SEARCH RESULTS FOR: calcium

Nephrotic Syndrome: Pathogenesis and Clinical Findings

Destroys charge barrier to protein filtrationNephrotic Syndrome: Pathogenesis and Clinical FindingsAuthor: Yan YuReviewers:Alexander ArnoldDavid WaldnerSean SpenceStefan Mustata** MD at time of publicationLegend:Published August 19, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsExcessive (3.5g/day*? Ability of blood to retain fluids within vessels ? fluid leaks into extra-vascular spaceInjury to glomerular endothelium and epitheliumImmune complexes deposit into glomerulusDamaged glomerulus ? abnormally permeable to proteins within the blood ? plasma proteins are thus excessively filtered out? Oncotic pressure signals liver to ? albumin synthesis, only to have it filtered out by the kidneys? anabolic activity of liver ? ? lipoprotein synthesisHyperlipidemia*:(? serum LDL, VLDL, and TGs)Lipiduria(lipid/fatty casts; "Maltese cross" sign under polarized light)Since counter-balancing anticoagulant proteins are lost, clotting factors (i.e. 1, 7, 8, 10) now have more activityThrombo-embolic diseaseBlood becomes hyper-coagulable? Lipids are filtered into renal tubules, end up in urineMembranoproliferative Glomerulonephritis (MPGN)Lupus Glomerulonephritis Post-infectious GlomeruloneprhitisIgA NephropathyDamages podocytes on epithelial side of glomerulus ("podocyte effacement"; foot processes flattening)Diabetes MellitusChronic hyperglycemia damages glomeruliDeposition of Immunoglobulin light chains in glomerulusAmyloidosisAnasarca(If generalized)Peri-orbital edema (classic sign)Focal Segmental Glomerular Sclerosis (FSGS)Membranous GlomeruloneprhitisAntibodies attack podocytes, thickening glomerular basement membraneOverflow of immunoglobulin light chains into urine (More filtered than can be reabsorbed)Proteinuria >3.5g/day*The Anion Gap is mostly due to the negative charge of plasma albumin? Anion GapNotes: The four classic features (*) of Nephrotic Syndrome are PEAL (Proteinuria (>3.5 g/day), Edema, hypo-Albuminemia, and hyperLipidemia)For each 10 g/L drop in albumin below 40:Add 2.5 to the calculated anion gap (AG) to get the "correct" AG valueAdd 0.2 mmol/L to total calcium or get an ionized calcium, which is unaffected50% of serum Ca2+ is albumin-bound, so total serum calcium ? Serum total Ca2+ does not reflect ionized Ca2+ ? Blood oncotic pressure" title="Destroys charge barrier to protein filtrationNephrotic Syndrome: Pathogenesis and Clinical FindingsAuthor: Yan YuReviewers:Alexander ArnoldDavid WaldnerSean SpenceStefan Mustata** MD at time of publicationLegend:Published August 19, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsExcessive ("Nephrotic-range") loss of albumin in the urineHypo-albuminemia*Loss of anti-coagulant proteins (Antithrombin, Plasminogen, and proteins C and S) in urineMinimal Change Disease (MCD)"Underfill" edema*Proteinuria >3.5g/day*? Ability of blood to retain fluids within vessels ? fluid leaks into extra-vascular spaceInjury to glomerular endothelium and epitheliumImmune complexes deposit into glomerulusDamaged glomerulus ? abnormally permeable to proteins within the blood ? plasma proteins are thus excessively filtered out? Oncotic pressure signals liver to ? albumin synthesis, only to have it filtered out by the kidneys? anabolic activity of liver ? ? lipoprotein synthesisHyperlipidemia*:(? serum LDL, VLDL, and TGs)Lipiduria(lipid/fatty casts; "Maltese cross" sign under polarized light)Since counter-balancing anticoagulant proteins are lost, clotting factors (i.e. 1, 7, 8, 10) now have more activityThrombo-embolic diseaseBlood becomes hyper-coagulable? Lipids are filtered into renal tubules, end up in urineMembranoproliferative Glomerulonephritis (MPGN)Lupus Glomerulonephritis Post-infectious GlomeruloneprhitisIgA NephropathyDamages podocytes on epithelial side of glomerulus ("podocyte effacement"; foot processes flattening)Diabetes MellitusChronic hyperglycemia damages glomeruliDeposition of Immunoglobulin light chains in glomerulusAmyloidosisAnasarca(If generalized)Peri-orbital edema (classic sign)Focal Segmental Glomerular Sclerosis (FSGS)Membranous GlomeruloneprhitisAntibodies attack podocytes, thickening glomerular basement membraneOverflow of immunoglobulin light chains into urine (More filtered than can be reabsorbed)Proteinuria >3.5g/day*The Anion Gap is mostly due to the negative charge of plasma albumin? Anion GapNotes: The four classic features (*) of Nephrotic Syndrome are PEAL (Proteinuria (>3.5 g/day), Edema, hypo-Albuminemia, and hyperLipidemia)For each 10 g/L drop in albumin below 40:Add 2.5 to the calculated anion gap (AG) to get the "correct" AG valueAdd 0.2 mmol/L to total calcium or get an ionized calcium, which is unaffected50% of serum Ca2+ is albumin-bound, so total serum calcium ? Serum total Ca2+ does not reflect ionized Ca2+ ? Blood oncotic pressure" />

Hypercalcemia - Clinical Findings

Yu, Yan - Hypercalcemia - Clinical Findings - FINAL.pptx Hypercalcemia: Clinical FindingsAuthor: Yan YuReviewers:David WaldnerSean SpenceGreg Kline** MD at time of publicationLegend:Published May 7, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsHypercalcemia(serum [Ca2+] > 2.5mmol/L)Na+ channels on neuronal membranes become more resistant to opening (resists Na+ influx)Cognitive dysfunctionIf precipitation occurs in the urinary tract...Fatigue? contractility of GI tract smooth muscle? K+ movement out of TAL epithelial cells into the tubule lumen Alters charge balance across the cell membraneCa2+ precipitates with PO43- throughout the bodyDetected by the Ca-Sensing-Receptor (CaSR) on Thick Ascending Limb (TAL) epithelial cells? neuronal action potential generationSluggish neuronal activity...? appetiteConstipationFlank painInhibit insertion of Renal Outer Medullary K+ (ROMK) channels on TAL's luminal membrane? K+ in TAL lumen to drive Na+/Cl- reabsorption through the Na-K-Cl Cotransporter (NKCC)? Na/Cl in tubule lumen ? osmotically draws water into lumen? drinking (polydipsia)? Urine volume (polyuria)Rationale for the CaSR-pathway: ECF has enough Ca2+, no need for more K+ to be excreted into the tubule lumen to create a more + charge there that drives Ca2+ reabsorptionBehavior compensates to prevent dehydrationKidney stones (nephrolithiasis)Constantly feeling full because of reduced GI motilityCa2+ directly inhibits the insertion of aquaporin channels in the collecting duct membraneLess water reabsorbed into the renal vasculatureMore water remains in the tubule filtrateMuscle Weakness...in central nervous system:...at neuromuscular junction:A rhyme to help you recall the manifestations of one specific cause of hypercalcemia, primary hyperparathyroidism:Bones (Calcium levels are high often due to ? resorption from bones)Stones (? Calcium-containing kidney stones)Groans (GI and skeletal muscle issues) Psychic Moans (Cognitive dysfunction from neuronal disturbances)Note: sick/ICU patients have ? serum albumin, due to ? synthesis from a sick liver. Their lab Ca2+ values can be

Chondrocalcinosis Calcium Pyrophosphate Dihydrate Deposition Disease

Lung cancer clinical findings and paraneoplastic syndromes

Lung cancer: clinical findings and paraneoplastic syndromes Note: most presentations of lung cancer are very subtle with non-specific symptoms and signs (i.e. fever, weight loss, general malaise) Obstruction of proximal airway Inability to clear inhaled pathogens Postobstructive pneumonia Cough, fever, dyspnea Local tumor growth Spread of tumor to pleural surface Chest Pleural discomfort effusion • Obstruction or compression at local site Uncontrolled abnormal cell growth in one or both lungs 4 Lung Cancer Airway invasion Hemoptysis Lambert-Eaton syndrome (Production of auto-antibodies against Calcium channels) Muscle weakness I` effort to Compression at the Compression Superior vena ventilate the laryngeal nerve of brachial cava lungs nerve plexus compression Impaired innervation to the vocal cords Dyspnea Shortness of Arm/shoulder/ Face/arm breath Voice hoarseness neck pain edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Authors: Yoyo Chan Reviewers: Midas (Kening) Kang Usama Malik Leila Barss* * MD at time of publication Tumor secretes biologically active substances Paraneoplastic Syndromes 4 Associated symptoms with malignant diseases TGF131 extracellular matrix protein Fingers clubbing PTHrP T calcium release from bones Hypercalcemia Serum calcium >2.6 mmol/L ADH 1 SIADH T water reabsorption 1 Hyponatremia Serum sodium <135mEq/L Abbreviations: • ACTH: Adrenocorticotropic hormone • ADH: Anti-diuretic hormone • PTHrP: Parathyroid hormone-related protein • SIADH: Syndrome of inappropriate antidiuretic hormone production • TGFI31: Transforming growth factor beta 1 1` ACTH cortisol release and production Cushing's syndrome (symptoms and signs caused by prolonged cortisol exposure) Muscle weakness, hyperglycemia, severe hypokalemia

Celiac Disease: Complications

Celiac Disease: Complications Autoimmune response to dietary gluten in genetically predisposed individuals 4 Celiac Disease Note: most common presentation with minor symptoms and iron deficiency Modified gluten peptides activates HLA-DQ2 and DQ8 receptors on T cells Activation of B cells to produce anti-tTG2 autoantibodies 1 tanti-tTG2 Release of pro-inflammatory cytokines Villous Atrophy along duodenum and/or jejunum Loss of brush border Loss of enterokinase Defective mucosal barrier enzyme (failure to produce trypsin) Carbohydrate Protein Fat Secretory maldigestion maldigestion malabsorption diarrhea Legend: Fermentation by gut bacteria 1 Gas production Bloating Fat retained in stool Steatorrhea Abdominal pain Pathophysiology Mechanism Sign/Symptom/Lab Finding Growth Retardation Authors: Yoyo Chan Reviewers: Peter Bishay Usama Malik Sylvain Coderre* * MD at time of publication IgA response Autoimmune IgA deposits Lymphocyte response in sub-epidermal skin layer against enamel Dermatitis Herpetiformis (Chronic pruritic blisters) Nutritional deficiency Dental enamel hypoplasia Vitamin D and calcium deficiency Zinc, selenium Folate Iron Osteoporosis deficiency deficiency deficiency Anemia t Risk of miscarriages

Neuromuscular Junction (NMJ)- Physiology and pharmacology

Neuromuscular Junction (NMJ)- Physiology and pharmacology calcium ion ions voltage gated ca2+ channels acetylcholine ACh receptors nicotinic SNARE protein complex AChR receptor sodium muscle specific kinase action potential voltage gated Ca2+ channels activated release presynaptic terminal binds

