% confidence interval 3.42 to 11.23, p<0.0001), and the authors recommended that calcium concentrations be checked before and during treatment.

Differentiating Hypercalcemia from other Diseases

The differential diagnosis is resolved almost entirely by biochemical pattern recognition, anchored on the intact parathyroid hormone level.

Disorder	Intact PTH	PTHrP	25(OH)D	1,25(OH)2D	Urinary calcium	Distinguishing features
Primary hyperparathyroidism	Elevated or inappropriately normal	Not detected	Normal or low	Normal or high	Normal or high	Low or low-normal phosphate; nephrolithiasis; cortical bone loss at distal one third radius; usually postmenopausal women
Familial hypocalciuric hypercalcemia	Elevated or inappropriately normal	Not detected	Normal	Normal or slightly high	Low	Lifelong asymptomatic hypercalcemia, family history, normal bone density; calcium to creatinine clearance ratio below 0.01 raises suspicion; CASR sequencing confirms
Humoral hypercalcemia of malignancy	Suppressed	Elevated	Normal or low	Low or normal	High	Known or clinically evident malignancy; low phosphate; rapid onset; often severe
Local osteolytic hypercalcemia	Suppressed	Not detected or low	Normal or low	Low or normal	High	Extensive skeletal metastases or marrow infiltration; multiple myeloma with anaemia, renal impairment and monoclonal protein
Granulomatous disease	Suppressed	Not detected	Normal or low	Elevated	High	Sarcoidosis, tuberculosis or fungal infection; hilar lymphadenopathy on chest x ray; responds to glucocorticoid therapy
Lymphoma	Suppressed	Not detected in most cases	Normal or low	Elevated	High	Lymphadenopathy, B symptoms; overlaps biochemically with granulomatous disease
Vitamin D intoxication	Suppressed	Not detected	Markedly elevated	Normal or high	High	History of high dose supplementation; prolonged course because of adipose storage
Calcium-alkali syndrome	Suppressed	Not detected	Normal	Low or normal	Variable	High intake of calcium carbonate with absorbable alkali; metabolic alkalosis and renal impairment; risk of post-treatment hypocalcemia after antiresorptive therapy
CYP24A1 or SLC34A1 defect	Suppressed	Not detected	Normal	Elevated or inappropriately normal	High	Infantile or young adult onset; nephrocalcinosis and recurrent stones; sensitivity to vitamin D supplementation
Thyrotoxicosis	Suppressed	Not detected	Normal	Low or normal	High	Suppressed TSH with elevated free thyroid hormones; hypercalcemia usually mild
Immobilization	Suppressed	Not detected	Normal	Low or normal	High	Prolonged bed rest, spinal cord injury, or a preceding high bone turnover state; markedly elevated bone resorption markers
Tertiary hyperparathyroidism	Markedly elevated	Not detected	Variable	Variable	Variable	Long-standing chronic kidney disease or previous renal transplantation; hyperphosphataemia; parathyroid hyperplasia

The most consequential distinction in day to day practice is between primary hyperparathyroidism and familial hypocalciuric hypercalcemia, because the latter is benign and lifelong and should not be treated surgically. The calcium to creatinine clearance ratio is the consensus biochemical discriminator, but the two conditions overlap considerably and a definitive diagnosis of familial hypocalciuric hypercalcemia requires genetic testing. A two step approach measuring the calcium to creatinine clearance ratio from a 24 hour urine collection, followed by CASR mutation testing in all patients with a ratio of 0.020 or less, has a reported diagnostic sensitivity of 98%. The Fifth International Workshop suggests that familial hypocalciuric hypercalcemia be suspected in younger individuals with a ratio below 0.01 or a family history of hypercalcemia.

Diagnostic Algorithm

Hypercalcemia confirmed Albumin-adjusted total calcium or ionised calcium elevated on at least two occasions

Measure intact parathyroid hormone Review drug history: thiazide, lithium, calcium and vitamin D supplements

PTH elevated or inappropriately normal Parathyroid hormone dependent

PTH suppressed Parathyroid hormone independent

24 hour urine calcium and calcium to creatinine clearance ratio; serum phosphate; 25(OH)D; creatinine and eGFR Consider CASR, MEN1 and CDC73 testing Diagnoses: primary hyperparathyroidism, familial hypocalciuric hypercalcemia, lithium-associated disease, tertiary hyperparathyroidism

PTHrP; 25(OH)D and 1,25(OH)2D; serum and urine protein electrophoresis with free light chains; TSH; morning cortisol Imaging directed by findings Diagnoses: malignancy, granulomatous disease, vitamin D excess, calcium-alkali syndrome, thyrotoxicosis, immobilisation

Epidemiology and Demographics

Hypercalcemia has been reported to occur in up to 4% of the population. Primary hyperparathyroidism and malignancy together account for the overwhelming majority of cases, with the balance between them determined by the setting: parathyroid disease predominates in ambulatory practice, malignancy in hospitalized patients.

