Parathyroid-Related

• Benign Familial Hypercalcemia
• Primary Hyperparathyroidism (see Hyperparathyroidism)
• Tertiary Hyperparathyroidism (see Hyperparathyroidism)

Non-Parathyroid-Related

Drugs

• Lithium (see Lithium)
• Milk Alkali Syndrome (see Milk Alkali Syndrome)
• Thiazides (see Thiazides)
• Vitamin D Intoxication (see Vitamin D)
• Vitamin A Intoxication (see Vitamin A)

Endocrine Disease

• Adrenal Insufficiency (see Adrenal Insufficiency)
• Hyperthyroidism (see Hyperthyroidism)

Granulomatous Disease

• Chronic Berylliosis (see Beryllium)
• Sarcoidosis (Sarcoidosis)
• Tuberculosis (TB) (see Tuberculosis)

Malignancy

• Breast Cancer (see Breast Cancer)
• Multiple Myeloma (see Multiple Myeloma)
• Non-Hodgkin’s Lymphoma (see Lymphoma)
• Prostate Cancer (see Prostate Cancer)
• Renal Cell Carcinoma (see Renal Cancer)
  • Epidemiology
    • Hypercalcemia Occurs in 15% of Renal Cell Carcinoma Cases
  • Mechanisms
    • Osteolytic Bone Metastases
    • Parathyroid Hormone-Related Protein (PTHrp) Production
    • Increased Interleukin-6 (IL-6): which enhances the effect of PTHrp
    • Prostaglandin-Induced Enhancement of Bone Resorption
• Squamous Cell Lung Cancer (see Lung Cancer)
  • Epidemiology
    • Squamous Cell Histology: accounts for 51% of paraneoplastic hypercalcemia cases in lung cancer
    • Adenocarcinoma Histology: accounts for 22% of paraneoplastic hypercalcemia cases in lung cancer
    • Small Cell Histology: accounts for 15% of paraneoplastic hypercalcemia cases in lung cancer
  • Mechanisms
    • Osteolytic Bone Metastases
    • Tumor Production of PTH-Related Protein (PTHrP), Calcitriol, or Osteoclast-Activating Factors
• Other Squamous Cell Cancers

Other

• Immobilization
  • Epidemiology
    • Immobilization is a Common Etiology of Mild Hypercalcemia in Patients with Critical Illness
• Rhabdomyolysis (see Rhabdomyolysis)
  • Approximately 30% of Patients with Rhabdomyolysis are Hypercalcemic During the Recovery/Diuretic Phase of Acute Kidney Injury Due to Acute Tubular Necrosis
    • Due to Increased 1,25(OH)2D Occurring During this Phase

Major Factors Which Affect Serum Calcium Concentration (Am J Physiol Renal Physiol, 2010) [MEDLINE]

• Parathyroid Hormone (PTH)
  • Parathyroid Hormone (PTH) is Secreted Almost Immediately in Response to a Small Decrease in the Ionized Calcium Concentration (Which is Sensed by the Calcium-Sensing Receptor/CaSR in the Parathyroid Gland)
    • PTH Increases Calcium Absorption in the Distal Tubule, Consequently Decreasing Renal Calcium Excretion
    • PTH Increases Bone Resorption of Calcium
    • PTH Increases Renal Production of 1,25-Dihydroxyvitamin D, Which Functions to Increase Intestinal Calcium Absorption
• Vitamin D
  • Vitamin D is Enzymatically Converted in the Liver to 25-Hydroxyvitamin D (the Major Circulating Form of Vitamin D) and Then in the Kidney to 1,25-Dihydroxyvitamin D3, the Active Form of Vitamin D
  • The Most Important Biological Function of Vitamin D is to Promote Enterocyte Differentiation and the Intestinal Absorption of Calcium
    • Lesser Stimulation of Intestinal Phosphate Absorption
    • Direct Suppression of Parathyroid Hormone (PTH) Release from the Parathyroid Gland
    • Regulation of Osteoblast Function
    • Permissively Allowing Parathyroid Hormone (PTH)-Induced Osteoclast Activation and Bone Resorption
• Fibroblast Growth Factor 23 (FGF23)
  • Inhibits Renal Phosphate Reabsorption, Decreasing Serum Phosphate (Which Decreases Serum Calcium)
  • Inhibits Conversion of Vitamin D to its Active Form 1,25-Dihydroxyvitamin D (Calcitriol)
    • Decreases Calcium Absorption from Gastrointestinal Tract
  • Inhibits Parathyroid Hormone (PTH) Production
• Calcium Ion Itself
  • Calcium Acts at the Calcium-Sensing Receptor (CaSR) in the Parthyroid Gland to Inhibit PTH Secretion
  • Calcium Acts at the Calcium-Sensing Receptor (CaSR) in the Loop of Henle to Stimulate Renal Calcium Excretion
• Serum Phosphate Concentration