Crohn's Disease

Inflammatory Bowel Disease: Clinical findings in Crohn’s Disease Authors: Yan Yu Amy Maghera Reviewers: Jennifer Au Danny Guo Jason Baserman Jessica Tjong Kerri Novak* * MD at time of publication Behavioural Factors: Smoking, over-sanitation Genetic Susceptibility Environmental Factors Diet, bacteria/viruses, drugs, vitamin D Systemic immune response primarily against the GI tract. (Unclear mechanism, mediated by cytokine release and neutrophil inflammation) Inflammation of the GI tract lining - Inflammation is “transmural”, spanning the entire thickness of the intestinal wall from luminal mucosa to the serosa. - The inflammation occurs anywhere in the GI tract from the oral mucosa to the anal mucosa (from ‘gums to bum’) in skip lesion pattern. Atrophy, scarring of the intestinal villi Inflammatory cytokines destroy the mucosa epithelial cells of the GI tract wall, causing cell apoptosis and ulceration ↑ permeability of the blood vessels supplying the GI tract wall Chronic inflammation impairs healing responses Dysregulated wound healingàexcess extracellular matrix deposition Fibrosis leads to scar tissue and thickening of all layers of the GI tract Strictures Inflammation is systemic, affecting: Joints Arthropathy Erythema Impaired absorption of nutrients Weight loss Prolonged GI bleeding Anemia Transporter proteins responsible for Na+ reabsorption gradually disappear from the epithelium More sodium (and thus water) is retained in the GI tract lumen Microperforations can penetrate through the intestinal wall Anal fistulae (“holes” connecting the anus to the skin, bladder, peritoneum, small bowel, etc.) Continued inflammation and/or infection can lead to: Leakage of fluid out of capillaries into the GI tract Luminal edema and swelling Narrowing of GI lumenàbowel obstruction Skin Mouth Eyes Liver nodosum, pyoderma gangreno- sum >5 canker sores Uveitis Iritis, scleritis Sclerosing cholangitis ↓ fat absorption Fatty acids (negatively charged) bind Ca2+, freeing oxalate from Ca2+ ↑ oxalate absorbed into blood & filtered by kidney Calcium oxalate kidney stones Diarrhea Abdominal cramping and pain (see Bowel Obstruction page for full mechanism Anal abscesses Inflammatory masses Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published June 15, 2019 on www.thecalgaryguide.com

Multiple-Myeloma

Multiple Myeloma: Pathogenesis and clinical findings Plasma cell populations in the body normally produce non-clonal (a diverse array of) immunoglobulins Normal SPEP: no spike in the gamma (γ) region Notes: • MGUSismuchmorecommon than MM! • “Plasmacell”:Blymphocytes that produce antibodies/ immunoglobulins Stimulation by specific antigens Genetic changes/mutations accumulate over time in one type of plasma cell Abbreviations/Definitions: • SPEP - Serum Protein Electrophoresis • Ig – Immunoglobulin • Monoclonal – “of one specific genetic strain or subtype” One type of plasma cell starts to proliferate abnormally Monoclonal Gammopathy of Undetermined Significance (MGUS) (Premalignant, mild monoclonal plasma cell proliferation; asymptomatic) In 1-2% of cases, further cytogenetic changes over time stimulate further proliferation of this plasma cell line Multiple Myeloma (MM) (extensive monoclonal B lymphocyte proliferation, causing end organ damage) Slightly more monoclonal plasma cells will produce slightly more monoclonal Immunoglobulins Small spike in the gamma (γ) region of the SPEP (less prominent compared to the spike in MM) More monoclonal plasma cells result in far greater amounts of monoclonal immunoglobulins being secreted Large spike in gamma (γ) region of the SPEP Ig light chains accumulate in the tubules of kidney nephrons Light chain casts obstruct tubules Renal Insufficiency (↓GFR) Osteoblasts ↑ expression of RANK-ligand (RANKL, an apoptosis regulator), and ↓ expression of Osteoprotegerin (OPG, a decoy receptor for RANKL) ↑ osteoclast activity vs osteoblast activityàbone loss Clonal plasma cells overrun normal bone marrow, crowding out production of red blood cells, ↓ red blood cell counts Anemia Authors: Tristan Jones, Tyler Anker, Yan Yu Reviewers: Jennifer Au, Crystal Liu, Man- Chiu Poon*, Lynn Savoie* * MD at time of publication Damaged bones hurt, & become more brittle Bony pain, pathologic fractures Osteolytic bone lesions Osteoclasts release calcium from bone and into blood Hypercalcemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 12, 2020 on www.thecalgaryguide.com

Pseudogout

Pseudogout: Pathogenesis and clinical findings Authors: Usama Malik Yan Yu* Reviewers: Jennifer Au Stephanie Nguyen Martin Atkinson* * MD at time of publication Familial chondrocalcinosis Overactivity of the NTPPPH enzyme and mutations in the ANKH gene,↑ pyrophosphate production Hyperparathyroidism ↑ levels of parathyroid hormone produced, ↑ gut Ca2+ absorption Hemochromatosis Clearance of calcium pyrophosphate dihydrate (CPPD) crystals from joints is inhibited by iron Hypomagnesia The relative absence of magnesium impairs pyrophosphatase activity, reduces pyrophosphate breakdown Hypophosphatasia Defective mineralization of calcium and phosphorous in bones Idiopathic (vast majority of cases) Mechanism unknown ↑ serum concentrations of Ca2+ or Pyrophosphate Enhanced mineralization in chondrocytes (cells that make cartilage) Abbreviations • NTPPPH nucleoside triphosphate pyrophosphohydrolase • CPPD – Calcium Pyrophosphate Dihydrate Notes: • There are different types of calcium pyrophosphate crystal deposition (CPPD) disease. This slide only covers “pseudogout”. • Pyrophosphate (PPi) = 2 phosphate molecules = P2O74− • Pyrophosphate is made from the breakdown of Adenosine triphosphate (ATP): ATP -> AMP + PPi Once in cartilage, high levels of either calcium ions or pyrophosphate can result in them binding together, forming CPPD crystals Aggregated CPPD crystals shed into synovial fluid Neutrophils enter joint to phagocytose the crystals and release pyrophosphatase enzyme Repeated crystal precipitation into joint space over time (subacute process) CPPD crystals collect on collagen fibers in articular cartilage Chondrocalcinosis, seen on high-resolution ultrasound and/or x-ray CPPD crystals exhibit unique properties on polarizing microscopy Inflammatory cascade Positively birefringent (crystals appear blue parallel to axis of polarizer) PAINFUL, warm, swollen joint (sudden onset) ↑ C-reactive protein (CRP); erythrocyte sedimentation rate (ESR) Knees and wrist subjected to more trauma over a person’s lifetime Knee > Wrist >>> any other joint affected Wearing down of joint cartilage over time Rapidly progressive osteoarthritis (see osteoarthritis slide) Subchondral sclerosis & cysts, joint space narrowing, and osteophytes seen on x-ray bone loss, hemarthrosis Nerve damage over time “Charcot-like” joint: severe weightbearing to areas that joint destruction/deformity, Painless joint Lack of sensation can cause tolerate it poorly Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 16, 2020 on www.thecalgaryguide.com

GI-changes-during-pregnancy

Physiologic Changes in Pregnancy: Gastrointestinal (GI) Tract Pregnancyàhormonal and physical changes in the body Mechanisms poorly understood ↑ human chorionic ↑ estrogen ↑ progesterone gonadotropin (hCG) ↑ uterus size Uterus rises into abdominal cavity ↑ intra-gastric pressure ↑ backup of stomach contents Nausea & vomiting In the extreme case: Hyperemesis gravidarum (extreme vomiting causing weight loss, dehydration, ketosis) Liver displaced upwards Liver edge generally not palpable on exam ↑ blood pressure in veins within the abdomen Veins around rectum & anus stretch under pressure ↑ blood flow to the gum tissue ↑ tendency for gingival bleeding & ulceration Gingivitis ↑ neo- vascularization in lesions on skin Pyogenic granuloma of pregnancy (shiny red papule with a raspberry-like surface) Mechanism poorly understood Ptyalism (excessive salivation) Difficulty swallowing excess saliva ↑ gallbladder stasis Biliary sludge given time to solidify within gallbladder Gallstones ↓ mobilization of intracellular calcium within smooth muscle cells Smooth muscle relaxation in tissues such as the gallbladder & GI tract Changes in taste perception Dysgeusia Cultural influences and psychological factors Change in diet and dietary cravings ↓ lower esophageal sphincter tone Retrograde transport of gastric contents into esophagus Gastroesophageal reflux ↓ GI motility Delayed gastric and intestinal emptying Stool builds up in colon, and hardens as water is resorbed Constipation Pooling of blood within rectal veins àvenous thrombosis Hemorrhoids Fragile veins, more easily torn Rectal bleeding Change in gut microbiome Authors: Simonne Horwitz, Yan Yu* Reviewers: Claire Lothian, Crystal Liu, Ronald Cusano* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 29, 2020 on www.thecalgaryguide.com

Placenta-Previa

Placenta Previa: Pathogenesis and Clinical Findings Authors: Wendy Yao, Yan Yu* Reviewers: Danielle Chang, Crystal Liu, Aysah Amath* * MD at time of publication Note on Physical Exam: • Do not perform bimanual exam during vaginal bleed until placenta previa is ruled out (2nd trimester onwards) • If patient presents with bleeding, a pelvic exam = risk of damaging placentaàmore bleeding • Use transvaginal ultrasound to confirm location of placenta Previous C/S Multiple gestation Maternal smoking Placenta Previa Presence of placental tissue that extends over the internal cervical os. (Pathogenesis unknown; preceding textboxes are risk factors only) Previous placenta previa Increased maternal age Increased parity Total placenta previa Placenta completely covers the cervix Partial placenta previa Placenta covers cervix partially Marginal placenta previa Placenta near the edge of the cervix Diagnosed early in pregnancy on routine abdominal ultrasound at 18-20 weeks Stretching of lower segment of uterus during 3rd trimester OR Alternate scenario: One scenario: This stretching elongates the space between the cervix and the placenta, relocating the stationary lower edge of the placenta away from the cervical os Placenta previa resolves on its own Reassuring: Placenta >2cm from cervical os on ultrasound This stretching fails to move the placental away from the cervical os Previa persists as uterus changes in preparation for labour: Thinning of the lower segment of the uterus Uterine contractions Shearing forces to the placental attachment site Painless bright red vaginal bleeding (90%) ↑ risk of clinically significant hemorrhage Cervix becomes thinner (effaced) and opens (dilates) Bleeding limits oxygen delivery to placenta, injuring placental tissue Tissue injuryàActivates intracellular G-protein signalling pathways Release of stored intracellular calcium àmyometrial contraction Uterine contraction and bleeding (10%) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 2, 2020 on www.thecalgaryguide.com

Anesthetic-Considerations-Aortic-Stenosis

Anesthetic Considerations: Hemodynamic Goals (“CRRAP Goals”) for Patients with Aortic Stenosis Undergoing Non-Cardiac Surgery CRRAP Goals: Contractility, Rate, Rhythm, Afterload, Preload Pathophysiology Driving Anesthetic Management Hemodynamic Anesthetic Intervention (CRRAP) Goals Author: Ryan Brenneis Reviewers: Stephen Chrusch Hannah Yaphe Yan Yu* Karl Darcus* * MD at time of publication Aortic stenosis = Narrow aortic valve opening Notes: -Cardiac Output = Heart Rate x Stroke Volume -Stroke volume has 3 determinates: 1. Contractility 2. Afterload 3. Preload If the patient’s heart cannot ↑ contractility to maintain cardiac output... ↑ resistance to forward blood flow àheart must ↑ its contractility (↑ the forcefulness of its contractions) to overcome this resistance Applying ↑ force over time causes left ventricle to undergo concentric hypertrophy Contractility deteriorates over time Heart rate must compensate for maintaining cardiac output Coronary Perfusion Pressure = Diastolic BP (DBP) – Left Ventricular End Diastolic Pressure (LVEDP) ↑ cardiac muscle massà↑ myocardial metabolism and oxygen demand ↑ left ventricular wall stiffnessà↓ LV filling while relaxed (diastolic dysfunction) Intraoperative ↓ in contractility compromises cardiac output Bradycardia ↓ cardiac output Tachycardia ↓ filling time of left ventricle (↓ preload) Coronary perfusion occurs during diastole Coronaries require a high DBP to maintain perfusion Tachycardia ↓ perfusion time Hypotension ↓ coronary perfusion pressure Possible myocardial ischemiaà ↓ blood pumped into vessels 40% of LV preload supplied from atrial kick Loss of atrial kick with arrhythmias à↓ cardiac output Note: Aortic stenosis severity (see slide on aortic stenosis) and the type/risk of surgery guide the hemodynamic consequences and need for intervention Adequate intravascular volume required to passively fill stiff ventricle Contractility ↓ use of negative inotropic Maintain drugs, e.g. calcium channel contractility blockers (“Inotrope”: drug that alters heart’s contractility) Rate Keep heart rate above 60 bpm Keep heart rate below 80 bpm Consider transcutaneous pacing, anticholinergics, & sympathetic agonists ↑ anesthetic depth, consider beta blocker (e.g. Esmolol) Afterload Maintain a Mean Arterial Pressure >70mmHg Consider sympathomimetic drugs to treat hypotension Monitor blood pressure closely via arterial line Consider increasing anesthetic depth for severe hypertension Rhythm Maintain Sinus Rhythm Consider presurgical placement of defibrillator pads & crash cart Amiodarone ready & available during operation, to terminate any arrhythmias Preload Maintain Euvolemia Possible use of transesophageal echo to monitor preload Ensure adequate venous access- consider central venous catheter and large bore IV’s Legend: Pathophysiology Mechanism Goal Anesthetic Intervention Published October 25, 2020 on www.thecalgaryguide.com