Primary Hyperparathyroidism

In a study of 3.5 million enrollees in an integrated health system, 15,234 patients had chronic hypercalcemia and 13,327 of these (87%) had primary hyperparathyroidism. Incidence fluctuated between 34 and 120 per 100,000 person-years among women (mean 66) and between 13 and 36 per 100,000 person-years among men (mean 25). Incidence rose with age and the sex difference widened, from 12 to 24 per 100,000 for both sexes below 50 years, to 80 and 36 per 100,000 for women and men aged 50 to 59 years, and to 196 and 95 per 100,000 for women and men aged 70 to 79 years. Incidence was highest among Black patients (92 per 100,000 women and 46 per 100,000 men), followed by white patients (81 and 29), with lower rates among Asian (52 and 28), Hispanic (49 and 17) and other patients (25 and 6). Prevalence tripled during the study period, rising from 76 to 233 per 100,000 women and from 30 to 85 per 100,000 men.

Long-term community surveillance shows that these figures are strongly influenced by testing patterns rather than by changing biology, with incidence peaks of 121.7 per 100,000 person-years from 1974 and 86.2 per 100,000 person-years from 1998 corresponding to the introduction of automated calcium measurement and to osteoporosis screening respectively.

Hypercalcemia of Malignancy

Among adult solid cancer hospitalizations in a national inpatient database between January 2012 and September 2015, approximately 1.7% (126,875 of 7,501,209) were associated with hypercalcemia of malignancy, corresponding to about 1 in 59 admissions. The mean age was 65.7 years, 49% were female, 73% had metastatic disease and 22% received a palliative care consultation. An estimated 10% to 20% of all patients with cancer develop hypercalcemia at some point in their disease course, particularly in advanced disease.

Distribution of Causes among Inpatients

In a hospital series of 125 patients with hypercalcemia excluding those with end-stage renal disease, malignancy accounted for 42 cases (33.6%), hyperparathyroidism for 37 (29.6%) and milk-alkali syndrome for 11 (8.8%). Among the 35 patients with severe hypercalcemia, defined as a corrected serum calcium of 3.5 mmol/L, malignancy accounted for 13 (37.1%) and milk-alkali syndrome for 9 (25.7%), making it the second leading cause of severe hypercalcemia in that cohort.

Risk Factors

• Postmenopausal status and advancing age, the dominant demographic risk profile for primary hyperparathyroidism
• Advanced malignancy, particularly squamous carcinoma, breast cancer, renal cell carcinoma, multiple myeloma and lymphoma
• Lithium therapy
• Thiazide diuretic therapy, which may unmask underlying parathyroid disease
• High intake of calcium and vitamin D supplements, particularly in postmenopausal or pregnant women
• Chronic kidney disease, dialysis dependence and prior renal transplantation
• Granulomatous disease, including sarcoidosis and tuberculosis
• Family history of hypercalcemia, kidney stones or endocrine tumors, raising the possibility of familial hypocalciuric hypercalcemia or multiple endocrine neoplasia type 1
• Prolonged immobilization, especially after spinal cord injury or in a pre-existing high bone turnover state
• Prior neck irradiation

Screening

Population screening for hypercalcemia in asymptomatic, apparently healthy adults is not recommended. A GRADE-based clinical practice guideline for the periodic health examination recommends against the use of serum calcium, electrocardiogram or bone mineral density measurement for the detection of hypocalcemia or hypercalcemia in this population. In practice, most contemporary cases are detected incidentally on multichannel chemistry panels obtained for other indications, which is the principal reason for the observed rise in the recorded incidence of primary hyperparathyroidism.