Mechanisms of Calcium Transport in the Blood (J Clin Invest, 1970) [MEDLINE] (Lancet, 1998) [MEDLINE]

• Calcium Bound to Serum Proteins (Predominantly Albumin): 40-45%
• Calcium Bound to Small Inorganic/Organic Anions (Phosphate, Citrate, Sulfate, Lactate, etc): 15%
• Free (Ionized) Calcium: 40-45%
  • Ionized Calcium Concentration is Tightly Regulated by Parathyroid Hormone and Vitamin D
  • Only the Ionized Calcium is Metabolically Active (i.e. Transportable into Cells)

Relationship Between Total Serum Calcium Concentration and Ionized Calcium Concentration

General Comments

• Normal Range of Total Serum Calcium Concentration (Varies by Laboratory): 8.5-10.5 mg/dL (2.12 to 2.62 mmol/L)
  • Wide Range of Normal Calcium Values is Accounted for by Individual Variations in the Serum Albumin Concentration and Hydration Status
  • Measurement of the Total Serum Calcium Concentration Can Be Misleading, Since There Can Be a Discordance Between Total Serum Calcium Concentration and Ionized Calcium Concentration (J Clin Endocrinol Metab, 1978) [MEDLINE]
• Normal Range of Ionized Calcium Concentration (Adult): 1.16-1.31 mmol/L (4.65-5.25 mg/dL)
• When Albumin and Other Serum Protein Concentrations Vary Significantly, Total Serum Calcium Levels May Vary
  • However, the Ionized Calcium Concentration (Which is Hormonally Regulated by Parathyroid Hormone and Vitamin D) Remains Relatively Stable

Conditions Which Decrease the Total Serum Calcium Concentration, But Do Not Change the Ionized Calcium Concentration

• Hypoalbuminemia (see Hypoalbuminemia)
  • Total Serum Calcium Concentration Changes in Parallel to the Serum Albumin Concentration
    • In the Setting of Hypoalbuminemia (Due to Liver Disease, Renal Disease, etc), Total Serum Calcium Concentration Decreases
  • Historical Correction of Total Serum Calcium Concentration for Serum Albumin
    • Total Serum Calcium Decreases by Approximately 0.8 mg/dL (0.2 mmol/L) for Every 1.0 g/dL (10 g/L) Decrease in the Serum Albumin Concentration
    • Despite the Widespread Use of This Equation, the Accuracy of This Correction is Believed to Be Poor, Particularly in Patients with Critical Illness and Advanced Chronic Kidney Disease (Crit Care Med, 2003) [MEDLINE] (J Am Soc Nephrol, 2008) [MEDLINE] (Clin J Am Soc Nephrol, 2010) [MEDLINE] (Semin Dial, 2010) [MEDLINE] (Scand J Clin Lab Invest, 2017) [MEDLINE] (BMJ Open, 2018) [MEDLINE] (Clin Chem, 2018) [MEDLINE]
    • Poor Clinical Accuracy of This Equation May Be Explained by Metabolic Acidosis, Which Leads to an Underestimate of the Ionized Calcium Concentration
    • Some Studies Cite the Sensitivity of This Correction Equation at Only 5% (JPEN J Parenter Enteral Nutr, 2004) [MEDLINE]
  • More Modern Methods to Correct the Total Serum Calcium Concentration for Serum Albumin Have Not Been Widely Validated (and are Therefore, are Not Widely Used) (JPEN J Parenter Enteral Nutr, 2004) [MEDLINE] (Clin J Am Soc Nephrol, 2018) [MEDLINE] (J Appl Lab Med, 2020) [MEDLINE] (Clin Chim Acta, 2022) [MEDLINE]
  • Consequently, the Measurement of Ionized Calcium Remains the Gold Standard to Assess Calcium Status
  • If the Total Serum Calcium Concentration is Decreased, But the Ionized Calcium Concentration is Normal, This is Termed “Pseudohypocalcemia”

