SEARCH RESULTS FOR: Hypomagnesemia

Approach to Arterial Blood Gases ABGs

Approach to Arterial Blood Gases (ABGs) Normal pO2 should be FiO2 x 4-5 (FiO2 in room air= 21%) pH >7.40 = Alkalemia 1. Adequate oxygenation? 2. Define the acid-base disturbance Diarrhea (Loss of electrolytes not reabsorbed through bowel) Normal ABG on Room Air = 7.40 / 40 / 90 / 24 pO2 ↓ than expected Possible hypoxemia See slide on Hypoxemia: Pathogenesis and Clinical Findings (pH) (Loss of acidic fluids from stomach) (HCO3-) (pCO2) (pO2) Renal Tubular Acidosis (RTA) pH <7.40 = Acidemia Metabolic derangement (Due to poisons, infection, or ketones) Gain of acid (H+) Brain unable to promote respiratory drive (ex. drugs, trauma) Inability for chest wall to expand (ex. obesity, neuromuscular weakness, pleural or chest wall abnormalities) Vomiting or nasogastric suction Impaired tubular transport of H+ (Due to loop/thiazide diuretics, hypomagnesemia, congenital abnormalities) 1o Hyperaldosteronism = ↑ H+ ion secretion at distal tubule (Due to tumours, congenital abnormalities , malignant hypertension, etc) Type II RTA = HCO3- not reabsorbed Type I or IV RTA = H+ not secreted GI or renal loss of HCO3- Hypoventilation ↑ CO2 from ↓ exhalation Respiratory Acidosis Acute= ↑10:↑1, Chronic= ↑10:↑3 GI or renal loss of acid (H+) ↑ HCO3- from ↓ H+ to bind with Metabolic Alkalosis ↑7:↑10 ↑ Ventilation from stress, trauma, infection ↓ CO2 from ↑ exhalation Respiratory Alkalosis Acute= ↓10:↓2, Chronic= ↓10:↓4 3. Identify the primary (1o) process 4. Compensatory mechanisms in lungs and kidneys attempt to lose/retain CO2 or HCO3- to maintain normal pH. Determine if compensation is appropriate (approximate normal ratio of change in pCO2 : HCO3- is shown in green boxes). If inappropriate, there is a secondary (2o) process occurring HCO3- binds with extra H+ ↓ HCO3- Metabolic Acidosis ↓12 :↓10 Less CO2 than expected, due to ↑ exhalation = Less acid in serum 2o Respiratory alkalosis More CO2 than expected, due to ↓ exhalation = More acid in serum 2o Respiratory acidosis Less HCO3- than expected, due to 2o gain of H+ or loss of HCO3- 2o Metabolic acidosis More HCO3- than expected, due to 2o loss of H+ 2o Metabolic alkalosis Less CO2 than expected, due to ↑ exhalation = Less acid in serum 2o Respiratory alkalosis ↑ CO2 than expected, due to ↓ exhalation = More acid in serum 2o Respiratory acidosis Less HCO3- than expected, due to 2o gain of H+ or loss of HCO3- 2o Metabolic acidosis More HCO3- than expected, due to 2o loss of H+ 2o Metabolic alkalosis 5. Calculate anion gap (AG) to determine the presence and type of metabolic acidosis. This is done regardlessofthe1o or2oprocess, as there may also be a hidden metabolic acidosis 6. HAGMA only: In normal blood buffer system, acid gain should match bicarbonate lost. If not, identify if another process is causing an inappropriate loss or gain of HCO3- Gain of acid (∆AG) = AG-12 LossofHCO3- (∆HCO3-)=24-HCO3- 7. Calculate Osmolar Gap (for HAGMA) or Urine net charge (for NAGMA) to narrow the etiology Authors: Sravya Kakumanu Reviewers: Huneza Nadeem, Ben Campbell *Adam Bass, *Yan Yu * MD at time of publication (normal is ~12) Calculate AG = Na+- Cl- - HCO3- If a metabolic acidosis is present, ↓ HCO3- is compensatedby↑otherserumanionstomaintain neutral charge If no metabolic acidosis was identified in steps 2-4: No Metabolic acidosis present Classically, the compensating anion is Cl-,maintaininganormalAG AG ≤ 12 If a 1o or 2o metabolic acidosis was identified in steps 2-4: Normal Anion Gap Metabolic Acidosis (NAGMA) In this scenario, a normal distal nephron should be excreting excess acid Excess acid is normally excreted as ammonium (NH +) with Cl- 4 The more Cl- in the urine relative to cations, the more acid is being excreted Calculate urine (U) net charge to determine cause of NAGMA = UNa+ + UK+ - UCl- When the cause is addition of an abnormal acid, HCO3- is used up asabuffer,andthecompensatinganionistheabnormalacid's conjugate base – which is not measured in the AG calculation ↓ HCO3- is compensated by unmeasured anionsà the AG ↑ AG>12 High Anion Gap Metabolic Acidosis (HAGMA) Calculate ∆AG = AG-12 Calculate ∆HCO3- = 24-HCO3- ∆HCO3- > ∆AG Loss of HCO3- > Gain of acid Additional process causing further loss of HCO3- HAGMA + NAGMA ∆HCO3- = ∆AG Loss of HCO3- = Gain of acid Only acid gain from HAGMA causing HCO3- loss HAGMA only ∆HCO3- < ∆AG Loss of HCO3- < Gain of acid Additional process causing gain of HCO3- despite losses due to HAGMA HAGMA + Metabolic alkalosis See slide on Metabolic Alkalosis: Pathogenesis -ve U net charge Appropriately large Cl- excretionà Toxic alcohol ingestion ↑ serum osmolality (and H+) from metabolites produced, so osmolality helps identify etiology Calculate osmolar gap to determine cause of HAGMA = (measured serum osm) – (expected serum osm) = (measured serum osm) – (2(Na+) + urea + serum glucose) +ve U net charge Inappropriately small Cl- excretionà impaired acid excretion is the issue Type IV or Type I RTA See slide on Normal Anion Gap Metabolic Acidosis: Pathogenesis and Laboratory Findings HCO3 GI losses or Type II RTA - loss is the issue Osmolar gap > 10 (extra osmoles present) Toxic alcohol poisoning Osmolar gap ≤10 (normal) Test for other causes See slide on High Anion Gap Metabolic Acidosis: Pathogenesis and Laboratory Findings Legend: Disease State Mechanism Lab Finding/Calculation Published January 29, 2023 on www.thecalgaryguide.com

