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Hypocalcemia Physiology

Hypocalcemia: Physiology Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Authors: Serra Thai, Ryan Dion Reviewers: Jessica Hammal, Michelle J. Chen, Emily J. Doucette, Hanan Bassyouni* * MD at time of publication Parathyroid gland hypofunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge Syndrome) Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Systemic inflammation ↑ Calcium sequestration into cells (mechanism of action unknown) ↓ Liver function & albumin synthesis ↓ Or inappropriately normal parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↓ Albumin-bound calcium in blood ↓ PTHR signaling in kidneys ↓ PTHR signaling in osteoblastic lineage Vitamin D deficiency** (e.g. cells within bones ↓ intake, malabsorption) False hypocalcemia (↓ total serum calcium with normal Ca2+ levels) Acute pancreatitis** ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule Chronic kidney disease (CKD)** ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane proteins) expression in thick ascending limb (TAL) of the loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in distal convoluted tubule ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells Pancreatic enzymes are prematurely activated ↓ Sodium reabsorption triggers electrochemical gradient changes ↓ Glomerular filtration due to ↓ kidney function ↓ Activated vitamin D (calcitriol) synthesis Claudin14 binds cation channels composed of Claudin16 & 19 in TAL tight junctions Lipase released from pancreatic autodigestion breaks down peripancreatic fat ↓ Renal phosphate filtration from blood ↓ Binding of vitamin D regulated calcium transporters in duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions ↓ Probability of calcium transport channels opening ↓ Osteoclast differentiation (responsible for breaking down bone) Free fatty acids bind ionized Ca2+ to form insoluble calcium soaps (saponification) ↓ Circulating ionized calcium in blood ↑ Phosphate-calcium crystal formation ↓ Gastrointestinal ↓ Renal reabsorption ↓ Bone resorption of calcium of calcium reabsorption of calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 23, 2025 on www.thecalgaryguide.com Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen Emily J. Doucette Hanan Bassyouni* * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Chronic kidney disease (CKD) ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate-calcium complex formation **See corresponding Calgary Guide slide Legend: Pathophysiology Mechanism Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis** or severe illness Impaired Mg-dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (unknown mechanism of action) ↓ Liver function Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to active form) activity in kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Synthesis of activated vitamin D (calcitriol) Claudin14 binds to cation channels composed of Claudin16 & 19 found ↓ Binding of vitamin D in TAL tight junctions regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca & Mg transport from tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression & binding to receptors on osteoclast precursor cells ↓ Osteoclast differentiation (responsible for breaking down bone) ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Sign/Symptom/Lab Finding Complications Hypomagnesemia* Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↓ PTH receptor (PTHR) sensitivity Hypocalcemia: Physiology Authors: Serra Thai Ryan Dion Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness ↓ Parathyroid hormone (PTH) in circulation ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium *See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” ** See corresponding Calgary Guide slide: “Hypoca;cemia: Clinical Findings” Legend: ↑ Inflammation ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free (biologically active) Ca levels False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Hypocalcemia: Physiology Authors: Serra Thai Reviewers: Jessica Hammal Michelle J. Chen * MD at time of publication Parathyroid gland dysfunction from surgical removal, autoimmune disease, or congenital disease (e.g. DiGeorge) Hypomagnesemia** Pseudohypoparathyroidism (genetic resistance to PTH) Sepsis or severe illness Impaired magnesium- dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) in circulation ↓ PTH receptor (PTHR) sensitivity ↑ Ca sequestration into cells (unknown mechanism of action) ↓ Liver function ↓ Synthesis of albumin ↓ PTHR signaling in kidneys Vitamin D deficiency (e.g. ↓ intake, malabsorption) ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ 1-⍺ hydroxylase enzyme (converts