Targeted case finding is appropriate in defined groups:

Population	Recommended approach
Patients starting or receiving lithium	Measure serum calcium before treatment and periodically during treatment
Patients with suspected or known sarcoidosis	Baseline serum calcium testing, the single strong recommendation in the American Thoracic Society diagnostic guideline
First-degree relatives of a proband with multiple endocrine neoplasia type 1	Mutational analysis and biochemical surveillance, since first-degree relatives carry a 50% risk
Relatives of probands with familial hypocalciuric hypercalcemia	Serum calcium with mutation-specific carrier testing, which prevents unnecessary parathyroid surgery
Patients with chronic kidney disease and mineral and bone disorder	Serial monitoring of calcium, phosphate, parathyroid hormone and alkaline phosphatase, with avoidance of hypercalcemia when selecting phosphate binders and vitamin D analogues
Patients with newly diagnosed nephrolithiasis or unexplained osteoporosis	Serum calcium, with intact parathyroid hormone if hypercalcemia is confirmed

Routine measurement of parathyroid hormone in the absence of hypercalcemia is not recommended outside these targeted settings.

Natural History, Complications, and Prognosis

Natural History of Primary Hyperparathyroidism

In a prospective study of 121 patients with primary hyperparathyroidism, of whom 101 (83%) were asymptomatic, 61 (50%) underwent parathyroidectomy and 60 were followed without surgery for up to 10 years. Among the 52 asymptomatic patients managed without surgery, 14 (27%) showed disease progression, defined as development of at least one new indication for parathyroidectomy, while the remainder had no change in serum calcium, urinary calcium excretion or bone mineral density. Surgery normalized biochemical values and increased lumbar spine bone mineral density by 8 plus or minus 2% at 1 year and by 12 plus or minus 3% at 10 years, and femoral neck density by 6 plus or minus 1% at 1 year and by 14 plus or minus 4% at 10 years, with no significant change at the radius.

In a randomized comparison of surgery with observation in mild disease followed for 5 years, a significant positive treatment effect of surgery was found at the lumbar spine (p=0.011), femoral neck (p<0.001), ultradistal radius (p=0.042) and total body (p<0.001). In the observation group, bone mineral density fell significantly at the femoral neck (p<0.001), the 33% radius (p=0.001), the ultradistal radius (p=0.006) and the total body (p<0.001), while lumbar spine density remained stable.

Observational and cross-sectional studies continue to report associations between primary hyperparathyroidism and cardiovascular and neuropsychological abnormalities, but the causal relationship remains uncertain and randomized trials have not demonstrated a consistent long-term benefit of parathyroidectomy on these non-classical manifestations.

Complications

System	Complications
Renal	Nephrolithiasis, nephrocalcinosis, nephrogenic diabetes insipidus, acute kidney injury, chronic kidney disease
Skeletal	Osteoporosis with cortical predominance, fragility and vertebral fracture, osteitis fibrosa cystica and brown tumors in advanced disease
Gastrointestinal	Anorexia, nausea, vomiting, constipation, peptic ulcer disease, pancreatitis
Neuropsychiatric	Impaired concentration, depression, muscle weakness, confusion, stupor and coma in severe disease
Cardiovascular	Shortening of the QT interval, characteristic T wave changes, bradyarrhythmia and, rarely, cardiac arrest in extreme hypercalcemia
Postoperative	Hungry bone syndrome, transient or permanent hypocalcemia, recurrent laryngeal nerve injury, persistent or recurrent disease

Hungry bone syndrome, the profound and prolonged hypocalcemia with hypophosphatemia and hypomagnesaemia that may follow parathyroidectomy, is reported in 25% to 90% of patients with radiological evidence of hyperparathyroid bone disease compared with 0% to 6% of patients without skeletal involvement.

Prognosis

The prognosis of hypercalcemia is essentially the prognosis of its cause. Asymptomatic primary hyperparathyroidism is frequently stable over many years, and roughly three quarters of patients followed without surgery show no progression over a decade. Familial hypocalciuric hypercalcemia is a benign lifelong condition that generally requires no treatment.

Hypercalcemia complicating malignancy carries a markedly worse outlook. Compared with cancer hospitalizations without hypercalcemia, admissions with hypercalcemia of malignancy had a longer mean length of stay (7.3 versus 5.6 days, p<0.001), higher inpatient mortality (12.3% versus 5.5%, adjusted odds ratio 1.76, 95% confidence interval 1.69 to 1.84, p<0.0001) and a greater likelihood of discharge to another facility (27.4% versus 16.2%, p<0.0001). Mortality attributable to hypercalcemia of malignancy has nonetheless declined with the introduction of increasingly effective anticancer therapy, and long-term control depends on treatment of the underlying tumor.

Parathyroid carcinoma accounts for approximately 1% of cases of primary hyperparathyroidism. Reported recurrence rates range from 30% to 67% and overall 5-year survival ranges from 60% to 95%.