Tumour-Lysis-Syndrome

Tumour Lysis Syndrome High sensitivity to treatment Highly proliferative malignancy with ↑cell-turnover Large tumour mass Author: Joshua Yu Reviewers: Hannah Yaphe Davis Maclean Tejeswin Sharma Yan Yu* *Peter Duggan *ManChiu Poon *Lynn Savoie *Juliya Hemmett * MD at time of publication High serum phosphate High serum Advanced uric acid Age Volume depletion Pre-existing renal disease Patient risk factors Initiation of cancer treatment Massive tumour cell lysis and release of cellular contents into circulation overwhelms homeostatic mechanisms Tumour properties (hematologic malignancies most common) Though rare, aggressive tumours can spontaneously lyse without treatment Intracellular potassium released into bloodstream Intracellular phosphate released Hyperphosphatemia ↑ serum phosphate Intracellular lactate dehydrogenase (LDH) released ↑ serum LDH Intracellular nucleic acids released Nucleic acids metabolized to uric acid Hyperuricemia ↑ serum uric acid Hyperkalemia ↑ serum potassium (see Hyperkalemia: clinical findings) Uric acid (a crystallizing substance) ↑ precipitation of calcium phosphate ↑ filtration of poorly soluble uric acid into acidic environment of renal tubules Serum phosphate binds serum calcium, forming solid calcium phosphate precipitate crystals High levels of calcium phosphate ↑ uric acid precipitation Uric acid precipitates as crystals and deposits in kidney tubules and collecting ducts Tubular injury and/or intraluminal obstruction Endothelial dysfunction in renal vasculature Renal inflammation, vasoconstriction, and impaired renal vascular autoregulation Decreased renal filtration Acute Kidney Injury (see Acute Kidney Injury Overview) Crystal deposition in the heart Depletion of soluble calcium Hypocalcemia Calcium phosphate crystals deposit in kidneys Main mechanism of Acute Kidney Injury Cardiac Arrythmias ↓ serum calcium (see Hypocalcemia: clinical findings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 25, 2020 on www.thecalgaryguide.com

Calcium-Oxalate-Kidney-Stones

generalized-absence-seizures-petit-mal

Typical Absence (Petit Mal) Seizure Hyperventilation: A common trigger of absence seizures in pediatric patients with existing absence seizures ↑ respirationà↑ CO2 expelled from body & blood ↓ acidic CO2 levels in bloodà↑ blood pH (↓ blood acidity) Predisposes neurons to fire spontaneously and asynchronouslyà↓ seizure threshold Pathogenesis of absence seizure is complex and not yet fully elucidated, but evidence supports the cortical focus theory: Hyperexcitable focal neurons on cerebral cortex send activation signals down to thalamocortical neuron network Activated neurons in thalamus interact with cortical neurons to produce rhythmic oscillatory neuronal firing (brain waves) between these two regions of the brain Abnormal rhythmic and bilaterally synchronous activation of the cerebral cortex during wakefulness Between seizures (inter-ictal) Inter-ictal changes in neuronal firing patterns and connectivity in sensorimotor cortices (mechanism unclear) First degree relative with absence epilepsy Genetic predisposition/idiopathic (>90%) No single identified cause such as a structural lesion or single genetic mutation Multiple gene mutations that predispose to epilepsy when occurring together Authors: Alyssa Federico, Davis Maclean, Erika Russell, Harjot Atwal Reviewers: Ario Mirian, Shaily Singh*, Kim Smyth*, Yan Yu* * MD at time of publication Monogenetic mutation (<10%) Single gene mutation predisposing to epilepsy Mutations involve genes encoding voltage-gated calcium channels and gamma aminobutyric acid (GABA) receptors, which are important in regulating thalamocortical activity Absence Seizure: Brief lapse of consciousness with a vacant stare lasting 3-10 seconds, without convulsions or loss of motor tone. May occur up to 100 times per day. Seizure features (ictal phase) Absence seizures generally occur in the context of an epilepsy syndrome and present in childhood Childhood absence epilepsy: Most common form of pediatric epilepsy, characterized by absence seizures Juvenile absence epilepsy: Characterized by absence seizures +/- generalized tonic-clonic seizures Juvenile myoclonic epilepsy: Characterized by myoclonic seizures +/- absence seizures Post-seizure (post-ictal) Mechanisms unclear Consciousness regained immediately after seizure No post-ictal symptoms No memory of event Neuropsychiatric symptoms (poor attention, memory, mood, cognition) seen in 60% of children Smooth/rapid transition to seizure No aura (warning sign) prior to seizures Seizure activity directly or indirectly impairs communication between neural networksà alters activity of brain structures involved in maintaining awareness Some simple response to internal or external stimuli may remain intact (mechanisms unclear) Automatisms: Eye movements (fluttering), oral (lip smacking, swallowing, chewing), manual (finger tapping, scratching) Brain wave oscillations generated in the thalamus EEG findings: Generalized 3 Hz spike-wave activity with maximum amplitude in both frontal lobes Impaired awareness Inhibition of response to external stimuli Impaired school performance and social interactions Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 2, 2021 on www.thecalgaryguide.com

Lambert-Eaton-Myasthenic-Syndrome-Pathogenesis-and-Clinical-Findings

Lambert-Eaton Myasthenic Syndrome: Pathogenesis and Clinical Findings Authors: Alexandros Mouratidis Dmitriy Matveychuk Ario Mirian Reviewers: Austin Laing Davis Maclean Michal Krawcyzk Harjot Atwal Chris White* Yan Yu* * MD at time of publication Acquired autoimmunity: mechanism unknown, possibly associated with other autoimmune diseases A paraneoplastic syndrome of small cell lung cancer (SCLC) in >50% of patients Tumour membrane expresses voltage-gated calcium channels (VGCCs), which normally exist on neurons and function in neurotransmission Note: A paraneoplastic syndrome is a condition that arises due to cancer elsewhere in the body; possibly an immune response against tumour cells Positive anti-VGCC IgG on serology ↓ Stimulation of salivary glands à↓ production of saliva ↓ Nitric oxide & prostaglandin production by cavernosal endothelial cellsàImpaired vasodilation of penile arteries ↓ Acetylcholine-induced gastric motility ↓ Acetylcholine available to mediate muscle reflexes ↑ Variability in action potential initiation along muscle fibers Immune response to foreign cancer cells triggers production of antibodies against VGCCs on the cell surfaces of presynaptic neurons Antibodies bind VGCCs, blocking Ca2+ Antibodies bind, cross-link, and from entering presynaptic neurons ↓ Ca2+ influx into the presynaptic neuron during its depolarization internalize VGCCsà↓ VGCC on neuron surface Xerostomia (dry mouth) Erectile dysfunction Constipation ↓ Deep tendon reflexes Unstable motor unit action potentials on electromyography ↓ Baseline compound muscle action potentials (CMAPs: summated action potentials of all motor endplates in one muscle) on nerve conduction studies Since intracellular Ca2+ mediates neurotransmitter vesicle fusion with the presynaptic membrane, ↓ Ca2+ influx ↓release of neurotransmitters like acetylcholine into the synaptic cleft However, with repeated stimulation of the presynaptic neuron (e.g. exercise), there is ↑ Ca2+ accumulation within the axon terminal, allowing for more neurotransmitter vesicle fusion with the presynaptic membrane ↑ Acetylcholine available to mediate muscle reflexes With high frequency repetitive nerve stimulation, ↑ number of compound CMAPS can be generated ↓ Acetylcholine release into synapses leading to autonomic nerves ↓ Acetylcholine release into neuromuscular junction Autonomic dysfunction ↑ Deep tendon reflex amplitude Temporary improvement in muscle strength ↓ Number of muscle fibers activated by each action potential Post-activation facilitation: Repeated stimulation improves symptoms Larger proximal muscles involved in movement (i.e. walking) do not recruit sufficient number of muscle fibers for proper function Can affect any muscle group, but muscles involved in speech, swallowing, and periocular muscles are often afflicted Gait disturbance Symmetric skeletal muscle weakness Dysarthria (difficulty speaking) Dysphagia (difficulty swallowing) Ptosis (drooping of upper eyelid) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published July 18, 2021 on www.thecalgaryguide.com

Hypercortisolemia

Hypercortisolemia (Cushing’s Syndrome): Clinical Findings Cortisol is a net catabolic hormone affecting many body systems, serving to release energy into the blood in response to stress. Excess cortisol also impacts circulation and impairs immune function. Excess Serum Cortisol affects: Authors: Samin Dolatabadi, Yan Yu* Reviewers: Meena Assad, Amanda Henderson, Brooke Fallis, David Campbell* * MD at time of publication Bone and Calcium Metabolism Kidney and vasculature Excess cortisol in the renal tubule saturates the enzyme 11β- HSD2, which converts cortisol to cortisone Capacity of body to convert cortisol to cortisone is exceeded Excess cortisol can mimic aldosterone and bind to mineralocorticoid receptors (cortisone can’t bind to these receptors) ↑ Aldosterone effect → ↑ Na+ reabsorption from the cortical collecting duct into blood vessels Liver and Peripheral Tissue Cortisol ↑ gluco- neogenesis in liver, and ↑ insulin resistance by body tissue (unclear mechanisms) Hyper- glycemia Reproductive System Cortisol exerts negative feedback on hypothalamus à↓ gonadotropin releasing hormone (GnRH) secretion ↓ GnRH → ↓ LH/FSH → ↓ estrogen and testosterone production (especially important in females) Infertility, ↓ Libido, Irregular Menses Adipose Tissue Cortisol ↑ fat breakdown (lipolysis) Selective expression of cortisol receptor on different adipose tissuesàcentral, facial, dorsal fat is less broken down than in other areas (mechanism unclear) Combined with cortisol ↑ appetite: Skin & Connective Tissue ↑ Serum cortisol à↓ Fibroblast proliferation → ↓ Collagen synthesis Skin atrophy with loss of connective tissue Muscle ↑ Proteolysis & ↓ Protein synthesisà↓ muscle growth and function Immune System Normal serum cortisol protects against damaging effects of uncontrolled inflammatory and immune responses ↑ Serum cortisolà over-suppression of inflammation and impaired cell- mediated immunity ↑ Serum cortisol leads to ↓ Intestinal Ca2+ absorption and ↓ renal Ca2+ reabsorption ↓ Serum Ca2+ ↑ PTH secretion ↑ Serum cortisolà↑ RANKL:OPG ratio ↓ Osteoblast activity & ↑ Osteoclast activity Cardiac muscle Cardio- myopathy, Heart Failure Skeletal muscle, especially upper arms & thighs (for unclear reasons) Proximal Muscle Weakness Easy Bruising ↑ abdominal size stretches the fragile skin to become thinneràvenous blood of the underlying dermis becomes visible Purple Striae If hypertension is chronic Ca2+ resorption from bone into the blood Osteoporosis Supraclavicular & Dorsal Fat Pads Central Obesity Poor Wound Healing Susceptibility to infection Round Face (Moon Face) Abbreviations: • RANKL – Receptor activator of nuclear factor kappa-Β ligand • OPG – Osteoprotegerin • 11β-HSD2 – 11β-hydroxysteroid dehydrogenase type 2 Water follows Na+ into blood vessels to balance the osmotic pressure between the blood and renal tubules Water reabsorption → Expansion of blood volume Hypertension Both primary Cushing’s (e.g. adenomas that extend into zona reticularis of the adrenal cortex) and central/secondary Cushing’s (e.g. ↑ ACTH stimulation of zona reticularis) are associated with ↑ adrenal androgen secretion Removal of positively charged Na+ from tubular lumen creates a negative luminal environment K+ follows the electrical gradient and is secreted into tubular lumen ↓ Serum K+ concentration Hypokalemia Arrhythmia, Paralysis, Cramps (see Hypokalemia: Clinical Findings slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 17, 2021 on www.thecalgaryguide.com Hirsutism, Acne