Conditions Which Increase the Total Serum Calcium Concentration, But Do Not Change the Ionized Calcium Concentration

• Hyperalbuminemia (see Hyperalbuminemia)
  • Total Serum Calcium Concentration Changes in Parallel to the Serum Albumin Concentration
    • In the Setting of Hyperalbuminemia (Due to Extracellular Volume Deplteion, Fluid Movement Out of the Vascular Space, High Protein Diet, etc), Total Serum Calcium Concentration Increases
  • If the Total Serum Calcium Concentration is Increased, But the Ionized Calcium Concentration is Normal, This is Termed “Pseudohypercalcemia”
• Multiple Myeloma (see Multiple Myeloma)
  • In Some Cases, a Monoclonal Myeloma Protein Can Bind to Calcium with High Affinity, Increasing the Total Serum Calcium Concentration
    • Since Multiple Myeloma Can Cause True Hypercalcemia Due to Osteolytic Bone Metastases, Measuring an Ionized Calcium is Nescssary to Aid in the Diagnosis This Entity
    • Hyperproteinemia Can Also Cause a Spurious Increase in Serum Phsophate Concentration (see Hyperphosphatemia) (BMJ, 1989) [MEDLINE]
      • Due to Interference with the Molybdate Assay Used to Measure the Serum Phosphate Concentration

Conditions Which Decrease the Ionized Calcium Concentration, But Do Not Change the Total Serum Calcium Concentration

• Acute Respiratory Alkalosis/Hyperventilation (see Acute Respiratory Alkalosis and Hyperventilation)
  • Mechanism
    • Alkalemia Increases the Calcium Binding to Albumin, Decreasing the Ionized Calcium Concentration (Eur J Clin Invest, 1982) [MEDLINE]
      • Decrease in Ionized Calcium Concentration is Approximately 0.16 mg/dL (0.04 mmol/L or 0.08 mEq/L) for Each 0.1 Unit Increase in the pH
  • Clinical
    • For This Reason, Hyperventilation with Acute Respiratory Alkalosis Can Result in Clinical Symptoms of Hypocalcemia (Such as Muscle Cramps, Paresthesias, Tetany, and Seizures)
    • Similarly, In Vitro Changes in the pH in Whole Blood or Serum Laboratory Specimens Can Result in Changes in the Ionized Calcium Concentration (Lab Med, 2002) [MEDLINE]
    • In the Setting of Chronic Kidney Disease (CKD) with Coexisting Underlying Hypocalcemia, Bicarbonate Therapy (or Dialysis) Can Increase the Serum pH, Resulting in a Decreased Ionized Calcium Concentration and Clinical Symptoms of Hypocalcemia (Am J Kidney Dis, 1997) [MEDLINE] (Nephron, 2001) [MEDLINE]
• Chronic Respiratory Alkalosis (see Acute Respiratory Alkalosis)
  • Mechanism
    • Although the Mechanism is Unclear, It Appears to Be Due to Relative Hypoparathyroidism and Renal Resistance to Parathyroid Hormone (PTH) with Resultant Hypercalciuria, Decreasing the Ionized Calcium Concentration (Kidney Int, 1992) [MEDLINE]
• Acute Hyperphosphatemia (Due to Cellular Breakdown with Phosphate Release) (see Hyperphosphatemia)
  • Mechanism
    • Released Phosphate Binds to Circulating Calcium, Decreasing the Ionized Calcium Concentration
      • In Addition, in a Short Period of Time, Calcium-Phosphate Precipitates and Deposits in Soft Tissues, Additionally Resulting in a Decreased Total Serum Calcium Concentration