Hypomagnesemia

Hypomagnesemia: Physiology Hyperglycemia An increased amount of glucose enters renal tubules as glomerulus performs blood filtration ↑ [Solute] in renal tubules from ↑ glucose content exerts osmotic force that pulls water & electrolytes, including Mg2+, into renal tubules ↑ Urinary Mg2+ excretion Lack of insulin Lack of insulin receptor signaling in distal convoluted tubule (DCT) ↓ glucose uptake from renal tubules Hypercalcemia Ca2+ binds to Ca2+ sensing receptors on thick ascending limb (TAL) of loop of Henle, where resorption of Ca2+ & Mg2+ occurs Receptor activation ↓ Na-K- 2Cl (NKCC) transporter activity which maintains electro- chemical gradient in TAL Passive paracellular resorption of Ca2+ and Mg2+, dependent on electrochemical gradient, ↓ ↑ Extra- cellular fluid ↓ Resorption of Na+ & H2O from renal tubules Genetic disorders (e.g. Bartter syndrome, familial hypomagnesemia) Medications (e.g. loop & thiazide diuretics, certain antibiotics, calcineurin inhibitors) Some metabolic byproducts of these drugs are nephrotoxic Inability to absorb free fatty acids (FFAs) Mg2+, which associates with FFAs, is not absorbed through the gut Steatorrhea (fat in the stool) Mal- absorption (often due to inflammation or infection) & diarrhea Acute pancreatitis ↓ Lipase secretion from pancreas ↑ levels of undigested fats in small intestine ↓ Passive Mg resorption from tubules Mg saponification in necrotic fat 2+ Varying mechanisms causing defective Mg2+ re-absorption (e.g. impacts to PCT, TAL, DCT disrupting transporters and ion shifting; ↓ gut resorption of Mg2+) Nutrients & 2+ electrolytes are lost in stool undergoes Renal loss of magnesium Gastrointestinal loss of magnesium Hypomagnesemia Serum [Mg2+] < 0.7 mmol/L Impairs production and release of parathyroid hormone responsible for ↑ blood Ca2+ Hypocalcemia Muscle cells are unable to activate Mg2+ dependent ATP hydrolysis Impairs muscle relaxation and reduces the ability to stop muscular contraction Lack of Ca2+ disrupts neurotransmitter release and neuronal signaling Impairs rapid depolarization and repolarization during muscle contraction Neuromuscular excitability (large, rapid change in membrane voltage due to small stimulus) Delirium Apathy QRS widening and peaking of T waves on ECG Torsade de Pointes Constant muscle contraction compresses blood vessels Reduced blood supply to hands, wrists, feet, and ankles Trousseau sign (carpopedal spasm with inflation of BP cuff) Authors: Caroline Kokorudz Reviewers: Shyla Bharadia Allesha Eman Michelle J. Chen Dr. Adam Bass* * MD at time of publication Chvostek sign (facial muscle twitch with cheek touch) Seizures Tetany Weakness Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Loop diuretics