Overview of Calcium Phosphate Vitamin D Physiology

Overview of Calcium, Phosphate, and Vitamin D Physiology Note: In circulation, 40% of Ca2+ is bound to plasma proteins, mainly albumin, 10% is complexed with citrate, and 50% is unbound and biologically active. Bone PTH binds to osteoblasts ↑ Osteoblast production of receptor activator of nuclear factor kappa-B ligand (RANKL) and ↓ expression of osteoprotegerin (OPG), a decoy receptor for RANKL RANKL binds to receptor activator of nuclear factor kappa-B (RANK) on osteoclasts ↑ Osteoclast differentiation and activity ↑ Ca2+ resorption from bone into blood Sensed by Calcium-Sensing Receptor on Chief Cells of the Parathyroid Gland − − ↑ Serum phosphate (PO4) ↓ Serum calcium (Ca2+) Parathyroid Gland releases Parathyroid Hormone (PTH) into the blood, which acts on the kidneys and the bones Kidney ↑ Activation of Transient Receptor Potential Vanilloid subfamily member 5 (Ca2+ channel) in the distal convoluted tubule ↓ Expression of 24-hydroxylase enzyme (which functions to catabolize calcitriol) ↑ Expression of 1α- hydroxylase enzyme ↑ Conversion of 25-hydroxy vitamin D (Calcidiol) to the active form, 1,25-dihydroxy vitamin D (Calcitriol) ↑ Calcitriol Small Intestine ↑ Endocytosis of sodium phosphate co-transporters NaPi-2a and NaPi-2c, which reabsorb PO4 from ultrafiltrate in the renal tubules ↓ Reabsorption of PO 4 ↓ Serum PO Calcitriol negatively feeds back on parathyroid gland to inhibit PTH production ↑ Expression of sodium phosphate co- transporters NaPi-2a and NaPi-2b that absorb PO4 from intestinal lumen 4 ↑ Expression of apical epithelial Ca2+ channels (Transient Receptor Potential Vanilloid subfamily member 6) ↑ Entry of Ca2+ on apical side of enterocytes ↑ Reabsorption of Ca2+ in the distal convoluted tubule through Ca2+ channels ↑ Reabsorption of PO ↑ Expression of cytoplasmic Calbindin-D ↑ Transport of Ca2+ across enterocytes ↑ Absorption of Ca2+ in small intestine ↑ Serum Ca+2 ↑ Expression of basolateral plasma membrane calcium ATPase ↑ Extrusion of Ca2+ from enterocytes into bloodstream 4 Authors: Samin Dolatabadi, Hannah Yaphe Reviewers: Amanda Henderson, Meena Assad, Brooke Fallis, Yan Yu*, Hanan Bassyouni* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published Oct 15, 2017, updated Nov 11, 2021 on www.thecalgaryguide.com

complications-of-chronic-kidney-disease-ckd

Complications of Chronic Kidney Disease Chronic Kidney Disease (CKD) Authors: Samin Dolatabadi, Brooke Fallis Reviewers: Jessica Krahn, Meena Assad, Yan Yu* Juliya Hemmett* * MD at time of publication Abnormalities of kidney structure or function that is present for 3 or more months Kidney tubules atrophy & kidney interstitial tissue undergo fibrosis Kidney damage ↓ erythropoietin production (normally a kidney function) ↓stimulation of bone marrow → ↓ red blood cell production Build up of toxic substances (e.g. urea, guanidine, and indoxyl sulfate) ↓ Conversion of calcidiol to calcitriol in by kidney ↓ Calcitriol levels in blood ↓ Ca+2 absorption from small intestine Hypocalcemia ↓ Glomerular Filtration Rate ↑ Vascular calcification and endothelial dysfunction (e.g. changes in permeability, clotting response to inflammation, amongst other mechanisms) Atherosclerotic disease (see “Complications of Atherosclerosis” slide) ↓ Lipoprotein lipase, apoA-1, and Lecithin-cholesterol acyltransferase activity acting on serum lipoproteins (complex mechanisms) ↓ Lipoprotein clearance from blood Dyslipidemia (↑ LDL, ↑ triglycerides, ↓ HDL) Toxic damage ↓ red blood cell survival Anemia Uremic Syndrome ↓ Renal excretion of phosphate ↑ phosphate remaining in bloodstream Hyperphosphatemia ↑ serum phosphate binds with ionized calcium ↓ Renal excretion of K+ ↑ K+ remaining in bloodstream Hyperkalemia Edema ↓ Renal excretion of ammonium Reduced filtration capability ↑ organic anions remaining in blood→ ↑ anion gap ↓ Renal excretion of salt and water ↑ in extracellular fluid → systemic volume overload ↓ calcium in blood ↓ inhibition of Parathyroid Hormone (PTH) release ↑ PTH in blood Secondary hyperparathyroidism Metabolic Acidosis Hypertension Pitting Chronic kidney disease – mineral and bone disorder (CKD-MBD) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 4, 2022 on www.thecalgaryguide.com

induction-of-labour-ripening-of-the-cervix-mechanisms-and-methods

Induction of Labour & Ripening of the Cervix: Mechanisms and methods Bishop Score – based on: • Cervical dilation • Cervical effacement • Cervical consistency • Cervical position • Station Amniotic membranes ruptured IV artificial oxytocin administration Stimulates Ca2+ release from intracellular stores in myometrium smooth muscle Selected Indications for Induction of Labour (Risk of continuing pregnancy > delivering) Please refer to “Induction of labour: Indications and contraindications” slide Bishop Score > 6 Cervix favorable ↑ Natural release of prostaglandins from uterine wall Bishop Score 4-5 Proceed based on clinical picture Amniotic membranes intact Amniotomy to artificially rupture amniotic membranes Rush of amniotic fluid Bishop Score < 3 Cervix unfavorable and requires ripening Artificial prostaglandin into vagina (gel or vaginal insert) Ripening options Ripening balloon in cervix Pressure applied to internal and external cervical os Foley catheter in cervix Pressure applied to internal cervical os Act as calcium ionophores to áintracellular Ca2+ Activate EP1 and EP3 receptors on myometrial cells Lack of fluid cushion causes more fetal head engagement Fluid flow may carry umbilical cord with it Cord prolapse (if fetal head not engaged/ low enough in pelvis to block exit of cord) Degradation of collagen in the connective tissue stroma of cervix Cervix softens Cervical dilation Cervix stretches (until balloon falls out) Author: Lindey Felske Reviewers: Ran (Marissa) Zhang Brianna Ghali Ingrid Kristensen* * MD at time of publication Risk of uterine rupture (if prostaglandins used as a ripening method after previous C- section) Uterine contractions ↑ Myometrial contractility ↑ Pressure on cervix Labour If needed, proceed to amniotomy and/or oxytocin once cervix is favorable Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 4, 2022 on www.thecalgaryguide.com

presentation-of-sah

Subarachnoid Hemorrhage: Clinical Findings Sudden bleeding into space surrounding the brain (for pathogenesis, see Subarachnoid Hemorrhage: Pathogenesis) Authors: Jason An, M. Patrick Pankow Reviewers: Owen Stechishin, Dave Nicholl, Haotian Wang, Hannah Mathew, Ran (Marissa) Zhang, Yan Yu*, Cory Toth* * MD at time of publication Bleed into subarachnoid space Subarachnoid Hemorrhage (SAH) Posterior hypothalamus ischemia (↓ Blood flow and oxygen) Red blood cell lysis from energy depletion or complement activation Release of spasmogens (spasm inducing agents) Cerebral vasospasm (narrowing of arteries from persistent contraction) ↓ blood flow Cerebral ischemia Release catecholamines (hormones from the adrenal gland; e.g., epinephrine, norepinephrine) ↑ Intracellular calcium Release of antidiuretic hormone Antidiuretic hormone acts on the distal convoluted tubule and collecting duct in kidney to reabsorb water Dilution of serum sodium Hyponatremia (low blood sodium levels) Release of epileptogenic (potential seizure causing agents) into cerebral circulation Seizure Products from blood breakdown in cerebral spinal fluid Irritation of meninges (membranes surrounding the brain) Aseptic meningitis (non-infectious inflammation) Meningismus (neck pain + rigidity) Cerebral infarction (death of tissue) Obstructs cerebral spinal fluid flow and absorption at subarachnoid granulations Hydrocephalus (fluid build up in ventricles) ↓ Level of consciousness Reduced cerebral blood flow Dilation of cranial vessels to ↑ blood flow Rapid ↑ internal carotid artery intracranial pressure Refer to Increased Intracranial Pressure: Clinical Findings slide Internal carotid artery Pituitary ischemia Hypopituitarism [underactive pituitary gland, failing to produce 1+ pituitary hormone(s)] Refer to hypopituitarism slides Myocardial disruption Left ventricle dysfunction ↑ Pressure in left heart Blood forced backwards into pulmonary veins ↑ Pulmonary blood pressure Fluid from blood vessels leaks into lungs Dysrhythmias (disturbance in rate/rhythm of heart) causing ↓ cardiac output Syncope (loss of consciousness due to ↓ blood flow to the brain) Pulmonary edema (excess accumulation of fluid in lung) Cerebral hypoperfusion Sudden ↑in blood volume Vessels and meninges suddenly stretch Thunderclap Headache (worst headache of patient's life) Shortness of breath Reactive cerebral hyperemia (excess blood in vessels supplying the brain) Artery specific findings: Rapid ↑ internal carotid artery intracranial pressure Middle cerebral artery Posterior communicating artery Compression of outer CN3 Compression of inner CN3 Anterior communicating artery Nonreactive pupil Gaze palsy (eye deviates down and out) Diplopia (double vision) Ptosis (drooping of upper eyelid) Frontal lobe ischemia Avolition (complete lack of motivation) Ischemia of motor strip pertaining to the legs Bilateral leg weakness Motor strip ischemia Hemiparesis (weakness/ inability to move one side of the body) Ischemia of parietal association areas (brain regions integral for motor control of the eyes, the extremities and spatial cognition) Aphasia (impaired ability to speak and/or understand language)/ neglect Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 1, 2014, updated August 10, 2022 on www.thecalgaryguide.com

diabetes-insipidus-pathogenesis-and-clinical-findings

Diabetes Insipidus: Pathogenesis and clinical findings Hereditary Autoimmune/ Idiopathic Auto-antibodies destroy neurons that release antidiuretic hormone (ADH) Mass Effect/ Tumor Invasion Mass pressing on hypothalamus or pituitary Electrolyte Imbalance (mechanism unclear) Hereditary Lithium (Li) (mechanism unclear) Li enters principal cells of collecting ducts via ENaCs Li inhibits GSK3β, reducing adenylyl cyclase activity ↓ cAMP- dependent phosphorylation of aquaporin-2 ↑ Serum [Ca2+] Activation of CaSR in thick ascending limb of Loop of Henle ↓ NaCl reabsorption in thick ascending limb ↓ Generation of medullary osmotic gradient ↓ Serum [K+] ↑ Degradation of aquaporin-2 channels in collecting duct ↓ Aquaporin- 2 channels transporting water across apical membrane of collecting duct Mutation of AVPR2 gene on X chromosome Antidiuretic hormone (ADH) receptor cannot reach basolateral surface of principal cells of collecting duct Mutation of aquaporin-2 gene on chromosome 12 ↓ Fusion of aquaporins with apical membrane of collecting duct Mutation of WFS1 gene on chromosome 4 (Wolfram syndrome) ↓ Processing of antidiuretic hormone (ADH) precursors and ↓ADH-releasing neurons Surgery/ Trauma Injury to hypothalamus or pituitary stalk Mutation of PCSK1 gene on chromosome 5 Deficiency in PC1/3 (encoded by PCSK1) ↓ Processing of ADH by PC1/3 Aquaporin dysfunction ↓ Kidney response to ADH, which mediates reabsorption of water down its osmotic gradient through aquaporins ↓ Production of ADH by hypothalamus or ↓ secretion from ADH-releasing neurons in posterior pituitary (depending on location of lesion) Central Diabetes Insipidus Nephrogenic Diabetes Insipidus Abbreviations: AVPR2: arginine vasopressin receptor 2 CaSR: calcium-sensing receptor ENaC: epithelial sodium channel GSK3β: glycogen synthase kinase type 3 beta PC1/3: proprotein convertase Diabetes Insipidus Decreased ability of kidneys to concentrate urine ↓ Reabsorption of water from collecting duct into vasculature Author: Oswald Chen Reviewers: Huneza Nadeem, Ran (Marissa) Zhang, Yan Yu* Sam Fineblit* * MD at time of publication Urine becomes more dilute ↓ Urine osmolality ↑ Urine output ↓ Blood volume Blood becomes more concentrated Occurs during late sleep period Nocturia Polyuria (>3 L/day) ↑ Serum osmolality Activation of hypothalamic osmoreceptors Hypernatremia (Serum [Na+] >145 mEq/L) Polydipsia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 25, 2022 on www.thecalgaryguide.com