Conditions Which Increase the Ionized Calcium Concentration, But Do Not Change the Total Serum Calcium Concentration

• Chronic Metabolic Acidosis (see Metabolic Acidosis-General) (J Am Soc Nephrol, 2008) [MEDLINE] (Clin J Am Soc Nephrol, 2010) [MEDLINE]
  • Mechanism
    • Acidemia Decreases Calcium Binding to Albumin, Increasing the Ionized Calcium Concentration
• Parathryoid Hormone (PTH)
  • Mechanism
    • Parathyroid Hormone Decreases Calcium Binding to Albumin, Increasing the Ionized Calcium Concentration (J Clin Endocrinol Metab, 1979) [MEDLINE]
      • However, Since Sensitivities of Total Serum Calcium Concentration and Ionized Calcium Concentration were the Same in the Diagnosis of Primary Hyperparathyrodism, the Effect of PTH on Protein Binding of Calcium May Not Have Clinical Significance (Clin Biochem, 2011) [MEDLINE]

Parathyroid Hormone-Related Related Protein (PTHrP)

Background Physiology of Parathyroid Hormone-Related Related Protein (PTHrP)

• Parathyroid Hormone-Related Related Protein (PTHrP) is a Normal Gene Product Expressed in a Wide Variety of Neuroendocrine, Epithelial, and Mesoderm-Derived Tissues
  • Thus, in Addition to Patients with Solid Tumors, Patient with Non-Hodgkin Lymphoma, Chronic Myeloid Leukemia (in Blast Phase) and Adult T Cell Leukemia Lymphoma May Have PTHrP-Induced Hypercalcemia
• PTHrP Has Some Sequence Homology with PTH (Particularly at the Amino-Terminal End, Where the First 13 Amino Acids are Almost Identical)
  • As a Result of This Close Homology with PTH, PTHrP binds to the same PTH-1 receptor as does PTH and thus activates Similar Postreceptor Pathways
  • This Accounts for the Ability of PTHrP to Simulate Some of the Same Actions as PTH
    • Increased Bone Resorption
    • Increased Distal Tubular Calcium Reabsorption
    • Inhibition of Proximal Tubular Phosphate Transport
  • Structural Divergence After the First 13 Amino Acids of the Parathyroid Hormone-Related Related Protein (PTHrP) Accounts for its Immunologic Distinctiveness from PTH
    • PTHrP is Less Likely Than PTH to Stimulate 1,25-Dihydroxyvitamin D Production (Although 1,25-Dihydroxyvitamin D Measurement in Patients with PTHrP-Mediated hypercalcemia May Be Variable)
  • In Patients with Humoral Hypercalcemia of Malignancy, There is an uncoupling of bone resorption and formation, which results in a large flux of calcium from bone into the circulation
  • In combination with the reduced ability of the kidney to clear calcium, this results in the striking hypercalcemia that occurs in Humoral Hypercalcemia of Malignancy
  • Thus, Hypercalcemia in Humoral Hypercalcemia of Malignancy is Predominantly Due to the Combined Effects of PTHrP on Kidney and Bone [8,19,26]

Frequency of Malignancies Associated with Parathyroid Hormone-Related Related Protein (PTHrP)

