Calcium is mostly bound and associated with bones (˜99% of total body calcium, ˜1 kg).
Extracellular calcium concentration ranges from: 9.0 to 10.6 mg/dL
40% to 50% is protein bound (mostly albumin). Corrected total serum calcium concentration (SCa) for patients with hypoalbuminemia may be estimated as:
= Measured SCa + 0.8 × (4.0 – serum albumin concentration)
55% is diffusible (ultrafilterable)
40% to 50% exists as free ionized calcium.
10% is complexed (e.g., to bicarbonate, citrate, phosphate anions).
Intracellular calcium concentration is minute at approximately 100 nmol/L but may increase up to 10- to 100-fold during various cellular functions.
Physiologic roles of calcium: skeletal composition, neuromuscular excitation, cardiac and muscle contractility/function
Dietary calcium intake is approximately 1 g/d. 20% is absorbed by the GI tract.
Paracellular absorption does not depend on vitamin D but is based on the favorable intraluminal gradient at the jejunum and ileum when calcium intake is high.
Transcellular absorption occurs primarily in the duodenum when calcium intake is low:
Apical uptake by enterocytes is via the transient receptor potential TRPV6 calcium channel.
Cytoplasmic Ca2+ is taken up into mitochondria or endoplasmic reticulum or transported into the basolateral side via Ca2+-ATPase, or in the presence of high intracytoplasmic Ca2+ concentration, via the Na+-Ca2+ exchanger.
Calbindin D9k mediates Ca2+ transport across enterocytes into circulation.
Hormonal upregulation of GI absorption:
Calcitriol [1,25(OH)2D]: 1,25(OH)2D binds to its receptor (VDR) to increase TRPV6 expression, calbindin D9k, and Ca2+-ATPase, all acting in concert to increase Ca2+ absorption.
Others: parathyroid hormone (PTH), estrogens, prolactin, growth hormone
FIGURE 3.1 Epithelial calcium transport is similar in both enterocytes and renal distal tubules. In enterocytes, the responsible calcium channel is TRPV6. In renal distal tubules, the channel is TRPV5.
Intestinal Ca2+ absorption may be:
Increased in acromegaly (growth hormone, calcitriol), pregnancy and puberty (calcitriol), and excess vitamin D ingestion
Decreased with older age; diet with low Ca2+/PO42- ratio or high vegetable fiber, fat, or fructose; estrogen deficiency; corticosteroid use; or various medical conditions, including diabetes, kidney failure, malabsorptive disorders
8 to 10 g of calcium is filtered daily.
Ultrafilterable Ca2+ load is determined by glomerular filtration rate (GFR), glomerular surface, ultrafiltration coefficient Kf, and plasma calcium concentration.
PTH reduces glomerular Kf, hence ultrafiltered Ca2+ load.
Respiratory and metabolic acidoses increase plasma ionized Ca2+ (iCa2+), hence increased ultrafilterable Ca2+ load and wasting.
Acidemia enhances bone release of Ca2+, hence increased ultrafilterable Ca2+ load and potential renal wasting.
Despite the high amount of glomerular filtration of calcium, daily urinary excretion is ≤200 mg/d, due to effective tubular reabsorption along the entire nephron.
Ca2+ is reabsorbed paracellularly via convection along with Na+ and water. Low intraluminal Na+ at this segment enhances Na+ and water as well as Ca2+ reabsorption. This is the reason for dietary sodium restriction in patients with kidney stones.
Drugs that reduce proximal tubular Na+ reabsorption hence Ca2+ reabsorption include:
Any osmotic diuretic agent that limits Na+ and water reabsorption reduces proximal Ca2+ reabsorption. Example: mannitol.
Tenapanor, a sodium hydrogen exchanger 3 (NHE3) inhibitor, may be associated with calciuria.