Pubic Rami Fracture: Pathogenesis and clinical findings

Pubic Rami Fracture: Pathogenesis and clinical findings Authors: Kaela Schill Reviewers: M. Patrick Pankow, Tara Shannon, Alyssa Federico, Dr. Linda Mrkonjic* * MD at time of publication High energy impact Osteoporosis (most common) Bone loses calcium, becoming less dense weaker and more susceptible to fracture (See Osteoporosis: pathogenesis and clinical findings slide) Athletic injury in skeletally immature athletes (e.g., soccer, gymnastics) Open growth plates are weak and more susceptible to injury Lateral compression or vertical shear fracture Mild to moderate osteoporosis Fragility pubic rami fracture from low-energy impact (e.g., falls from standing, falls in the bathtub) Severe osteoporosis Spontaneous pubic rami fracture Sudden, forceful contraction of the hamstring muscles (e.g. sudden change of direction, sudden stop) Hamstring pulls a piece of the ischial tuberosity from the pelvis boneàpubic rami avulsion fracture (Posterior pelvic rim fracture requires CT to diagnose and is often missed) Missed or delayed diagnosis due to incomplete workup Pubic Rami Fracture Fracture of the anterior pelvic ring, can be the superior and/or inferior pubic rami Co-existing posterior pelvic ring fracture (e.g. acetabulum, sacrum) Fracture on both sides of pelvis Unstable pelvis Blood vessels in and surrounding the bone rupture during injury Blood accumulates under the skin Bruising around fracture site Inflammatory response to injury Recruitment of white blood cells and fluid to the area Swelling around fracture site Irritation at superior/inferior pubic rami muscle attachment sites (groin and hip abductor muscles) Pain in groin near fracture site ↑ Displacement and incomplete healing of the posterior and anterior pelvic ring fracture ↑ Morbidity and mortality ↑ Disuse osteoporosis ex: lower limbs, pelvis, and back ↑ Muscle stiffness ex: lower limbs, pelvis, and back ↑ Joint stiffness ex: lower limbs, pelvis, and back Fracture hematoma in pubic rami Hematoma distends the periosteum, irritating nerves in the area Moving/walking further irritates nerves in the area Moving and walking ↑ pain àinadequate movement ↓ Mobility (to avoid pain) Antalgic gait (stance phase of walking is shortened relative to swing phase) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

Concussion

Concussion: Acute pathophysiology and findings Authors: Calvin Howard Cormac Southam Yvette Ysabel Yao Reviewers: Emily Ryznar Mao Ding, Gary Klein* * MD at time of publication Activation of inhibitory cholinergic system of dorsal pontine tegmentum (structure with role in sleep- wake regulation) Disruption of reticular activating system (brain area that regulates arousal) Altered level of consciousness Direct blow to the head or the body that causes an impulsive force to the head (i.e., falls, motor vehicle accidents, sports, assaults) Skull acceleration / deceleration Coup (brain strikes skull on side of impact) Brain tissue swelling Cerebral edema (fluid build up around brain) ↑ Intracranial pressure Cerebral herniation (shifting of brain tissue into adjacent space) Contrecoup (brain strikes skull on opposite side of impact) Anatomical damage Skull fracture Broken bone fragments ruptures blood vessels Intracranial hemorrhage (bleeding into brain tissue) Papilledema (swelling around optic disk, where optic nerve enters eyeball) Disruption of messages from eye to brain Vision problems (i.e., blurred or double vision) Cellular damage Indiscriminate, rapid neurotransmitter release ↑Extracellular K+ and glutamate, accumulation of intracellular calcium Ionic disequilibrium across neuronal membrane Energy consumed by Na+/K+ ATPase pumps to re-establish ionic homeostasis ↑ Cerebral glucose metabolism ↑ Energy demand Brain injury Axonal stretch due to biomechanical forces Microtubule disruption Structural (cytoskeletal) disturbance Axonal degeneration Impaired neural communication Broken bone fragments Ruptures blood vessels Compresses blood vessels ↓ Cerebral blood flow ↓ Cerebral glucose supply ↓ Energy supply ↓ Oxygenated blood to brain Brain cell death Chronic brain atrophy Persistent impaired cognition Cellular energy crisis (mismatch between energy supply and demand due to effort in restoring homeostasis) Nausea, vomiting ↓ Participation in daily Confusion, disorientation, unsteadiness, headache activities and work Death Anxiety, depression Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 12, 2019, updated March 27, 2023 on www.thecalgaryguide.com

Carpal Tunnel Syndrome

Carpal Tunnel Syndrome: Pathogenesis and clinical findings Diabetes Mellitus (See Pathogenesis Slide) ↑ Blood sugar: deposition of advanced glycation end (AGE) products (proteins or lipids glycated when exposed to sugar) AGE attaches to and prevents tendons from moving properly Authors: Amanda Eslinger Yvette Ysabel Yao Reviewers: Matthew Harding Owen Stechishin Mao Ding, Cory Toth* * MD at time of publication Wrist trauma (distal radius fractures, carpal/metacarpal fractures, tendon ruptures) Repetitive Strain Injury (repetitive hand & wrist movements) Irritation, swelling & thickening of tendons in carpal tunnel Calcium deposits Calcifica tion Deposition Amyloidosis Amyloid (protein aggregates) deposition Gout (See Gout Slide) Uric acid crystal deposition Pregnancy ↑ Concentration of hormones & uterine pressure on inferior vena cava Backup of blood into systemic circulation Autoimmune (i.e. Rheumatoid arthritis, scleroderma, lupus, Sjogren’s syndrome) ↑ Inflammatory cytokines causing inflammation Hypo- thyroidism Myxedema (swelling of skin and underlying tissues) in carpal tunnel Idiopathic or Congenital Edema Narrowed carpal tunnel leads to ↑ internal pressure Carpal Tunnel Syndrome Vascular: median artery thrombosis in carpal tunnel Median nerve compression inside the carpal tunnel Mechanical disruption of median nerve Compression exacerbated with flexed wrists (i.e. sleep, driving, holding phone/cup) Disruption of daily activities and sleep Ischemia (↓ blood supply) to median nerve Hypoxia (↓ oxygenated blood flow) Metabolic conduction block (impaired axonal transport due to ischemia) Nerve conduction study (show sensory nerve impulses slowing across the wrist, followed by mild / moderate / severe loss of sensory nerve amplitude Damage to the myelin sheath ↓ Saltatory conduction (action potential propagation along myelinated axons) Neuropraxia (nerve compression blocks conduction) Interruption in axonal continuity Axonotmesis (endoneural tube stays intact but myelin & distal axon degenerates) Recovery possible Full disruption of myelin, axon & nerve sheath Neurotmesis (axons no longer have an endoneural tube to guide regrowth) Recovery impossible ↓ Ability to contract and use abductor pollicis brevis muscle ↓ Signals through median nerve Interference with signals to the brain causes unusual sensations Hypoalgesia (↓ pain Dysesthesia (tingling, burning, or sensitivity at 1st 3 1⁄2 digits) painful sensation at 1st 3 1⁄2 digits) Thenar muscle wasting Reduced hand dexterity Weak thumb abduction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 2nd, 2013, updated March 22, 2023 on www.thecalgaryguide.com

Physiology of Anti-diuretic hormone

Physiology of Anti-diuretic Hormone (ADH)/Arginine Vasopressin (AVP) Authors: Manaswi Yerrabattini Reviewers: Parker Lieb Mao Ding Shyla Bharadia Laura Hinz* * MD at time of publication Limbic activation (e.g., pain, nausea) Placental production of vasopressinase during pregnancy catalyzes the breakdown of ADH, leading to a temporary Diabetes Insipidus state (see Diabetes Insipidus: Pathogenesis and Clinical Findings slide) Systemic arteriole vasoconstriction Hypovolemia/Hypotension Hyperosmolar state (i.e., extracellular fluid osmolarity above a certain threshold, most commonly due to hypernatremia) Sensed by osmoreceptors in hypothalamus Angiotensin II synthesized through activation of Renin- Angiotensin-Aldosterone System (RAAS) (see Physiology of RAAS slide) Binds to receptors located in the hypothalamus ↓ pressure sensed by baroreceptors in the heart (left atrium and large veins) Receptors transmit signals to brain via the vagus nerve ↓ Arterial baroreceptor firing ↑ Sympathetic activity of nerves innervating afferent arterioles ↑ Hypothalamic secretion of ADH (peptide hormone), transportation to posterior pituitary, and release from posterior pituitary into blood circulation Blood Vessels (Minor role) Kidneys (Main role) ADH binds to to Vasopressin-2 receptors on basolateral side of principal cells in kidneys ↑ Insertion of aquaporin II channels onto apical membrane of late distal tubule and collecting ducts ↑ Water reabsorption ↓ Urine Output and Maintains narrow range of serum osmolarity ↑ Urine Osmolarity and preserves sodium homeostasis ADH binds to Vasopressin-1 receptors on smooth muscle of blood vessels ADH activates calcium signaling pathway ↑ Blood Pressure Maintains overall fluid volume status Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 20, 2023 on www.thecalgaryguide.com

Sustained Monomorphic Ventricular Tachycardia Pathogenesis

Sustained Monomorphic Ventricular Tachycardia: Pathogenesis Structural Heart Disease: (90% of cases) A ventricular scar forms (in the setting of coronary artery disease or cardiomyopathy) that cannot conduct electrical activity The scar is surrounded by a circular conduction pathway consisting of an ⍺- limb (slow conduction with a fast refractory period) and a β-limb (fast conduction but a slow refractory period) A correctly timed depolarization impulse arrives during the refractory period of the β-limb so it can only propagate through the ⍺-limb The β-limb’s refractory period ends just before the impulse leaves the ⍺-limb of the circular pathway Retrograde depolarization occurs into the ⍺ -limb, creating a self-sustaining closed- loop circuit within the ventricle “Re-entry” cause of tachyarrhythmia Idiopathic Causes: (10% of cases) Structurally normal heart on imaging Trigger(s) such as catecholamines ↑ cyclic adenosine monophosphate Intracellular calcium overload occurs in some ventricular myocytes ↑ Intracellular calcium activates sodium- calcium exchangers Sodium influx into the myocytes During normal myocyte repolarization, the net calcium-mediated depolarization reaches the myocyte threshold for an action potential A triggered action potential (termed a “delayed afterdepolarization”) repeatedly occurs within the ventricle “Triggered activity” cause of tachyarrhythmia Authors: Rahim Kanji Reviewers: Stephanie Happ, Raafi Ali, Derek Chew* * MD at time of publication Sustained Monomorphic Ventricular Tachycardia A wide QRS complex tachycardia originating from the ventricles lasting > 30 seconds. Common mechanisms include re-entry (e.g., scar-mediated) or a ventricular ectopic focus with increased automaticity. Refer to Sustained Monomorphic Ventricular Tachycardia: Clinical findings for details Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 22, 2023 on www.thecalgaryguide.com