Diagnosis

Diagnostic Study of Choice | History and Symptoms | Physical Examination | Laboratory Findings | Electrocardiogram | X Ray | CT | MRI | Echocardiography or Ultrasound | Other Imaging Findings | Other Diagnostic Studies

Diagnostic Study of Choice

The diagnosis rests on demonstration of an elevated albumin-adjusted total serum calcium or an elevated ionized calcium, confirmed on a repeat sample, followed by measurement of intact parathyroid hormone using a second or third generation assay. Parathyroid hormone measurement is the pivotal test because it separates parathyroid hormone dependent from parathyroid hormone independent disease and directs all subsequent investigation. Multiple determinations of albumin-adjusted and ionized calcium are recommended when normocalcemic disease is being considered, together with exclusion of all secondary causes of an elevated parathyroid hormone.

History and Symptoms

Presentation is dominated by the classic tetrad summarized as stones, bones, abdominal groans and psychic moans, although most contemporary patients with primary hyperparathyroidism are asymptomatic at diagnosis.

• Renal: polyuria, polydipsia, nocturia, renal colic, history of stone passage
• Skeletal: bone pain, fragility fracture, height loss
• Gastrointestinal: anorexia, nausea, vomiting, constipation, epigastric pain
• Neuropsychiatric: fatigue, weakness, poor concentration, low mood, confusion, drowsiness
• Systemic and drug history: weight loss, night sweats, cough, calcium and vitamin D supplement use, thiazide and lithium therapy, immobilization, family history of hypercalcemia or endocrine tumors

Physical Examination

Physical examination is frequently normal. Findings that may be present include signs of volume depletion, proximal muscle weakness and hypotonia, altered mental state, band keratopathy on slit lamp examination in long-standing hypercalcemia, and features of the underlying cause such as lymphadenopathy, breast or chest findings, or erythema nodosum in sarcoidosis. A palpable neck mass in a patient with severe hypercalcemia and a very high parathyroid hormone raises concern for parathyroid carcinoma.

Laboratory Findings

Test	Purpose
Albumin-adjusted total calcium and ionized calcium	Confirmation of hypercalcemia and assessment of severity
Intact parathyroid hormone	Separation of parathyroid hormone dependent from independent causes
Serum phosphate, magnesium, alkaline phosphatase	Support for parathyroid disease, assessment of bone turnover
Creatinine and estimated glomerular filtration rate	Assessment of renal involvement and an indication for surgery in primary hyperparathyroidism
25-hydroxyvitamin D and 1,25-dihydroxyvitamin D	Detection of vitamin D intoxication and of calcitriol mediated hypercalcemia
24 hour urinary calcium and calcium to creatinine clearance ratio	Differentiation of primary hyperparathyroidism from familial hypocalciuric hypercalcemia and assessment of stone risk
Parathyroid hormone-related protein	Confirmation of humoral hypercalcemia of malignancy when parathyroid hormone is suppressed
Serum and urine protein electrophoresis with free light chains	Detection of multiple myeloma
TSH and free thyroid hormones, morning cortisol	Detection of thyrotoxicosis and adrenal insufficiency
Genetic testing (CASR, MEN1, CDC73, RET, CYP24A1, SLC34A1)	Confirmation of a suspected familial or syndromic cause, carrier testing in relatives, and exclusion of phenocopies before surgery

Electrocardiogram

Hypercalcemia shortens the QT interval, and characteristic T wave alterations are the more discriminating finding. In a retrospective comparison of 64 hypercalcemic patients with 956 normocalcemic controls, characteristic T wave alterations were present in 78.13% of hypercalcemic patients compared with 14.64% of controls (p<0.001), with a sensitivity of 78.12%, specificity of 97.28% and accuracy of 96.08%, outperforming QT shortening alone (sensitivity 48.43%, specificity 76.99%). Mean intervals were shorter in hypercalcemic patients (QT 340.5 plus or minus 15.4 versus 380.6 plus or minus 75.5; QTc 404.2 plus or minus 78.4 versus 415.7 plus or minus 57.1; QTm 226.6 plus or minus 23.4 versus 270.6 plus or minus 27.0; all p<0.01). The electrocardiogram supports but does not establish the diagnosis, which remains biochemical.

X Ray

Plain radiography may show subperiosteal bone resorption at the radial aspect of the middle phalanges, a granular or salt and pepper appearance of the skull, distal clavicular resorption, brown tumors and, rarely, generalized osteopenia in advanced hyperparathyroid bone disease. A chest x ray is useful when granulomatous disease or thoracic malignancy is suspected, and may demonstrate hilar lymphadenopathy in sarcoidosis.