FIGURE 3.2 Renal handling of calcium. Ultrafilterable Ca2+ load is determined by glomerular filtration rate, glomerular surface, PTH-regulated ultrafiltration coefficient, and acid-base status. A. Ca2+ reabsorption follows sodium and water reabsorption paracellularly in the proximal tubules. Anything that inhibits sodium reabsorption at this segment may lead to calciuria (e.g., carbonic anhydrase inhibitor, SGLT2 inhibitor). B. Ca2+ reabsorption at the TAL occurs paracellularly, a process facilitated by the CLD16/19 complex and inhibited by CLD14. The binding of Ca2+ to CaSR inhibits ROMK while stimulating CLD14. The former results in reduced intraluminal K+ recycling, reduced positively charged lumen, thus increased calciuria/magnesiuria, while the latter results in inhibition of Ca2+/Mg2+ paracellular reabsorption. In contrast, PTH inhibits CLD14 and results in increased paracellular reabsorption of Ca2+/Mg2+. C. Ca2+ reabsorption at the DCT/CN occurs transcellularly via the calcium channel TRPV5. PTH can inhibit NCC, thus Na+ entry at this segment. The reduced intracellular Na+ favors basolateral Na+ entry via the Na+-Ca2+ exchanger, thereby enhancing Ca2+ reabsorption. Additionally, PTH increases TRPV5 expression for Ca2+ reabsorpion. Abbreviations: AQP1, aquaporin 1; CA, carbonic anhydrase; CLD, claudin; DCT/CN, distal convoluted tubule/connecting segment; NCC, sodium chloride cotransporter; NHE3, sodium hydrogen exchanger; NKCC, sodium potassium 2 chloride cotransporter; PTH, parathyroid hormone; ROMK, renal outer medullary potassium channel; SGLT2, sodium glucose cotransporter 2; TAL, thick ascending limb of Henle loop; TRPV5, transient receptor potential cation channel subfamily V5.
Carbonic anhydrase inhibitors that reduce sodium transport via indirect inhibition of NHE3 may also lead to calciuria.
Sodium glucose cotransporter type 2 (SGLT2) inhibitors
Ca2+ reabsorption occurs paracellularly. This process is regulated by multiple factors.
The positive luminal charge created by K+ recycling via renal outer medullary potassium channel (ROMK) following Na+-K+-2Cl– reabsorption that drives Ca2+ and Mg2+ paracellular reabsorption.
Claudin 16/19 paracellular shunt for Ca2+ and Mg2+ reabsorption
Paracellular claudin 14
Activation of calcium-sensing receptor (CaSR) by high extracellular Ca2+ inhibits ROMK, hence reduced intraluminal K+ recycling and the associated positively charged lumen that drives paracellular Ca2+ reabsorption.
Drugs that affect Ca2+ reabsorption at TAL:
Luminal uptake of Ca2+ occurs transcellularly via the apical TRPV5 calcium channel, followed by reabsorption into the basolateral side via Ca2+-ATPase and Na+-Ca2+ exchanger.
Regulators of Ca2+ reabsorption at DCT/CN
Increasing TRPV5 activity and abundance
Inhibiting the sodium chloride transporter (NCC): see Mechanism below
Calcitriol increases TRPV5 expression
Drugs that affect Ca2+ reabsorption at the DCT/CN:
Thiazides and amiloride increase Ca2+ reabsorption. Implicated mechanisms:
The relative volume depletion associated with thiazide diuretic use may increase proximal tubular Ca2+ reabsorption.
The inhibition of Na2+ reabsorption at the DCT/CN by thiazides/amiloride, respectively, hyperpolarizes the membrane voltage, thereby facilitating Ca2+ influx. This effect has been shown to be inhibited by dihydropyridine-type calcium channel blockers (CCBs).
PTH is the key regulatory hormone to maintain calcium homeostasis.
PTH binds to its receptor PTH1R and exerts its physiologic effects via bones and kidneys.
PTH effects on bones:
Chronic/prolonged PTH exposure increases bone resorption via increasing the bone resorption mediator Receptor Activator of NF-κB Ligand (RANKL) level while suppressing the secretion of the anti-osteoclastogenesis factor OPG. RANKL is normally secreted by osteoblasts to stimulate osteoclastic proliferation and activity (increase bone resorption).