Carbonic Anhydrase Inhibitor Diuretics

Carbonic Anhydrase Inhibitor Diuretics: Renal mechanism and side effects Authors: Stephanie Happ Reviewers: Matthew Hobart Raafi Ali Adam Bass* * MD at time of publication Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells in the proximal convoluted tubule (PCT) Activation of the Renin- Angiotensin-Aldosterone Systemfromvolume depletion Activation of principle cell Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ and waste K+ ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H2O available for excretion Mild diuresis (increase in frequencyandvolumeof urine) ↓ Blood volume Hypotension ↓ Na+ and HCO3- reabsorption in the PCT ↑ HCO3- delivery to cortical collecting duct Urine alkalization (increased pH) Chronic urine alkalization ↓Solubilityof citrate ↓ Urinary citrate ↓ Citrate binding with Ca2+à↑ Ca2+ complexing with oxalate ↑ Spontaneous nucleation, growth and agglomeration of calcium oxalate crystals Formation of calcium oxalate renal calculi ↑ HCO3- is lost in the urine ↓ pH of the blood Type II Renal Tubular Acidosis See Type II/Proximal Renal Tubular Acidosis slide CAI prevents the up- regulationofglutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia (↑ serum NH3 ) ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 3, 2024 on www.thecalgaryguide.com Carbonic Anhydrase Inhibitor Diuretics: Renal Mechanism and Side Effects Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells of the proximal convoluted tubule (PCT) Authors: Stephanie Happ Reviewers: Matt Hobart Name Name* * MD at time of publication ↓ Na+ and HCO3- reabsorption in the PCT ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H O available for 2 excretion Mild diuresis ↓ Blood volume Hypotension ↑ HCO3- delivery to cortical collecting duct Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ ↑ Intracellular Na+ drives Na+/K+ ATPase activity on the principal cells (moving 2 K+ into cell and 3 Na+ out into the peritubular capillary) ↑ Intracellular K+ drives H+/K+ ATPase activity on the intercalated cells (moving 1 H+ into cell and 1 K+ out into the tubular filtrate) ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide Urine alkalization ↑ HCO3- is lost in the urine, leading to ↓ pH of the blood Renal Tubular Acidosis Type II See Type II/Proximal Renal Tubular Acidosis slide CAI inhibit the up-regulation of glutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Chronic urine alkalization leads to marked ↓ in urinary citrate ↓ Ability of citrate to bind to Ca2+ and calcium oxalate stones ↓ Inhibition of spontaneous nucleation ↓ Prevention of growth and agglomeration of crystals Formation of calcium oxalate renal calculi Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com

Dantrolene

Dantrolene: Mechanism of Action and Adverse Side Effects Medication indicated for the treatment of muscle spasms associated with malignant hyperthermia (reaction to certain anesthetics resulting in a rapid and dangerous increase in body temperature, muscle rigidity, and other symptoms), and spasticity associated with various neurological disorders such as multiple sclerosis, cerebral palsy, and spinal cord injury. Dantrolene Authors: Madison Amyotte, Arzina Jaffer Reviewers: Jasleen Brar, Mao Ding Luiza Radu Joanna Moser* * MD at time of publication Metabolized in the liver by the cytochrome P450 enzyme Metabolic process forms a high concentration of hydroxylamine Hydroxylamine is a highly toxic metabolite associated with dantrolene induced liver injury Impaired Liver Function Binds to ryanodine receptors (RYR1) in the sarcoplasmic reticulum of skeletal muscle cells Prevents ryanodine channel from opening when triggered by the action potential in the muscle Prevents calcium release from the sarcoplasmic reticulum Prevents binding of calcium to troponin on the actin filaments in the cytosol of the skeletal muscle cells Myosin-binding site on the actin remains covered by the tropomyosin Prevents cross-bridge formation between myosin and actin within the sarcomere Prevents muscle contraction ↓ Progression of muscle rigidity and spasms ↓ Heat produced by muscular contraction Skeletal & respiratory muscle weakness ↓ Body temperature ↓ Inspiratory capacity Dyspnea Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 18, 2024 on www.thecalgaryguide.com

Metastatic Bone Lesions

Metastatic Bone Cancer: Pathogenesis & Clinical Findings Primary solid tumours from breast, prostate, or lung commonly migrate into bones Bone Metastases Migration of primary solid tumours (commonly from the breast, prostate, or lungs) into bones. Once tumours metastasize to bone, they are generally incurable and contribute to significant morbidity prior to a patient’s death Authors: Curtis Ostertag Reviewers: Mankirat Bhogal Nojan Mannani Michelle J. Chen Dr. Gerhard Kiefer* * MD at time of publication Cell-to-cell communication between tumour cells & bone cells (osteoclasts & osteoblasts) Tumours release TNF-⍺, RANK-L, and PTHRP which ↑ osteoclast activity & ↓ osteoblast activity Change in relative activity of bone cells results in osteolysis (breakdown of bone) Calcium is released into the bloodstream Hypercalcemia Osteoblastic metastasis (common in prostate cancer) Tumor growth Secondary bone formation in response to bone destruction TGF-β, PDGF, & IGF are released from the degraded bone matrix, which can stimulate tumors & osteoblasts Weakened bone increases risk of fracture Pathologic fracture ↑ Mortality Bone tissue expands into surrounding space Nerve compression Disruption of cortical bone or surrounding soft tissues Diffuse & achy rest/night pain Long bone masses compress peripheral nerves Neuropathy Vertebral masses compress spinal nerves/cord Radiculopathy /Myelopathy ↓ Quality of life Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 9, 2024 on www.thecalgaryguide.com

Massive Transfusion Protocol

Massive Transfusion Protocol: Considerations and rationale Massive transfusion protocol (MTP) is a tool used by clinicians when there is a need to rapidly administer a large amount of blood products, including packed red blood cells (pRBCs), fresh frozen plasma (FFP), and platelets. Complications of MTP are commonly referred to as “The Lethal Triad” referring to hypothermia, acidosis and coagulopathy. Authors: Kayleigh Yang Arzina Jaffer Reviewers: Jasleen Brar, Luiza Radu, Karl Darcus* * MD at time of publication Intervention Indications Initial Response Pathophysiology Transfusion Targets ≥ 3 pRBCs unit transfusion requirement in 1 hour Shock index (heart rate/systolic blood pressure) > 1 Blood volume loss >50% in ≤3 hours ABC Score ≥ 3 of: 1. Penetrating mechanism of injury 2. Systolic blood pressure < 90 mmHg 3. Heart rate > 120 beats per minute 4. Evidence of hemoperitoneum or hemopericardium on ultrasound (positive FAST U/S exam) RABT Score ≥ 2 of: 1. Penetrating mechanism of injury 2. Shock index > 1 3. Positive FAST U/S 4. Known or suspected pelvic fracture Call for help Activate institution's MTP protocol Send for STAT type and screen Establish large-bore intravenous access Fluid resuscitation Collect and send STAT bloodwork including hemoglobin, platelet, INR, fibrinogen, electrolytes, creatinine and arterial blood gas (ABG). Citrate present in blood products to avoid clotting during storage Stored pRBCs break down and release potassium due to time mediated degeneration Temporary accumulation of citrate in patient's blood with rapid use of blood products Citrate chelates calcium Less negative cell membrane resting potential Anaerobic metabolism Promotes hypocalcaemia Changes in membrane excitability Lactic acid buildup Coagulopathy (see coagulation cascade slide) Cardiac dysrhythmias (peaked T-waves, atrial block, “sine wave”, asystolic EKG changes) Metabolic acidosis End organ damage Continued blood loss Volume overload Avoid hypocalcemia Avoid hyperkalemia pH 7.35-7.45 Bleeding source control Hemoglobin >70-90 Platelets >50 INR <1.5 Fibrinogen >1.5 Avoid dilutional coagulopathy (clotting factor dilution) Mean Arterial Pressure (MAP) >60mmHg Temperature >35.0°C Slow (over 5-10 minutes) IV calcium administration Inhaled beta agonists Insulin/Dextrose EKG monitoring Sodium bicarbonate Increase minute ventilation Fastest control method to prevent further blood loss (i.e., packing wounds) Early tranexamic acid administration Administer pRBCs, FFP, and platelets in a 1:1:1 ratio (fibrinogen replacement indicated if <1.5 despite FFP) Minimize crystalloid use Administer crystalloids in a 3:1 ratio to estimated blood loss until blood products available Administer vasopressors to meet target, do not overshoot Temperature monitoring Fluid warming ↑ [Potassium] in pRBCs solution Administration of pRBCs ↑ potassium in patient's blood Blood loss ↓ Hemoglobin Tissue hypoperfusion Tissue hypoxia ↑ Diluent volume ↓ Concentration of clotting factors Tissue death ↓ Coagulation ability ↑ Transfusion requirements Early fluid resuscitation Rapid transfusion of cooled or room-temperature blood products/fluids ↑ Blood pressure Development of hypothermia ↑ Bleeding and clot dislodgement potential ↓ Enzyme activity in the coagulation cascade ↓ Coagulation ability Legend: Pathophysiology Mechanism Targets Intervention Published Sept 5, 2024 on www.thecalgaryguide.com

Diffuse Axonal Injury

Diffuse Axonal Injury: Pathogenesis and Clinical Findings Authors: Stephanie de Waal Reviewers: Braxton Phillips Shahab Marzoughi Gary Michael Klein* * MD at time of publication Shear injury to small intracranial vessels Fall from height High-speed motor vehicle accident Blunt trauma Unrestricted head movement with impact Rotational acceleration and/or deceleration forces applied to brain Shearing forces applied to white matter tracts of brain Sphenoid bone causes shear injury to pituitary stalk Primary Axotomy Shear force disconnects neurons at white-grey matter junctions Secondary Axotomy Stretch injury to axons create mechanical damage to axon sodium channels Uncontrolled sodium influx into neurons Reversal of sodium- Shear injury to hypothalamo- neurohypophysial portal system Intra-parenchymal Hemorrhage Panhypopituitarism (decreased production and secretion of pituitary hormones) Increased intracellular sodium creates increased osmotic pressure between extracellular and intracellular space Water moves passively along osmotic gradient into intracellular space Neuron swelling Hemorrhagic lesion on MRI calcium exchangers Activation of voltage gated calcium channels Calcium enters the damaged neuron Proteolytic activity increases with elevated intracellular calcium Activated proteases cause delayed cytoskeleton damage Damage to neuron cytoskeleton impairs transport of axonal proteins Protein accumulates within axon creating bulb structure at the terminal Disconnection of axon terminal from adjacent dendrites and cell bodies Diffuse Axonal Injury Axonal bulbs on pathology Damage to cortical, subcortical, and brainstem white matter tracts leads to a constellation of symptoms Post-traumatic seizures Damage to temporal lobe Damage to primary motor cortex Lesions in ascending reticular activating system impact consciousness Memory deficits Motor deficits Coma & brain death Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sep 18, 2024 on www.thecalgaryguide.com