CT

Non-contrast computed tomography of the abdomen and pelvis detects nephrolithiasis and nephrocalcinosis and is used to establish renal target organ involvement in primary hyperparathyroidism. Four-dimensional computed tomography provides detailed anatomical localization of abnormal parathyroid tissue before surgery, at the cost of thyroid radiation exposure that must be weighed against the diagnostic benefit. Computed tomography of the chest, abdomen and pelvis is also used in the search for an occult malignancy when parathyroid hormone is suppressed.

MRI

Magnetic resonance imaging is a second-line localization technique for parathyroid tissue, useful in reoperative cases, in ectopic mediastinal glands and when radiation exposure is a particular concern, such as in pregnancy.

Echocardiography or Ultrasound

High-resolution cervical ultrasonography is recommended for operative planning in primary hyperparathyroidism and simultaneously evaluates coexisting thyroid disease that may alter the surgical plan. Patients with non-localizing imaging remain surgical candidates. Renal ultrasonography is used to detect nephrolithiasis and nephrocalcinosis. Echocardiography has no role in establishing the diagnosis and is reserved for evaluation of concurrent cardiac disease.

Other Imaging Findings

Technetium-99m sestamibi scintigraphy, with or without single photon emission computed tomography, is widely used for preoperative localization, usually in combination with ultrasonography. Selective venous sampling for parathyroid hormone and parathyroid arteriography retain a role in reoperative cases. Imaging is indicated in surgical candidates for operative planning and never for diagnosis, since a negative study does not exclude primary hyperparathyroidism.

Dual-energy X-ray absorptiometry should include the lumbar spine, hip and distal one third radius, the last being the site most sensitive to the cortical bone loss characteristic of primary hyperparathyroidism. Vertebral imaging is used to detect subclinical vertebral fracture, which is common in disease otherwise considered asymptomatic.

Other Diagnostic Studies

Preoperative parathyroid biopsy should be avoided. Intraoperative parathyroid hormone monitoring using a validated protocol is recommended when a focused, image-guided approach is undertaken. Ex vivo aspiration of resected tissue may be used to confirm parathyroid origin during surgery. Bone biopsy is rarely required outside the setting of chronic kidney disease and mineral and bone disorder.

Treatment

Medical Therapy | Surgery | Primary Prevention | Secondary Prevention | Cost-Effectiveness of Therapy | Future or Investigational Therapies

Initial Management

The urgency of treatment is governed by the severity of the hypercalcemia, the rate at which it developed and the presence of symptoms. Mild asymptomatic hypercalcemia does not require acute intervention and the priority is diagnostic evaluation. Symptomatic hypercalcemia and any albumin-adjusted calcium above 3.50 mmol/L (14.0 mg/dL) are treated as a metabolic emergency.

• Restore extracellular volume. Intravenous isotonic saline, commonly several litres over the first 24 hours with the rate adjusted for cardiac and renal reserve, reverses the volume depletion produced by nephrogenic diabetes insipidus, restores glomerular filtration and increases urinary calcium excretion.
• Withdraw contributing agents. Stop calcium and vitamin D supplements, thiazide diuretics, lithium where clinically feasible, vitamin A derivatives and calcium-containing antacids.
• Do not use loop diuretics routinely. The evidence base for furosemide in hypercalcemia consists of case reports published before the introduction of bisphosphonates, in contrast to multiple randomized controlled trials supporting antiresorptive therapy, and its routine use should no longer be recommended. Loop diuretics remain appropriate for the management of fluid overload during rehydration.
• Begin antiresorptive therapy early in moderate to severe hypercalcemia, without waiting for the aetiological workup to be completed, since volume repletion alone rarely normalizes the serum calcium when bone resorption is the driving mechanism.
• Mobilize the patient as soon as safely possible.