Intermittent increase/administration of PTH increases bone mass via increasing osteoblast proliferation and survival.
PTH effects on kidneys:
TAL: PTH enhances TAL paracellular Ca2+ reabsorption via inhibition of claudin 14 expression.
FIGURE 3.3 Calcium metabolism. Parathyroid hormone (PTH) released from parathyroid gland binds to its receptor PTH1R in the bones and kidneys. In bones, this leads to increased bone resorption. In kidneys, there is reduced calciuria in the thick ascending limb of Henle loop and distal convoluted tubules/connecting segment. Additionally, PTH stimulates 1α-hydroxylase, which increases the hydroxylation of 25(OH)D to 1,25(OH)2D. The latter increases gastrointestinal Ca2+ absorption. All effects driven by PTH lead to increased serum Ca2+ level. The resulting increase in 1,25(OH)2D and Ca2+ in turn bind to their respective receptors in the parathyroid gland as negative feedback to reduce PTH synthesis and release. Of note, the fibroblast growth factor (FGF-23) reduces 1,25(OH)2D levels via inhibition of 1-α hydroxylase while stimulating 24-hydroxylase activity. The latter deactivates 1,25(OH)2D into 1,24,25(OH)2-vitamin D. FGF-23 also exerts an inhibitory effect on the parathyroid gland. Abbreviations: GI, gastrointestinal; Na-Pi, sodium phosphate cotransporter; NCC, sodium chloride transporter; PTHrp, parathyroid hormone-related peptide; ROMK, renal outer medullary potassium channel; SCa2+, serum calcium level; TRPV5, transient receptor potential calcium channel. Red arrows, inhibitory; Green solid arrows, stimulatory; Black open arrows, enzymatic transformation; Unidirectional blue arrows, Systemic effects; Double headed blue arrow, End organ effect of PTH or PTHrp; Red X, negative feedback on PTH gland.
DCT/CN: PTH increases DCT/CN transcellular Ca2+ reabsorption by increasing apical expression of the calcium channel TRPV5 and reducing NCC activity.
Increase 1α-hydroxylase activity: The resultant increase in 1,25(OH)2D level [via hydroxylation of 25(OH)D] leads to increased intestinal calcium absorption.
Regulators of PTH:
1,25(OH)2D inhibits parathyroid cells via binding to vitamin D receptor (VDR).
Extracellular ionized calcium (iCa2+) inhibits parathyroid cells via binding to CaSR.
Ultraviolet (UV) light (skin exposure) converts 7-dehydrocholesterol to cholecalciferol.
Liver hydroxylates cholecalciferol at the 25-carbon to 25(OH)D.
FIGURE 3.4 Vitamin D metabolism. Red arrows: inhibitory effect; Green arrows: stimulatory effect. D2 and D3 refer to the source of vitamin D: D2 is plant based, whereas D3 is animal or human derived. “Diol” and “triol” refer to the number of OH groups present on vitamin D. Both cholecalciferol and ergocalciferol have one existing OH group prior to the 25-hydroxylation step. 25-Hydroxylation by the liver converts these molecules into “diol” and subsequent 1α-hydroxylation by the kidneys converts them into “triol.” Abbreviations: 1,25(OH)2D, 1,25-dihyroxy-vitamin D; 25(OH)D, 25-hydroxy-vitamin D; FGF-23, fibroblast growth factor 23; NCC, sodium chloride transporter; PTH, parathyroid hormone; UV, ultraviolet.
Kidney hydroxylates 25(OH)D (via 1α-hydroxylase) to 1,25(OH)2D. This is calcitriol, the most biologically active form of vitamin D.
24-Hydroxylation of 1,25(OH)2D (by 24-hydroxylase) to 1,24,25(OH)3—vitamin D renders vitamin D inactive.
Overactivity of 24-hydroxylase leads to 1,25(OH)2D deficiency.