Malignant Hyperthermia

Malignant Hyperthermia: Pathogenesis & clinical findings Authors: Haotian Wang, Jen Guo Reviewers: Julena Foglia, Priyanka Grewal, Luiza Radu Kevin Gregg* * MD at time of publication Depolarizing muscle relaxant (e.g., succinylcholine) & volatile anesthetic (e.g., sevoflurane, desflurane, isoflurane, halothane, NOT nitrous oxide) Autosomal dominant mutation in ryanodine receptor (RyR1; RyR1 transports calcium out of the sarcoplasmic reticulum during muscle depolarization) LowerthresholdforactivationofRyR1 state Prolonged opening of RyR1 ↑ Ca2+ in myocyte cytoplasm Capacity of the reuptake protein to carry Ca2+ is overwhelmed Sustained muscle contraction à hypermetabolic state Malignant Hyperthermia Vigorous exercise & heat (rare) Rare life-threatening clinical syndrome that occurs in genetically susceptible patients upon exposure to a triggering agent Skeletal muscle rigidity (i.e., masseter muscle spasm) Sustained muscle contraction Myocytes (muscle cells) deplete available ATP Hypermetabolic state ↑ O2 consumption ↑ Heart rate to meet O2 demand ↑ CO2 production Unexplained ↑ end tidal CO2 (early sign) ↑ Temperature Hyperthermia (late sign) ↓ O2 supply ↑ Anaerobic metabolism ↑ Lactic acid production Metabolic acidosis Cell death Leakage of muscle contents into circulation ↑ Serum creatinine kinase Development of rhabdomyolysis (rapid breakdown of muscle tissue) Myoglobinuria (presence of excess myoglobin in urine) Acute kidney injury** Hyperkalemia Electrolyte imbalances (i.e., hyperkalemia) Abnormal myocyte contraction Cardiac dysfunction Dysrhythmias Cardiovascular collapse Release of thromboplastin (converts prothrombinàthrombin) & other prothrombotic substances (promotes clot formation) Imbalance between thrombotic & antithrombotic pathway ↑ Clot formation from activation of the extrinsic & common pathways Disseminated intravascular coagulation** Tachypnea (in absence of prominent mechanical ventilation) Tachycardia (early sign) Cardiovascular collapse Vital organ failure Coma **See corresponding Calgary Guide slide(s) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 25, 2015; updated Oct 2, 2024 on www.thecalgaryguide.com

Secondary hypoglycemia Insulin Mediated

Hypoglycemia: Insulin mediated secondary causes Insulinoma (pancreatic beta islet cell tumour) Non-insulinoma pancreatic islet cell disorder (e.g. Non-insulinoma pancreatogenous hypoglycemia syndrome) Nesidioblastosis (pancreatic islet tissues formed from pancreatic duct budding) formation ↑ In number & size of abnormal pancreatic beta islet cells throughout the entire pancreas ↑ Insulin production & secretion by abnormal pancreatic islet cells ↑ Glycogen synthesis Insulin autoimmune syndrome Autoantibodies bind to insulin molecules released post-meal Insulin molecules unable to exert effects Hyperglycemia Promotes insulin release ↓ Plasma glucose concentration ↓ Insulin release & ↓ total insulin levels Insulin molecules dissociate from autoantibodies ↑ Free insulin levels (inappropriate for the ↓ plasma glucose levels) ↓ Glycogenolysis (glycogen breakdown to glucose) Hypoglycemia (serum glucose of <3mmol/L) Intake of insulin secretagogues (e.g. Sulphonylureas, Meglitinide analogues) Binds to adenosine triphosphate (ATP) dependant potassium channels on pancreatic islet cells Inhibit potassium ion efflux through ATP-dependent potassium channels Pancreatic islet cell depolarization Opens voltage-gated calcium channel Calcium influx into pancreatic islet cells ↑ Insulin release ↓ Gluconeogenesis (glucose synthesis from non-carbohydrate compounds) Exogenous insulin intake Suppress endogenous insulin production (by beta cells) Low C-peptide levels (byproduct of endogenous pro- insulin being converted to insulin) 90% caused by somatic mutations of pancreatic beta islet cells 10% due to genetic changes linked to MEN1(Multipl e endocrine neoplasia type-1) gene mutation ↑ Pancreatic islet cells proliferation ↑ Insulin secretion by hyperplastic (increasing in number) pancreatic islet cells Neuroglycopenic symptoms (altered mental status, seizures) Neurogenic symptoms (palpitations, tremulousness, diaphoresis Authors: Iffat Naeem Run Xuan (Karen) Zeng Reviewers: Gurreet Bhandal Luiza Radu Yan Yu* Samuel Fineblit* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 29, 2024 on www.thecalgaryguide.com

Bone Remodeling Physiology

Bone Remodeling: Physiology Glucocorticoids ↓ Osteoblast (bone building cells) activity, ↑ osteoclast (bone cells that break down bone) activity Hyperparathyroidism ↓ Blood Ca2+ ↑ Parathyroid hormone (serum Ca2+ concentration increasing hormone) Trauma Osteoblasts detect breach in matrix integrity Hyperthyroidism ↑ Triiodothyronine (T3) ↑ Bone turnover Puberty ↑ Growth hormone ↑ Blood calcium (Ca2+) ↑ Calcitonin (reduces serum Ca2+ by ↓ renal Ca2+ reabsorption & ↑ osteoclast activity) Net bone resorption process (bone tissue released from bones) Surveillance osteoblasts produce receptor activator of nuclear activator kappa beta (RANKL; osteoclast stimulating protein) Monocytes fuse into osteoclasts (cells for bone breakdown) Osteoclast actions Secrete HCl to dissolve hydroxyapatite (bone matrix forming inorganic mineral) Serum markers of bone resorption: C-Telopeptide (CTX) P-Telopeptide (PTX) Net bone formation process Hormones activate osteoblast Osteoblast actions Secrete osteoprotegerin that binds RANKL Secrete osteoid seam (a new layer of unmineralized organic bone matrix) Osteoblasts deposit hydroxyapatite on seam Phagocytose osteocytes within bone matrix Authors: Andrew Wu, Jason Kreutz Reviewers:Mizuki Lopez, Gurreet Bhandal, Luiza Radu *Samuel Fineblit * MD at time of publication Secrete collagenase enzyme to help digest collagen ↓ Osteoclast activity Osteoblasts become osteocytes (mature cells) within bone Serum markers of bone formation: ↑ Alkaline phosphatase (ALP) ↑ Bone-specific alkaline phosphatase (BSAP; an enzyme produced by osteoblasts during mineralization of bone) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Calcium Channel Blockers

Calcium Channel Blockers: Mechanisms & side effects Authors: Caroline Kokorudz Reviewers: Rafael Sanguinetti Andrew Wu Luiza Radu Timothy Pollak* * MD at time of publication Calcium channel blocker medications inhibit Ca2+ channels in smooth muscle Reduction of Ca2+ influx into smooth muscle cells Inhibits calcium-dependent aldosterone synthesis reducing Na+ & H2O resorption in renal distal tubules Negative feedback to pituitary gland causing ↑ ACTH (adrenocorticotropic hormone) ↑ Androgens (testosterone) Testosterone acts on gingival cells (multiple cell types that support teeth) & connective tissue matrix Gingival hyperplasia (gum overgrowth) Non-dihydropyridines: (Phenylalkylamines [verapamil], Benzothiazepines [diltiazem]) less potent vasodilators & selective for heart muscle Prevents smooth muscle contraction Dihydropyridines: (amlodipine, felodipine, nifedipine) vasodilate vascular smooth muscle ↓ Arterial resistance and blood pressure in coronary & peripheral arteries Coronary artery vasodilation ↓ Pressure in coronary arteries ↑ Blood flow through coronary arteries Reduced ischemia relieves angina Inhibits L-type Ca2+ channels, preventing rapid nodal depolarization Reduces excitation of sinoatrial (SA) & atrioventricular (AV) nodal tissues ↓ Conduction speed of electrical impulses ↓ Contractile strength of cardiomyocytes (heart muscle cell) ↓ Systemic vascular resistance & cardiac afterload (heart pumping resistance) ↑ Blood volume flowing into significantly smaller vessels ↑ Capillary blood pressure ↑ Circulation to face Flushes (red & warm) ↓ Cardiac output ↓ Tissue perfusion & attempt to ↑ cardiac output Worsens heart failure ↓ Oxygen demand of heart muscle More favorable oxygen supply to demand ratio Relieves angina ↓ Blood pressure ↓ Cerebral perfusion Syncope (fainting) Relieves angina Capillary fluid leak increased to interstitial space Peripheral edema ↑ Intracranial pressure Compresses nerve endings Headache ↓ Heart rate Bradycardia Suppresses dysrhythmias (abnormal heart rhythm) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 21, 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

Dopamine Antagonists Metoclopramide & Domperidone

Dopamine Antagonists Metoclopramide & Domperidone: Mechanism of Action and Adverse Effects Authors: Ishjot Litt Naima Riaz Reviewers: Run Xuan (Karen) Zeng Luiza Radu Esther Ho* * MD at time of publication Binds to & blocks dopamine D2 receptors in the chemoreceptor trigger zone (CTZ) in medulla oblongata Binds to & blocks serotonin (5-HT3) receptors in the CTZ in medulla oblongata Binds to & blocks dopamine D1 & D2 receptors in the nucleus accumbens of the basal forebrain Binds to & blocks dopamine D2 receptors in the substantia nigra of the basal ganglia Binds to & blocks dopamine D2 receptors in the anterior pituitary Binds to & blocks dopamine D2 receptors in myenteric plexuses of the proximal gut Binds to & blocks dopamine D2 receptors in the myocardium Incoming vagal afferents (sensory nerve signals) reduce dopamine release at the CTZ Incoming vagal afferents (sensory nerve signals) reduce serotonin release at the CTZ ↓ Binding of dopamine released by neurons in the ventral tegmental area (VTA) of the midbrain ↓ Dopamine’s inhibitory effect on neurons in the ventrolateral (VL) nucleus of the thalamus ↓ Binding of dopamine released by neurons in the hypothalamus ↑ Acetylcholine (Ach) release from parasympathetic neuronal nerve endings ↓ Dopamine binding at the CTZ ↓ Serotonin binding at CTZ ↓ Activation of wake-promoting VTA neurons ↑ Excitatory activity of neurons in the VL nucleus of the thalamus ↓ Dopamine’s inhibitory effect on prolactin secretion Influx of calcium ions into smooth muscle ↓ Dorsal motor nucleus activity of the vagus nerve in the medulla oblongata ↓ Nucleus solitary tract activity (processes sensory signals from body) ↓ Vomiting center activity Suppressed vomiting reflex ↓ Vomiting Central Actions ↓ Excitatory signals to promote wakefulness Drowsiness Extrapyramidal symptoms (EPS; impaired motor control) Dystonia (sustained muscle spasm & abnormal posture), akathisia (restlessness), chorea (rapid, irregular movement), parkinsonism (tremors, rigidity) EPS symptoms occur mostly with metoclopramide. Domperidone does not readily cross CNS and is less likely to produce EPS symptoms. Continuous activation signal to corticospinal motor control system Hyperprolactinemia (↑ prolactin secretion) ↑ Involuntary movements Peripheral Actions Torsade de Pointes (polymorphic ventricular tachycardia; rapid & irregular heart rhythm on ECG) Membrane depolarization ↑ Velocity of excitatory waves on smooth muscle walls ↑ Gut tone & rhythm of contraction ↑ Gastric and small intestinal motility & ↑ lower esophageal sphincter tone Blocks potassium channel Inhibits potassium ion outflow Delayed ventricular repolarization (>440 milliseconds in men & >460 milliseconds in women) Myocardium unable to compensate for arrhythmia Ventricular fibrillation Cardiac Arrest Death Bradycardia (Slow than normal heart rate) Long QT Syndrome Extended QT interval seen on electrocardiogram (ECG) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2025 on www.thecalgaryguide.com