Acute Management Algorithm

Symptomatic hypercalcemia, or albumin-adjusted calcium above 3.50 mmol/L (14.0 mg/dL)

Volume repletion with isotonic saline Stop calcium, vitamin D, thiazide, lithium and vitamin A derivatives Avoid loop diuretics unless fluid overload develops

Preserved renal function Intravenous zoledronic acid or pamidronate Add calcitonin in severe disease for rapid onset

Renal impairment or hypercalcemia refractory to a bisphosphonate Subcutaneous denosumab

Recheck calcium at 24 to 72 hours Add a glucocorticoid if 1,25(OH)2D is elevated (granulomatous disease or lymphoma) Consider haemodialysis with low-calcium dialysate if hypercalcemia is life-threatening or renal failure precludes hydration

Monitor for hypocalcaemia, which may be prolonged Correct vitamin D deficiency and provide calcium as tolerated Direct definitive therapy at the underlying cause

Medical Therapy

Antiresorptive Therapy in Hypercalcemia of Malignancy

The Endocrine Society makes a strong recommendation for treatment with either denosumab or an intravenous bisphosphonate in adults with hypercalcemia of malignancy. Conditional recommendations, all based on low certainty evidence, suggest using denosumab rather than an intravenous bisphosphonate, combining calcitonin with an intravenous bisphosphonate or denosumab as initial treatment in severe hypercalcemia, and using denosumab in disease that is refractory or recurrent after bisphosphonate therapy.

The supporting systematic review of 21 studies found that a higher proportion of patients receiving a bisphosphonate achieved resolution of hypercalcemia compared with placebo, that there was no significant difference in resolution between denosumab and a bisphosphonate, that two thirds of patients with refractory or recurrent disease treated with denosumab after bisphosphonate therapy achieved resolution, and that adding calcitonin to bisphosphonate therapy did not affect resolution of hypercalcemia, time to normocalcemia or hypocalcemia. The certainty of evidence for all eight clinical questions was low to very low.

Agent	Onset and duration	Key evidence
Zoledronic acid	Effect within 2 to 4 days, maximal by day 4 to 7	Complete response by day 10 in 88.4% at 4 mg (p=.002) and 86.7% at 8 mg (p=.015) versus 69.7% with pamidronate 90 mg; normalization by day 4 in approximately 50% versus 33.3%; median duration of complete response 32 days at 4 mg, 43 days at 8 mg and 18 days with pamidronate
Pamidronate	Similar onset, shorter duration	Inferior to zoledronic acid in the pooled analysis above
Denosumab	Effect within days; not renally cleared	In bisphosphonate-refractory disease (n=33), 21 patients (64%) reached a corrected calcium of 11.5 mg/dL (2.9 mmol/L) or less by day 10 and 12 (33%) reached 10.8 mg/dL (2.7 mmol/L) or less; during the study 23 (70%) and 21 (64%) respectively; estimated median response duration 104 days
Calcitonin	Onset within hours, tachyphylaxis within 48 hours	Used for rapid partial lowering while an antiresorptive takes effect; trial-level synthesis found no added effect on resolution
Glucocorticoid	Days	Suggested for hypercalcemia due to tumors associated with high calcitriol levels, with addition of an intravenous bisphosphonate or denosumab if hypercalcemia remains severe or symptomatic
Calcimimetic	Days	Suggested for hypercalcemia due to parathyroid carcinoma, as an alternative to an antiresorptive

A retrospective cohort of 317 patients treated for hypercalcemia of malignancy provides real-world context. After adjustment, denosumab lowered calcium by 2.0 mg/dL (a fall of 15.9%), intravenous bisphosphonate alone by 1.8 mg/dL (13.9%) and intravenous bisphosphonate combined with calcitonin by 2.7 mg/dL (20.9%). The denosumab and combination groups reached their lowest calcium within 48 hours compared with 72 hours for bisphosphonate alone, and hypocalcemia occurred significantly less often with denosumab.

Medical Therapy in Primary Hyperparathyroidism

For patients with symptomatic or asymptomatic disease who are not candidates for or decline surgery, a systematic review and meta-analysis of randomized controlled trials found that cinacalcet probably reduces serum calcium and parathyroid hormone concentrations, and that alendronate, denosumab, vitamin D and estrogen therapy all increase bone density. Cinacalcet and vitamin D may cause little or no increase in overall adverse events. Very low quality evidence raised the possibility of an increase in serious adverse events with alendronate and denosumab, and low quality evidence indicated increased bleeding and mastalgia with estrogen therapy.

In a randomized, double-blind, placebo-controlled trial of 78 patients, 73% of cinacalcet-treated patients achieved the primary endpoint of a serum calcium of 10.3 mg/dL (2.57 mmol/L) or less with a reduction of at least 0.5 mg/dL (0.12 mmol/L) from baseline, compared with 5% of placebo-treated patients (p<0.001). Fasting predose parathyroid hormone fell by 7.6% with cinacalcet and rose by 7.7% with placebo (p<0.01). Bone mineral density was unchanged while bone resorption and formation markers increased (p<0.05). In an open-label extension of 45 subjects treated for up to 5.5 years, normocalcemia was maintained and parathyroid hormone remained reduced, with no significant effect on areal bone mineral density. Calcimimetics and antiresorptive agents are therefore not interchangeable: the former lowers calcium without improving bone density, the latter improves bone density without normalizing calcium.