Underactivity of 24-hydroxylase (e.g., loss-of-function mutation of the enzyme) leads to 1,25(OH)2D excess.
Regulation of 24-hydroxylase:
Of note, 1,25(OH)2D synthesis increases during puberty, pregnancy, and lactation.
Physiologic effects of 1,25(OH)2D:
Increases intestinal absorption of calcium and phosphate
Stimulates FGF-23 and 24-hydroxylase
Provides negative feedback on PTH via:
Reducing PTH gene transcription
Increasing VDR and CaSR expressions on parathyroid cells
Reducing parathyroid cell proliferation
Maintains healthy bone formation and mineral homeostasis
Regulates various cellular functions involving the immune and cardiovascular systems and the differentiation, proliferation, and apoptosis of normal and malignant cells
Primary function is to increase ionized calcium level in response to hypocalcemia
Increases 1,25(OH)2D level via:
Stimulation of 1α-hydroxylase activity
Inhibition of 24-hydroxylase activity
Increases calcium reabsorption at TAL and DCT/CN
PTH also induces phosphaturia by suppressing the transcriptions of genes encoding proximal tubular sodium phosphate transporters NPT2a and NPT2c that normally function to reabsorb luminal phosphate.
FGF-23 is a peptide produced by osteocytes and osteoblasts.
Functions of FGF-23:
Induces phosphaturia by suppressing proximal tubular NPT2a and NPT2c expressions
Reduces 1,25(OH)2D activity via inhibition of 1α-hydroxylase and stimulation of 24-hydroxylase activity
Regulatory factors of FGF-23:
Factors that can increase FGF-23 level: 1,25(OH)2D, phosphate, PTH, calcium, inflammatory markers, angiotensin II and aldosterone, hypoxia, anemia, erythropoietin, magnesium deficiency, lithium, obesity, diabetes
Factors that can decrease FGF-23 level: insulin/insulin-like growth factor-1 (IGF1), hypocalcemia
Increased FGF-23 level has been shown to be associated with:
Increased mortality in critically ill patients with and without acute kidney injury (AKI)
Left ventricular hypertrophy, heart failure, volume status in patients with end-stage kidney disease (ESKD)
Infectious complications, increased inflammatory cytokines
Reduced erythrocytosis (anemia of CKD)
2019 meta-analysis based on sources from PubMed, Cochrane Central, Scopus, and Web of Science, published from inception dates up to March 2019, involving 26 prospective cohort studies and 16 randomized controlled trials (RCTs) revealed:
Data from cohort studies revealed that dietary calcium intake ranging from 200 to 1,500 mg/d did not affect the risk of cardiovascular disease, coronary heart disease (CHD), or stroke.
However, calcium supplements alone may raise CHD risk, especially myocardial infarction (MI).
The differential diagnoses of true hypercalcemic disorders may be based on major levels involved in normal calcium regulation (Fig. 3.5 and Table 3.1).
Classic primary hyperparathyroidism (PHPT), hypercalcemic PHPT:
Patients present with both elevated PTH levels and hypercalcemia.
Parathyroid adenoma (80%), diffuse hyperplasia (10% to 15%), or carcinoma (5%)
Multiple endocrine neoplasia type 1 (MEN-1):
Autosomal dominant inactivating germline mutation of a tumor-suppressor gene (MEN-1 gene)
May involve parathyroid, anterior pituitary, enteropancreatic, other endocrine tumors
Multiple endocrine neoplasia type 2A (MEN-2A):
Autosomal dominant activating mutation of the RET proto-oncogene
May involve thyroid medulla, adrenal medulla, parathyroid with associated increase in calcitonin, catecholamines, and PTH
FIGURE 3.5 Calcium disorders may arise at different levels of calcium metabolism. 1: Parathyroid hormone; 2: Parathyroid receptor; 3: Bone metabolism; 4: Renal calcium excretion; 5: 1α-Hydroxylase; 6: 1,25(OH)2D; 7: Vitamin D receptor; 8: Intestinal calcium absorption; and 9: Calcium-sensing receptor. See Table 3.1 for hypercalcemic conditions that correspond to these 9 different levels of calcium metabolism. Abbreviations: GI, gastrointestinal; Na-Pi, sodium phosphate cotransporter; PTHrp, parathyroid hormone-related peptide; ROMK, renal outer medullary potassium channel; SCa2+, serum calcium level; TRPV5, transient receptor potential calcium channel.