Loop Diuretics: Mechanism & side effects Inhibit Na+/K+/2Cl- (NKCC) symporter at thick ascending limb of Loop of Henle (aLOH) Authors: Andrew Wu, Rafael Sanguinetti Reviewers: Luiza Radu, Adam Bass* * MD at time of publication Over-inhibition of ion symporter in ear at high concentrations Damage to tight junctions in the blood vessel epithelium in the ear Disruption of the blood- cochlear barrier Hearing loss Opening of ATP-sensitive K+ channels on pancreatic β- cells causes efflux of K+ ↓ Intracellular K+ causes a negative intracellular charge ↓ Ability for pancreatic β- cells to depolarize & release insulin Hyperglycemia (rare) Stimulation of prostaglandin E2 (PGE2) synthesis in the cortical & medullary aLOH Stimulation of endothelial nitric oxide synthase releases nitric oxide Systemic venodilation (dilation of veins) ↓ Systemic vascular resistance ↓ Blood pressure ↓ Na+ in renal interstitium ↓ Water reabsorption (water follows Na+) Interstitial washout (↑ NaCl & water wasting in interstitium) ↓ Sodium (Na+) reabsorption ↑ Positive luminal charge at thick aLOH ↓ Electrochemical gradient reduces cellular transport of cations ↓ Ca2+ & Mg2+ reabsorption in the aLOH Hypocalcaemia & hypomagnesemia ↑ Na+ delivery to the distal convoluted tubule (DCT) ↑ Intracellular Na+ at collecting duct ↑ K+ efflux via renal outer medullary potassium channel (ROMK) ↓ Fluid status ↓ Serum Na+ ↓Serum Cl- ↑ Luminal K+ at alpha intercalated cell Chemical gradient ↑ K+/H+ antiporter activity ↑ K+ excretion Hypokalemia Chemical gradient shifts K+ into cells creating a charge gradient to shift H+ out Hyponatremia Hypovolemia Hypochloremia ↓ Volume status activates angiotensin II, which plays a role in sodium and volume retention ↑ Na+/H+ antiporter 3 (NHE3) activity in the proximal tubule Kidneys excrete & conserve ions to preserve intracellular charge gradient ↑ H+ loss in the urine ↓ Serum H+ ↑ Proximal Na+ reabsorption causes ↑ urate reabsorption via urate-hydroxyl exchangers Hyperuricemia Contraction alkalosis (loss of Na+-rich, HCO3- low fluid) & hypokalemia ↑ Serum HCO3- Metabolic alkalosis (systemic pH > 7.45 due to metabolic process) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 18, 2024 on www.thecalgaryguide.com

Hypocalcemia Pathogenesis

Hypocalcemia: Pathogenesis Malnutrition ↓ Oral intake Acquired (e.g. neck surgery) Autoimmune (e.g., autoimmune polyglandular syndrome) Infiltrative (e.g., hemochro matosis, Wilson’s disease) Congenital (e.g., DiGeorge) Hypomagnesemia Magnesium is needed to produce PTH Malabsorption ↓ Small bowel surface area ↓ Absorption of 25-OH Vitamin D (calcidiol) ↓ Conversion of calcidiol to 1-25 (OH)2 Vitamin D (calcitriol) by 1-α- hydroxylase ↓ Calcitriol (impacts GI absorption of calcium) Chronic Renal Failure ↓ Renal parenchymal mass (site of 1-α- hydroxylase production) Vitamin D Dependent Type 1 Rickets Mutation in the gene that encodes 1-α- hydroxylase ↓ Sun exposure ↓ 1-α-hydroxylase Pancreatitis Destruction or atrophy of parathyroid gland ↓ Parathyroid hormone (PTH) Calcitriol resistance (e.g., Vitamin D Type 2 rickets) Inflammation of pancreas ↑ Release of lipase enzyme into serum ↑ Breakdown of fat by lipase ↑ Free fatty acids in serum ↑ Ca2+ binding to negatively charged tail of free fatty acids ↑ Parathyroid hormone (PTH) PTH resistance Genetic mutation causes body to not respond to PTH ↓ Renal calcium reabsorption ↑ Calcium excretion ↓ Osteoclast activity ↓ Calcium release from bone ↓ Action of PTH on intestinal cells ↓ Absorption of calcium in the small intestine ↑ Serum phosphate (PO4) (e.g. tumor lysis, rhabdomyolysis) ↑ Ca2+ binding to negatively charged PO4 ↑ Serum pH ↓ H+ in serum binding to proteins ↑ Ca2+ binding to proteins Calcium sequestration ↓ Absorption of calcium in the small intestine Hypocalcemia Author: Breanna Fang Reviewers: Gurreet Bhandal, Raafi Ali, Luiza Radu Samuel Fineblit* * MD at time of publication Serum calcium levels below 2.10mmol/L Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 22, 2024 on www.thecalgaryguide.com

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