Vitamin D deficiency should be repleted in primary hyperparathyroidism. Several studies have confirmed that repletion is safe when the serum calcium is below 3.0 mmol/L (12 mg/dL).

Cause-Specific Measures

• Granulomatous disease and lymphoma: a glucocorticoid reduces extrarenal 1-alpha-hydroxylase activity; sun avoidance and restriction of dietary calcium and vitamin D are adjuncts.
• Vitamin D intoxication: withdrawal of the supplement, volume repletion and a glucocorticoid; recovery is slow because of adipose storage of vitamin D.
• Calcium-alkali syndrome: restoration of extracellular volume, discontinuation of calcium supplementation and correction of alkalosis are the mainstays. Antiresorptive therapy should be used with caution, since in one series all five patients treated with a bisphosphonate developed hypocalcemia compared with one of five managed conventionally (p=0.047).
• Familial hypocalciuric hypercalcemia: no treatment is required and parathyroidectomy is contraindicated.
• Refractory or life-threatening hypercalcemia with renal failure or heart failure that precludes adequate hydration: hemodialysis with a low-calcium dialysate.

Procedural / Surgical Therapy

Parathyroidectomy is the only definitive treatment for primary hyperparathyroidism and is the treatment of choice for symptomatic disease and for asymptomatic disease with evidence of target organ involvement. In the meta-analysis of randomized trials, surgery achieved biochemical cure in 96.1% of patients, supported by high quality evidence, and increased bone mineral density; no convincing evidence supported an effect on fracture, quality of life, occurrence of kidney stones or renal function, although that evidence was of low or very low quality.

Domain	Indication for parathyroidectomy in asymptomatic primary hyperparathyroidism
Serum calcium	More than 1 mg/dL (0.25 mmol/L) above the upper limit of the reference range
Skeletal	Bone mineral density T-score of −2.5 or below at the lumbar spine, total hip, femoral neck or distal one third radius, or a vertebral fracture on imaging
Renal	Estimated glomerular filtration rate below 60 mL/min, 24 hour urinary calcium above 400 mg/day (10 mmol/day) with increased stone risk on biochemical stone risk analysis, or nephrolithiasis or nephrocalcinosis on imaging
Age	Younger than 50 years

Surgery is also appropriate when monitoring is not feasible or not desired by the patient.

Both focused, image-guided parathyroidectomy and bilateral neck exploration are appropriate operations with high cure rates. Intraoperative parathyroid hormone monitoring using a reliable protocol is recommended when a focused approach is used, and focused surgery is not routinely recommended for known or suspected multiglandular disease. Devascularized normal parathyroid tissue should be autotransplanted. Cure is defined as eucalcaemia beyond 6 months. Postoperative complications are few and uncommon, occurring in fewer than 3% of cases in centres performing more than 40 parathyroidectomies per year.

Parathyroid carcinoma requires oncological resection, undertaken after medical control of what is often severe hypercalcemia and guided by preoperative imaging. Extensive tumor genotyping is recommended to identify targetable alterations, and all cases should be reviewed by a specialist tumor board. Patients operated on for atypical parathyroid tumors or for parathyroid tumors with loss of immunohistochemical expression of parafibromin also require long-term monitoring.

Long-Term Management

Patients with primary hyperparathyroidism who do not undergo surgery require structured surveillance rather than discharge. Annual measurement of serum calcium and of serum creatinine with estimated glomerular filtration rate, and bone mineral density measurement at intervals of one to two years including the distal one third radius, allow detection of the roughly one quarter of patients who develop a new indication for surgery over a decade. Renal imaging is obtained if symptoms or biochemical stone risk suggest new stone disease. Annual checks of calcium are appropriate, although routine parathyroid hormone monitoring in the absence of hypercalcemia is not recommended.