Table 3.1 Hypercalcemic disorders as they correspond to different levels of calcium metabolism
Patients present with elevated PTH levels but normal serum calcium levels.
Diagnosis of normocalcemic PHPT is a diagnosis of exclusion. The following secondary causes of hyperparathyroidism must be ruled out:
Conditions that could directly stimulate PTH secretion (e.g., vitamin D deficiency, malabsorptive disorders, primary hypercalciuria, CKD, metabolic bone diseases, lithium use, thiazide diuretics, tyrosine kinase inhibitors [sunitinib, imatinib can induce skeletal resistance to PTH, hence secondary hyperparathyroidism])
Conditions that could induce mild hypocalcemia and result in increased PTH secretion (e.g., use of bisphosphonate or denosumab)
Prevalence of clinical manifestations such as kidney stones, low bone mineral density, and hypertension (HTN) has been reported to be similar to those with hypercalcemic PHPT.
Patients with PHPT who present with elevated SCa levels but normal PTH level.
Clinical manifestations have been reported to be similar to those with classic PHPT.
Hypercalcemia of pregnancy:
PTHrp is produced from mammary and placental tissues in response to prolactin-receptor activation.
Paraneoplastic syndromes associated with breast cancer and squamous cell lung carcinoma
Rare hereditary condition due to activating mutations of the PTH receptor (PTH1R)
Clinical manifestations: short-limbed dwarfism, severe hypercalcemia, hypophosphatemia, and metaphyseal chondrodysplasia
Direct invasion (bone metastatic disease)
Osteoclastic activating factors (interleukins IL-1, IL-6), prostaglandins, transforming growth factors, tumor necrosis factor α
Immobilization (increased bone resorption)
Paget disease with excessive bone resorption followed by increase in bone formation and sclerosis
Loss-of-function mutation of 24-hydroxylase leads to high levels of 1,25(OH)2D and hypercalcemia (both of which suppress PTH).
Resultant phenotype: hypercalcemia with associated nephrocalcinosis or nephrolithiasis
Treatment: ketoconazole (inhibitor of 1α-hydroxylase) corrects hypercalcemia.
Tumor-associated: Hodgkin and non-Hodgkin lymphomas, ovarian dysgerminomas, leiomyoblastoma, among others. It has been suggested that cancer cells from these malignancies recruit and stimulate adjacent macrophages to express 1α-hydroxylase. Full mechanisms remain to be elucidated.
Ingestion of vitamin supplements
Familial hypocalciuric hypercalcemia (FHH):
Rare autosomal dominant hereditary condition due to inactivating mutations of the gene encoding CaSR. Recall that in the TAL, CaSR senses hypercalcemia and inhibits ROMK, thereby reducing luminal K+ recycling and loss of the positive luminal charge that normally facilitates paracellular calcium reabsorption. Whereas normal activation of CaSR induces calciuria, inactivating mutation of CaSR reduces calciuria by enhancing TAL paracellular Ca2+ reabsorption.
Moderate chronic hypercalcemia; normo- to hypophosphatemia due to elevated PTH levels; normo- to hypermagnesemia due to increased TAL paracellular reabsorption
Plasma PTH is normal to moderately high. Inactivating mutation of CaSR allows for uninhibited PTH secretion, thus, elevated PTH levels. This explains why FHH may be mistaken for PHPT.
1,25(OH)2D level may be high in response to elevated PTH levels.