inactive vitamin D to its active form) activity in the kidneys ↑ Claudin14 (tight junction membrane protein) proteins are expressed in the thick ascending loop of Henle ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule Chronic kidney disease ↓ Sodium reabsorption ↓ Synthesis of activated vitamin D (calcitriol) ↓ Renal blood flow Electrochemical gradient changes Claudin14 binds to cation channels composed of Claudin16 & 19 found in TAL tight junctions ↓ Glomerular filtration ↓ Phosphate excretion ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum Binding blocks paracellular Ca (and Mg) transport from the tubule into vasculature through tight junctions between cells ↓ Probability of calcium transport channels opening ↑ Phosphate-calcium complex formation ↓ Gastrointestinal reabsorption of Ca ↓ Renal reabsorption of calcium ↓ PTHR signaling in osteoblastic lineage cells in bones ↓ Nuclear factor kappa B ligand (RANKL) expression and binding to its receptors on osteoclast precursor cells ↓ Differentiation of osteoclasts which are responsible for breaking down (resorbing) bone ↓ Bone resorption ↓ Albumin- bound calcium with normal free Ca levels due to homeostatic mechanisms False hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2+] <2.1mmol/L+) Published MONTH, DAY, YEAR on www.thecalgaryguide.com **See corresponding Calgary Guide slide: “Hypomagnesemia: Physiology” Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Pseudohypoparathyroidism Sepsis/severe illness ↓PTHR activation in kidneys CKD ↓ Renal blood flow ↓ Glomerular filtration ↓ Sodium- hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation **See corresponding Calgary Guide slide(s) Legend: ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Pathophysiology Mechanism Sign/Symptom/Lab Finding Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Parathyroid hormone (PTH) ↑ Claudin14 (tight junction membrane protein) activity in the thick ascending loop of Henle ↑ Binding of claudin14 to claudin16 Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↑ Calcium sequestration ↓ Liver function into cells (mechanism of action ↓ Synthesis of albumin ↓ PTH receptor remains (PTHR) sensitivity ↓ Albumin- unknown) bound calcium with normal ↓ PTHR activation in bones free Ca levels due to homeostatic mechanisms ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Osteoblast stimulation ↓ Nuclear factor kappa b ligand (RANKL) secretion ↓ Nuclear factor kappa b receptor (RANK) binding on osteoclast precursors cells ↓Osteoclast production ↓ Bone resorption False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Complications Hypocalcemia: Physiology Hypomagnesemia** Authors: Serra Thai Pseudohypoparathyroidism Reviewers: Jessica Hammal * MD at time of publication Vitamin D deficiency: ↓ intake, malabsorption ↓ 1-alpha hydroxylase enzyme activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9k, PMCa2B, NCX2) in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) CKD ↓ Renal blood flow ↓ Glomerular filtration **See corresponding Calgary Guide slide(s) Legend: Sepsis/severe illness Impaired magnesium dependent generation of cyclic adenosine monophosphate ↑ Inflammation ↓ Signaling proteins ↓ Parathyroid hormone (PTH) ↓ PTH receptor (PTHR) sensitivity ↑ Calcium sequestration into cells (mechanism of action remains unknown) Pathophysiology Mechanism ↓PTHR1 activation in kidneys ↓ Activation of G- coupled protein signaling pathways ↑ Expression of sodium-phosphate co-transporters (NaPiIIa & NaPIIc) in proximal tubule ↓ Expression & phosphorylation of transient receptor potential vanilloid (TRPV5, calcium transporter channel) in distal convoluted tubule ↓ PTHR1 activation in bones ↓ Osteoblast ↑ Claudin14 (tight stimulation junction membrane protein) activity in the thick ascending loop of Henle ↓ Nuclear factor kappa b ligand (RANKL) secretion ↑ Binding of claudin14 to claudin16 ↓ Nuclear factor kappa b receptor Inhibition of (RANK) binding on osteoclast ↓ Phosphate excretion Electrochemical ↓ Amount of claudin 16 & 19 gradient TRPV5 & ↓ from forming precursors cells changes probability of cation-permeable channels pores in the tight ↑ Phosphate opening junctions calcium ↓Osteoclast production complex formation ↓ Paracellular transport of calcium ↓ Renal reabsorption of calcium ↓ Bone resorption Published MONTH, DAY, YEAR on www.thecalgaryguide.com ↓ Liver function ↓ Synthesis of albumin ↓ Albumin- bound calcium with normal free calcium levels due to homeostatic mechanisms False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Undigested fats in small intestine Free fatty acids percipitate calcium Hypocalcemia** (serum [Ca2 <2.1mmol/L+]) Sign/Symptom/Lab Finding Complications Hypocalcemia: Physiology Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity Vitamin D deficiency: ↓intake, malabsorption ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Authors: Serra Thai Reviewers: Jessica Hammal * MD at time of publication Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Vitamin D deficiency: ↓intake, malabsorption Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Hypomagnesemia** Impaired magnesium dependent generation of cyclic adenosine monophosphate ↓ Parathyroid hormone (PTH) ↓ PTH sensitivity ↓ Enzyme 1-alpha hydroxylase activity ↓ Synthesis of activated vitamin D (calcitriol) ↓ Binding of vitamin D regulated calcium transporters in the duodenum & jejunum ↓ Gastrointestinal reabsorption of calcium Legend: ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle Inhibition of claudin 16 & 19 from forming cation permeable pores in the tight junctions ↓ Transcription of calcium transporter genes in the distal convoluted tubule ↓ Probability of calcium transport channels opening ↓ Renal reabsorption of calcium ↓ Sodium-hydrogen exchanger 3 (NHE3) activity & expression in proximal tubule ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications ↑ Inflammation Sepsis/severe illness ↑ Calcium sequestration into cells ↓ Liver synthesis of albumin ↓ Albumin- calcium binding False Hypocalcemia Acute pancreatitis ↓ Lipase secretion from pancreas ↑ Levels of undigested fats in small intestine Free fatty acids percipitate calcium ↓ PTH receptor activation in bones ↓ Osteoblast stimulation ↓ RANKL ligand secretion ↓ RAANK receptor binding ↓Osteoclast production ↓ Bone resorption Hypocalcemia (serum [Ca2+] <2.1mmol/L) Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com Hypocalcemia: Physiology Chronic kidney disease ↓ Renal blood flow ↓ Glomerular filtration Parathyroid gland dysfunction: removal, autoimmune, congenital (DiGeorge) Vitamin D deficiency: ↓intake, malabsorption Sepsis/severe illness ↓ NHE3 activity and expression in proximal tubule ↓PTH receptor activation in kidneys ↑ Claudin14 activity in the thick ascending loop of Henle ↓ Parathyroid hormone (PTH) ↓ Transcription of calcium transporter genes (TRPV5, calbindin D28K, NCX) in the distal convoluted tubule ↓ Enzyme 1-alpha hydroxylase activity ↓ PTH receptor activation in bones ↓ osteoblast stimulation ↓ RANKL ligand secretion ↑ Inflammation ↓ PTH sensitivity ↓ Glomerular filtration ↓ Liver synthesis of serum albumin False Hypocalcemia ↑ Calcium sequestration into cells** ↓ Lipase secretion from pancreas Acute pancreatitis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding ↓ Albumin- bound calcium Current mechanism is unknown ↑ levels of undigested fats in small intestine Complications Hypomagnesemia Multiple blood transfusions ↓ Sodium reabsorption Electrochemical gradient changes ↓ Phosphate excretion ↑ Phosphate calcium complex formation Inhibits claudin16 and 19 from forming cation permeable pores in the tight junctions ↓Probability of calcium transport channels opening ↓ Synthesis of activated vitamin D (calcitriol) ↓ RAANK receptor binding ↓ Calcium reabsorption ↓ Binding of vitamin D regulated calcium transporters (TRPV6, calbindin9K, PMCa2B, NCX2) in the duodenum and jejunum ↓osteoclast production ↓ Bone resorption ↓ Serum calcium Hypocalcemia <2.1 mmol/L ↑ Precipitation of calcium by free fatty acids Authors: Name Name Name Name* Reviewers: Name Name Name Name* * MD at time of publication Published MONTH, DAY, YEAR on www.thecalgaryguide.com https://journals.physiology.org/doi/full/10.1152/physrev.00003.2004?rfr_dat=cr_pub++0pubmed&url_ver=Z39.88- 2003&rfr_id=ori%3Arid%3Acrossref.org – Calcium Absoprtion across Epithelia https://academic.oup.com/endo/article-abstract/137/1/13/2498579 - PTH and Calcium Signaling Pathways https://www.pnas.org/doi/10.1073/pnas.1616733114 - Information on Claudin 14 https://onlinelibrary-wiley-com.ezproxy.lib.ucalgary.ca/doi/full/10.1111/apha.13959 - effects of PTH on renal calcium and phosphate handling https://www.ncbi.nlm.nih.gov/books/NBK430912/ - Hypocalcemia overview + causes + pathophys https://www.orthobullets.com/basic-science/9010/bone-signaling-and-rankl - information about bone signaling https://www.sciencedirect.com/science/article/abs/pii/S0889852921000682?via%3Dihub – Calcium homeostasis article https://pubmed.ncbi.nlm.nih.gov/3012979/#:~:text=Abstract,intestine%2C%20require%20the%20parathyroid%20hormone. vitamin D metabolism and function – https://pmc.ncbi.nlm.nih.gov/articles/PMC2669834/#:~:text=Calcium%20is%20actively%20absorbed%20from,for%20proper %20mineralization%20of%20bone. – more vitamin D metabolism and specific receptors https://jidc.org/index.php/journal/article/view/32903236/2331 - sepsis + hypocalcemia