• Parathyroid Hormone-Related Related Protein (PTHrP)-Associated Hypercalcemia of Malignancy (i.e Humoral Hypercalcemia of Malignancy) is the Most Common Etiology of Hypercalcemia in Patients with Non-Metastatic Solid Tumors (and in Some Patients with Non-Hodgkin Lymphoma)
  • Humoral Hypercalcemia of Malignancy Accounts for Up to 80% of Cases with Hypercalcemia of Malignancy (Lancet, 1992) [MEDLINE] (J Clin Endocrinol Metab, 1994) [MEDLINE] (J Clin Endocrinol Metab, 2003) [MEDLINE]
  • Patients with Humoral Hypercalcemia Generally Have Advanced Disease and a Poor Prognosis (Cancer, 1994) [MEDLINE] (J Clin Endocrinol Metab, 1994) [MEDLINE] (Med Oncol, 2019) [MEDLINE]

Effects of Hypercalcemia on Cardiac Physiology

• Hypercalcemia Shortens the Duration of Plateau of the Cardiac Fiber Action Potential

Diagnosis Based on Parathyroid Hormone (PTH) Level

Normal-High Parathyroid Hormone (PTH) Level

• Parathyroid-Related Etiology
  • Normal-High 24 hr Urinary Calcium: suggests primary hyperparathyroidism
  • Low 24 hr Urinary Calcium: suggests benign familial hypercalcemia

Low Parathyroid Hormone (PTH) Level

• Drug-Induced Hypercalcemia
• Endocrine Disease
  • Adrenal Insufficiency
  • Hyperthyroidism
• Granulomatous Disease
  • Sarcoidosis
  • Tuberculosis
• Malignancy

General Comments

• Relationship of Symptoms to Calcium Level
  • Clinical Symptoms in Hypercalcemia are Related to the Calcium Level and the Rapidity of Increase in the Calcium Level

Cardiovascular Manifestations

• Arrhythmias
  • Clinical
    • Arrhythmias Can Occur at Calcium Levels 14-15
• Atrioventricular Heart Blocks
  • Epidemiology
    • Heart Blocks Predominantly Occur in the Setting of Severe Hypercalcemia
  • Clinical
    • First Degree Atrioventricular Block (see First Degree Atrioventricular Block)
    • Second Degree Atrioventricular Block-Mobitz Type I (Wenckebach) (see Second Degree Atrioventricular Block-Mobitz Type I)
    • Second Degree Atrioventricular Block-Mobitz Type II (see Second Degree Atrioventricular Block-Mobitz Type II)
    • Third Degree Atrioventricular Block (see Third Degree Atrioventricular Block)
• Increased Sensitivity to Digoxin(see Digoxin)
  • Clinical: enhanced digoxin toxicity
• Lengthened T-Wave Duration
  • Physiology
    • Serum Calcium is Positively Correlated with the T-Wave Duration
• Shortened Q-T Interval (see Shortened Q-T Interval)
  • Physiology
    • Serum Calcium is Negatively Correlated with the QT (and QTc) Interval Duration
• Sinus Bradycardia (see Sinus Bradycardia)
  • Epidemiology
    • Sinus Bradycardia Predominantly Occurs in the Setting of Severe Hypercalcemia

Gastrointestinal Manifestations

• Abdominal Pain (see Abdominal Pain)
• Acute Pancreatitis (see Acute Pancreatitis)
• Anorexia (see Anorexia)
• Constipation (see Nausea and Vomiting)
• Peptic Ulcer Disease (PUD) (see Peptic Ulcer Disease)

Neurologic Manifestations

• Fatigue (see Fatigue)
• Confusion/Delirium (see Delirium)
• Depression (see Depression)
• Increased Sleep Requirement/Coma (see Obtundation-Coma)
• Posterior Reversible Encephalopathy Syndrome (PRES) (see Posterior Reversible Encephalopathy Syndrome)
• Generalized Weakness (see Weakness)

Renal Manifestations

• Decreased Concentrating Ability/Polyuria (see Polyuria)
• Metastatic Calcification (see Metastatic Calcification)
• Nephrocalcinosis
• Nephrolithiasis (see Nephrolithiasis)