Fractional excretion of calcium may be calculated as 24-hour calcium clearance divided by 24-hour creatinine clearance, which is referred to as “calcium-to-creatinine clearance ratio” (CCCR):
CCCR = UV/P of calcium ÷ UV/P of creatinine; Since V is the same for both,
CCCR = U/P (calcium) ÷ U/P (creatinine) = ([urine calcium] × [SCr])/([urine creatinine] × [SCa])
CCCR < 0.010 indicates FHH, whereas CCCR > 0.020 suggests PHPT.
Treatment: The use of calcimimetics has been reported to be successful in a small case series.
Calcium-containing products (calcium carbonate, Nicorette gum, calcium-supplemented bottled carbonated water, etc.)
Excessive vitamin D (over-the-counter vitamin supplements)
Medications: lithium (may lead to hyperparathyroidism), thiazide diuretics, antacids (calcium carbonate—patients present with both hypercalcemia and metabolic alkalosis), vitamin A overload (increased bone resorption)
Fatigue, poor concentration, headaches, depression, anxiety
Ocular: conjunctivitis, band keratopathy
Cardiac: shortened QT, arrhythmias
GI: constipation, nausea, vomiting, peptic ulcer disease, pancreatitis
Kidney-related complications: polyuria, nephrogenic diabetes insipidus, kidney stones, medullary and cortical calcium depositions (nephrocalcinosis)
Loop diuretics may be added if hypervolemic to enhance paracellular Ca2+ excretion from thick ascending loop of Henle.
Inhibit bone resorption and calcitriol synthesis
Preferred agents for hypercalcemia associated with cancer
Commonly used agents:
Intravenous pamidronate, oral alendronate, clodronate
Calcitonin: rapid onset of action (within hours), but only short-term benefit due to tachyphylaxis
Zoledronic acid has been used successfully in patients with sarcoid-induced hypercalcemia and may become first-line agent for this indication (contraindicated for estimated GFR [eGFR] <35 mL/min/1.73 m2).
Mithramycin: cytostatic drug
Potent inhibitor of bone resorption
Rapid onset of action, effect lasts days, but high adverse effects (transaminitis, thrombocytopenia)
Reserved for malignant hypercalcemia. Note that in malignant hypercalcemia, prostaglandin antagonists (e.g., aspirin, indomethacin) may also be considered.
Corticosteroids: 0.5 to 1.0 mg/kg prednisone daily
Reduces GI absorption of calcium
May be used in hypervitaminosis D (either endogenous source such as sarcoid/granulomatous diseases or exogenous vitamin D ingestion)
Corticosteroid is ineffective in patients with vitamin D-24-hydroxylase mutations. Ketoconazole is used instead (see below).
May be considered in lymphoproliferative malignancies such as lymphoma, multiple myeloma, or even solid organ malignancy such as breast cancer
Inhibits calcitriol synthesis via inhibition of 1-α hydroxylase
May be used for patients with vitamin D-24-hydroxylase loss-of-function mutation
Calcimimetics (also see Secondary Hyperparathyroidism, Calcimimetics below):
CaSR agonists such as cinacalcet, etelcalcetide
May be used for hyperparathyroidism (primary, secondary, or even parathyroid carcinoma), particularly for nonsurgical candidates
Propranolol for thyrotoxicosis-induced hypercalcemia
Estrogens in women with PHPT (Although estrogen increases GI calcium absorption, it also inhibits PTH-driven bone resorption. The net effect is reduction in hypercalcemia.)
Treatment consideration for malignancy-associated hypercalcemia:
Denosumab (Prolia, Xgeva) is a human mAb that binds to and inhibits the bone resorption mediator RANKL. RANKL is normally secreted by osteoblasts to stimulate osteoclastic proliferation and activity (increase bone resorption). Inhibition of RANKL by denosumab thus inhibits osteoclastic activity.
Denosumab may ameliorate malignancy-associated hypercalcemia due to bone involvement.
May cause severe hypocalcemia in patients with ESKD and should be avoided
Age <50 years old regardless of clinical manifestations due to the eventual development of significant complications if left untreated over lifetime
Serum calcium level >1.0 mg/dL above normal range (or ionized calcium > 0.12 mmol/L above normal range).