In malignancy, durable control of hypercalcemia depends on effective treatment of the underlying tumor, and antiresorptive therapy is a temporizing measure. In patients with advanced cancer and metastatic bone disease, denosumab delayed the time to first hypercalcemia of malignancy compared with zoledronic acid, with a 37% reduction in the hazard ratio (0.63, 95% confidence interval 0.41 to 0.98, p=0.042), and reduced the risk of recurrent events by 52% (rate ratio 0.48, 95% confidence interval 0.29 to 0.81, p=0.006); fewer patients receiving denosumab experienced a hypercalcemic event (1.7% versus 2.7%, p=0.028) over a median 12.9 months on study.

Primary Prevention

• Avoid excessive combined calcium and vitamin D supplementation, the principal driver of the contemporary calcium-alkali syndrome.
• Measure serum calcium before starting lithium and periodically thereafter.
• Recognize that thiazide therapy may unmask rather than cause hypercalcemia, and evaluate for parathyroid disease rather than assuming the drug is solely responsible.
• In chronic kidney disease, select phosphate binders and vitamin D analogues so as to avoid hypercalcemia.
• Avoid vitamin D bolus prophylaxis in infants with a family history suggesting a CYP24A1 or SLC34A1 defect.

Secondary Prevention

• Monitor for hypocalcemia after parathyroidectomy and anticipate hungry bone syndrome in patients with preoperative radiological bone disease, high alkaline phosphatase, large adenomas, older age or vitamin D deficiency; treatment is with high-dose calcium and active vitamin D metabolites, with correction of magnesium deficiency.
• In advanced chronic kidney disease undergoing parathyroidectomy for secondary hyperparathyroidism, preoperative strategies to reduce postoperative hypocalcemia have been studied but remain of uncertain effectiveness, with no randomized trials and substantial heterogeneity across the available literature.
• Confirm cure with eucalcaemia beyond 6 months and continue long-term surveillance in familial, syndromic and carcinoma cases.
• Correct vitamin D deficiency and maintain adequate hydration and mobility to reduce recurrent stone formation.

Special Populations

Pregnancy and Lactation

Physiological changes in calcium metabolism during pregnancy complicate both diagnosis and management, and close monitoring of serum calcium is required to optimize maternal and fetal outcomes. Medical options are severely limited by inadequate safety data, and surgery during the second trimester is advised when hypercalcemia is severe, defined as an albumin-adjusted calcium greater than 3.0 mmol/L (12.0 mg/dL).

A systematic review of 382 published cases of gestational hyperparathyroidism found that 108 (28.3%) underwent parathyroidectomy during pregnancy and 274 (71.7%) were managed non-surgically. Most operations took place during the second trimester (67.6%). Complications or deaths were less likely after second trimester surgery (4.48%) than after third trimester surgery (21.1%), and the overall infant complication rate was lower with surgical than with conservative management (9.1% versus 38.9%). Interdisciplinary management involving endocrinology, endocrine surgery and obstetrics is recommended.

Chronic Kidney Disease and Transplantation

In chronic kidney disease, hypercalcemia most often reflects treatment with calcium-based phosphate binders or active vitamin D analogues, or autonomous parathyroid function. Management targets phosphate lowering while maintaining calcium, and adjusts or withdraws the offending agent before considering parathyroid surgery. Hypercalcemia after renal transplantation commonly reflects persistent tertiary hyperparathyroidism.

Infants and Children

Idiopathic infantile hypercalcemia is a rare genetic disorder with an estimated prevalence of 1 in 33,000, caused by pathogenic variants in CYP24A1 or SLC34A1 and characterized by excessive 1,25-dihydroxyvitamin D mediated intestinal calcium absorption. Management includes cessation of calcium intake, discontinuation of native vitamin D supplementation, hyperhydration and occasional use of bisphosphonates, with long-term follow-up directed at detection of nephrocalcinosis. Other paediatric causes include subcutaneous fat necrosis of the newborn, Williams syndrome and neonatal severe hyperparathyroidism due to biallelic CASR mutations.

Familial and Syndromic Disease

Patients with multiple endocrine neoplasia type 1 and related syndromes typically have multiglandular disease, a higher rate of persistent and recurrent hypercalcemia after surgery and a need for lifelong surveillance; care is best delivered by multidisciplinary teams experienced in endocrine tumors. Genetic testing has value in confirming the diagnosis in a proband, in mutation-specific carrier testing of relatives, and in ruling out phenocopies such as familial hypocalciuric hypercalcemia that would otherwise lead to inappropriate surgery.

Case Studies

Case #1

See also

• Calcium metabolism
• Dent's Disease
• Hypocalcaemia
• Electrolyte disturbance
• Disorders of calcium metabolism
• ATC code V03#V03AG Drugs for treatment of hypercalcemia