Normal Saline (see Normal Saline)

• Mechanism
  • Normal Saline Increases the Glomerular Filtration Rate and Decreases Distal Tubular Sodium and Calcium Absorption
    • Normal Saline Typically Lowers the Serum Calcium 1.5-2.5 mg/dL
• Dose: 3-4 L of normal saline per 24-48 hrs
• Onset of Action: hours
• Duration of Action: hours

Furosemide (Lasix) (see Furosemide)

• Mechanism
  • Furosemide Inhibits Sodium and Calcium Absorption in Thick Ascending Loop of Henle
• Dose: give only after intravenous fluid repletion
• Onset of Action: hours
• Duration of Action: hours

Calcitonin (see Calcitonin)

• Mechanism
  • Calcitonin Decreases Bone Calcium Release/increases Renal Excretion (Useful for Diseases Characterized by Increased Bone Turnover)
    • Calcitonin Typically Lowers the Serum Calcium About 1-2 mg/dL
• Dose: 4-8 μg/kg IM/SQ q6-8 hours
• Onset of Action: hours
• Duration of Action: transient (may be <24 hrs)

Pamidronate (see Pamidronate)

• Mechanism
  • Bisphosphonates Bind to Hydroxyapatite
• Dose: 60 mg IV over 4 hours
• Onset of Action: 1-2 days (peak in 7 days)
• Duration of Action : days-4 weeks
• Adverse Effects
  • Fever (see Fever)
  • Leukopenia (see Leukopenia)
  • Myalgias (see Myalgias)

Prednisone (see Corticosteroids)

• Indications Useful for Tumors/conditions Which Have 1,25-Vitamin D3 as Part of Their Mechanism)
  • Non-Hodgkin’s Lymphoma (see Lymphoma)
  • Multiple Myeloma (see Multiple Myeloma)
  • Breast Cancer (see Breast Cancer)
  • Vitamin D Toxicity (see Vitamin D)
  • Granulomatous Disease
• Mechanism
  • Prednisone Increases Calcium Excretion
• Dose
  • Prednisone: 40-100 mg/day in 4 divided doses x 3-5 days
  • Hydrocortisone: 100 q8hrs X 3-5 days
• Onset of Action: hours
• Duration of Action: days

Gallium Nitrate (see Gallium Nitrate)

• Mechanism
  • Gallium Nitrate Typically Lowers the Serum Calcium 1-5 mg/dL
• Dose: 200 mg/m2 per day IV for 5 days (continuous)
• Onset of Action: peaks at 8 days
• Duration of Action: days-weeks
• Adverse Effects: renal

Mithramycin (Plicamycin) (see Mithramycin)

• Mechanism
  • Mithramycin Inhibits Osteoclasts
    • Mithramycin Lowers the Serum Calcium 1-5 mg/dl
• Dose: 15-25 ug/kg IV over 4-6 hours q24-48 hours
• Onset of Action: 12 hours
• Duration of Action: days-weeks
• Adverse Effects
  • Bone Marrow Toxicity
  • Renal
  • Hepatic
  • Hypokalemia (see Hypokalemia)
  • Stomatitis
  • Nausea (see Nausea and Vomiting)

Hemodialysis with Low Calcium Dialysate (see Hemodialysis)

• Indications
  • Emergent Severe Hypercalcemia

Indomethacin/Aspirin (see Indomethacin and Acetylsalicylic Acid)

• Indications
  • Malignancy-Associated Hypercalcemia
    • Renal Cell Carcinoma (see Renal Cancer)
  • Humoral Hypercalcemia
  • Hypercalcemia with Osteolytic Lesions
• Mechanism
  • Indomethacin/Aspirin Inhibit Prostaglandin E Synthesis

Denosumab (Xgeva, Prolia) (see Denosumab)

• Indications
  • Hypercalcemia of Malignancy: Xgeva is FDA-approved for this indication