Marked bone density reduction with T-score ≤-2.5 at lumbar spine, femoral neck, total hip, or the one-third radius for postmenopausal women or men >50 years old
Objective evidence of kidney involvement (e.g., stones, hypercalciuria >400 mg/d, reduced kidney function attributable to PHPT)
Presence of severe symptoms: neurocognitive and/or neuropsychiatric symptoms attributable to PHPT, underlying cardiovascular disease with potential disease acceleration, fibromyalgia, gastroesophageal reflux, reduced functional capacity, altered sleep patterns
Patient surgical preference due to difficult/impossible follow-up
Localization with imaging studies to allow minimally invasive surgery may be preferred over four-gland exploration without presurgical imaging.
Localization studies: combination 99mTc-sestamibi scintigraphy and/or single-photon emission computed tomography (SPECT) and ultrasound
If positive for adenoma → focused surgery
Otherwise, consider four-dimensional computed tomography (CT), exploratory surgery
Definition: profound (SCa < 6 mg/dL) and prolonged (>4 days postoperative) hypocalcemia along with hypophosphatemia and hypomagnesemia following parathyroidectomy for severe hyperparathyroidism
Risks: severe hyperparathyroidism with associated skeletal manifestations, preoperative indices of high bone turnover, osteitis fibrosa cystica, and/or “brown tumors”
Continuing high skeletal calcium uptake for bone formation without the opposing calcium leak from bone resorption due to the acute fall in PTH following parathyroidectomy
Intravenous calcium supplement (6 to 12 g/d), followed by oral therapy when safe, plus
Calcitriol (2 to 4 µg/d), plus
Correction of hypomagnesemia (Magnesium serves as a cofactor for vitamin D-binding protein, 25-hydroxylase, 1α-hydroxylase, and 24-hydroxylase enzymes. Optimal vitamin D activity requires magnesium.)
Preoperative repletion of vitamin D and use of bisphosphonates (e.g., intravenous administration of pamidronate 30 mg daily × 2 consecutive days or single dose of 60 mg) have been suggested to ameliorate postoperative hungry bone syndrome.
Acute respiratory alkalosis or severe metabolic alkalosis: Clinically significant reduction in ionized calcium (iCa2+) may occur due to increased Ca2+ complexing to the increased levels of organic anions associated with alkalemia. Free iCa2+ is low, but total serum calcium levels remain the same.
Hypoalbuminemia: low total serum calcium with normal iCa2+ levels due to reduced albumin-bound calcium fraction
Similar to hypercalcemia, the differential diagnoses of true hypocalcemia may be based on the levels outlined for normal serum calcium metabolism. In narrowing down the differential diagnoses, consider how vitamin D and serum phosphorus are affected at each level. See Figure 3.5 and Table 3.2.
Causes: Neck irradiation, amyloid infiltration of parathyroid glands, idiopathic, sporadic, or postoperative hypoparathyroidism
Laboratory findings: hypocalcemia, high phosphorus level, low 1,25(OH)2D, high PTH levels
Albright hereditary osteodystrophy:
Hereditary condition linked to dysfunctional G-proteins that fail to mediate intracellular signaling by PTH.
Patients present with short fourth and fifth metacarpals and rounded facies.
Drug induced: tyrosine kinase inhibitors sunitinib, imatinib
Reported conditions include lethal Blomstrand chondrodysplasia and primary failure of tooth eruption.
Hungry bone syndrome: reduced bone resorption relative to bone formation due to the abrupt lowering of PTH level following parathyroidectomy
Table 3.2 Hypocalcemic disorders as they correspond to different levels of calcium metabolism
Notable laboratory findings: hypocalcemia, elevated PTH, hypophosphatemia due to reduced intestinal absorption of both Ca2+ and PO42- and PTH-induced phosphaturia
Vitamin D resistance due to mutations of VDR
Kidney failure (labs as above, except PO42- level is normal to high)