Osgood Schlatter Disease

Osgood-Schlatter Disease: Pathogenesis and clinical findings Growth-related factors Anatomical variations that may ↑ risk Tibial tubercle develops as a secondary ossification centre, starting with a cartilaginous outgrowth Developing cartilaginous tibial apophysis has ↓ resistance to mechanical stress ↑ Susceptibility to injury prior to tibial apophysis and epiphysis fusion Adolescent growth spurt Longitudinal growth of tibia exceeds ability of quadriceps-patellar tendon unit to stretch ↓ Quadriceps flexibility Repetitive knee extensor mechanism activities during adolescence (eg. jumping, running) Patellar tendon inserts more proximally or broadly on tibia ↓ Patellar tendon moment arm length causes ↑ biomechanical forces on tibial tubercle Patella alta (superior displacement of the patella within the trochlear groove) *temporal relationship uncertain Quadriceps require ↑ forces to achieve full extension Patellar tendon overuse ↑ Patellar tendon tension ↑ Traction stress on the patellar tendon insertion at the cartilaginous tibial tubercle apophysis in one or both knees Osgood-Schlatter Disease Self-limiting osteochondrosis or traction apophysitis (inflammation of the growth plate) of the proximal tibial tubercle at the insertion of the patellar tendon Tibial tubercle apophysis hypertrophies & develops chronic micro-avulsions (tibial apophyseal ossification centers & cartilage is pulled off the tibial metaphysis) ↑ Inflammation at injury site Proximal patellar tendon micro- Repetitive strain/forces on the proximal tibial apophysis Tibial apophysis undergoes partial arrest Asymmetric proximal tibial epiphyseal growth abnormality (posterior > anterior) Genu recurvatum (knee hyperextension) (rare) due to traction apophysitis avulses from the tibial apophysis overcomes bone-tendon attachment strength Activated immune cells release cytokines at injury site Sensitization of nociceptors in periosteum and surrounding tissues Tenderness and Antalgic swelling of gait patellar tendon Proximal tibial apophyseal fragmentation (visible on X-ray) Avulsion fracture of tibial tubercle Calcium is abnormally deposited in the tendon Calcific tendinopathy in patellar tendon (visible on X-ray) Anterior knee pain that worsens with exercise Inflammatory mediators recruit osteoblast precursors to stabilize injury site ↑ Osteoblast activity drives bone remodeling and formation of ossicles (small pieces of bone) Bone remodeling causes united ossicles (ossicle fusion with tibial tuberosity) Ununited ossicle imbedded within patellar tendon (visible on X-ray) Bony prominence of tibial tubercle (visible on X-ray) Residual ununited ossicle remains after apophysis fuses with proximal tibial metaphysis Persistent visible prominence after proximal tibial apophyseal closure Authors: Emily J. Doucette Reviewers: Michelle J. Chan Yan Yu* Gerhard Kiefer* * MD at time of publication Persistent pain & discomfort with ↓ strength & function Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 16, 2025 on www.thecalgaryguide.com

Acetylcholinesterase inhibitors

Authors: Trevor Low Sunny Fong Reviewers: Billy Sun* Melinda Davis* * MD at time of publication Overstimulation of nicotinic acetylcholine receptors Overstimulation of muscarinic acetylcholine receptors Involuntary muscle twitches ↑Activity of respiratory smooth muscle & glands Acetylcholinesterase inhibitors: Mechanism of action and side effects Administration of acetylcholinesterase inhibitor (e.g., neostigmine or pyridostigmine) Reversible inhibition of acetylcholinesterase activity Cholinergic effects ↓ Breakdown of acetylcholine in the synaptic cleft Acetylcholine accumulates in the synaptic cleft Excessive accumulation of acetylcholine in synapses Acetylcholine competitively displaces non-depolarizing neuromuscular blockers** from nicotinic receptors in the neuromuscular junction ↑ Acetylcholine binding to pre-synaptic nicotinic receptors on neurons ↑ acetylcholine binding to post-synaptic nicotinic receptors on muscles Pre-synaptic nicotinic receptor depolarizes terminal membrane Post-synaptic nicotinic receptor activation results in action potential in muscle ↑ Vesicular release of acetylcholine by voltage- gated calcium signaling Muscle contraction occurs via excitation- contraction coupling Legend: Neurotransmission is sustained during Reversal of neuromuscular block repeated stimulation **See corresponding Calgary Guide slide Mechanism ↑ Activation of muscarinic receptors in myocardium ↑ Activation of muscarinic receptors in endothelial tissue Endothelial cells release nitric oxide Acetylcholine- activated potassium channels open Nitrous oxide causes vascular smooth muscle relaxation Sinoatrial node of the heart becomes hyperpolarized Vasodilation ↓ Vascular resistance Bradycardia Hypotension Depolarization block of nicotinic receptors in muscles Flaccid skeletal muscle paralysis Respiratory muscle paralysis & failure Bronchospasm & excess secretions Prolonged period of inadequate respiration ↓ Oxygen saturation ↑ Carbon dioxide ↑ Activation of gastrointestinal muscarinic receptors Stimulation of gastrointestinal muscles Activation of salivary muscarinic receptors ↑ Amplitude & duration of gut peristalsis ↑ Activity of salivary glands Overstimulation of the enteric nervous system Nausea ± vomiting ↑ Salivation Pathophysiology Sign/Symptom/Lab Finding Complications Published May 31, 2025 on www.thecalgaryguide.com

Volatile Gases

Volatile Gases (e.g. desflurane, sevoflurane, isoflurane): Physiology & clinical findings Volatile agent (gas) delivered to the lungs Mean alveolar concentration of gas increases Gas enters the bloodstream via alveolar gas exchange Gas dissolves into lipid membranes within the central nervous system ↓ Pre-synaptic release of excitatory neurotransmitters (N- methyl-D-aspartate (NMDA), acetylcholine, serotonin, & glutamate) Inhibition of post- synaptic excitatory neurotransmitter receptors (NMDA, acetylcholine, serotonin, & glutamate) Distortion of electrophysiology of post-synaptic sodium channels Activation of post- synaptic potassium channels ↑ Presynaptic release of gamma- aminobutyric Post-synaptic cell acid (GABA) hyperpolarization Impaired neuronal depolarization ↓ Excitatory post- synaptic input ↑ Inhibitory post- synaptic input Disruption of synaptic transmission in cerebral cortex, basolateral amygdala, hippocampus, etc. Cerebral vasodilation & ↑ cerebral blood flow Authors: Punit Bhatt Billy Sun Reviewers: Priyanka Grewal Luiza Radu Melinda Davis* *MD at time of publication ↓ Pre-synaptic reuptake of GABA Activation of post- synaptic GABA receptors Amnesia Loss of consciousness ↑ Intracranial pressure Compression of brainstem resulting in stimulation of the vomiting region Nausea & Vomiting Legend: Disruption of potassium signaling in cerebral & systemic vasculature Decreased systemic vascular resistance Disruption of calcium signaling in cardiac myocytes Induction of Anesthesia Impaired smooth muscle contractility Negative inotropic effect Hypotension ↓ Stroke volume & consequently decreased cardiac output Tachycardia Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Disruption of synaptic transmission in medullary, respiratory, & phrenic motor neurons Neuromuscular blockade QT Prolongation Torsades de Pointes (Polymorphic Ventricular Tachycardia) Respiratory depression Hypercapnia (Elevated CO2 concentration in the blood) Muscle relaxation Unregulated release of calcium in susceptible patients Malignant hyperthermia (a life-threatening reaction to certain anesthetics)** ** See malignant hyperthermia slide Published Aug 12, 2025 on www.thecalgaryguide.com

Propofol

Propofol: Mechanism of Action & Side Effects Primary Process ↑ Allosteric binding affinity (binds to a site other than the active site on the receptor to induce conformational changes) of Gamma- aminobutyric acid (GABA) to GABAA receptor in brain (ionotropic receptor) GABA remains bound to GABAA receptor Prolonged opening of chloride channels in neuronal cell membrane Influx of negatively charged chloride into neuron Hyper- polarization of nerve cell membrane ↑ Difficulty reaching threshold for action potential ↓ Number of successful action potentials Inhibition of central nervous system Central Nervous System ↓ Neuronal activity ↓ Level of consciousness, achieving sedation or general anesthesia (dose-dependent effect) ↓ Cerebral metabolic activity ↓ Cerebral blood flow ↓ Intracranial pressure Respiratory System Inhibition of central respiratory centers in brainstem Relaxation of upper airway muscles ↓ Hypercapnic & hypoxic ventilatory drive Airway obstruction ↓ Respiratory rate ↓ Tidal volume Hypoxemia Hypercapnia Apnea Cardiovascular System Inhibition of sympathetic cardiovascular activity Inhibition of cardiac smooth & striated muscle activity ↓ Baroreceptor response to decrease in blood pressure Vasodilation ↓ Myocardial contractility ↓ Systemic (minor effect) vascular resistance Diminished reflex tachycardia Diminished vasoconstrictor response Hypotension Authors: Caitlin Bittman Ryden Armstrong Reviewers: Billy Sun, Joseph Tropiano Priyanka Grewal Luiza Radu Melinda Davis* * MD at time of publication Secondary Process Direct interaction with α1 subunit of L-type calcium channels Alteration of calcium channel conformation Inhibition of voltage-gated calcium channels ↓ Response to depolarization signals Smooth & striated muscle relaxation throughout body ↓ Calcium ion influx into smooth & striated muscle cells, & ↓ cell depolarization Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 3, 2018; updated Aug 28, 2025 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

Sturge-Weber Syndrome

Sturge-Weber Syndrome (SWS): Pathogenesis, mechanisms & clinical findings Somatic mosaic mutations (embryonic development mutations producing multiple cell lines) occur in the GNAQ gene Abnormal regulation of intracellular signaling pathways during early embryogenesis Mechanism unclear. Attributed to primary defect(s) in a subset of angioblasts (precursor embryonic cells for the endothelial cells lining blood vessels) or in other cells supporting vascular function Authors: Dylan Hollman* Reviewers: Mina Youakim Jessica Revington Fatemeh Jafarian* * MD at time of publication **See corresponding Calgary Guide slide Localized abnormal vasculogenesis (initial creation of blood vessels during embryonic development) & vascular function Facial vascular malformations Intracranial vascular malformations Ocular vascular malformations Nevus flammeus (port-wine stain birthmark) along skin in the distribution of the trigeminal nerve (ophthalmic/maxillary branches) Leptomeningeal capillary-venous malformation (abnormal blood vessel cluster in the brain/spinal covering) Heterochromia (different colored eyes) Episcleral & conjunctival VMs (abnormal blood vessels on the eye surface) Corresponding overgrowth of cutaneous (skin) vasculature Corresponding overgrowth of underlying soft tissues & facial bones Impaired venous drainage ↓ normal blood flow in the brain & ↑ overall venous pressure, causing venous hypertension Mechanism unclear. Associated with disruption of the hypothalamic-pituitary axis Choroidal hemangioma (benign blood vessel tumor in the choroid layer of the eye) Growth hormone deficiency Nodularity (nodule growths on skin) ↑ Venous pressure & ↓ venous blood flow cause venous stasis (blood pooling in veins) ↑ Accumulation of coagulation factors in the veins contributes to an ↑ risk of thrombosis (blood clots) ↑ Venous pressure in the episclera (outer layer of the eye) contributes to ↑ intraocular pressure Hypothyroidism** ↓ Venous blood flow impairs overall circulation & ↓ tissue oxygenation (chronic tissue ischemia) Thrombi (blood clots) travel through vasculature & can further ↓ or block blood flow ↑ Intraocular pressure gradually damages the optic nerve & contributes to vision loss Stroke-like events Glaucoma Interruption of blood flow & oxygen delivery to the brain damages key areas of brain tissue & ↓ clearance of waste products Hemiparesis (weakness on one side of the body) Cerebral hemiatrophy (loss of tissue or shrinkage of one side of the brain) ↑ Risk of focal cortical dysplasia (abnormal organization of brain cells in specific brain locations) ↑ Risk of brain atrophy ↑ Intraparenchymal calcification (calcium deposits in brain tissue) Chronic damage to brain tissue & continued impairment of key neurological functions Visual field defects Seizures Intellectual disability Behavioral problems Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 20, 2025 on www.thecalgaryguide.com Gingival/palatal angiomatosis (abnormal blood vessel growth in gum tissue & palate) Gingival hyperplasia (overgrowth of gum tissue) Legend: Sturge-Weber syndrome (SWS): Pathogenesis and clinical findings Somatic mosaic mutations in the GNAQ gene Authors: Dylan Hollman* Reviewers: Mina Youakim Fatemeh Jafarian* * MD at time of publication Abnormal regulation of intracellular signalling pathway in early embryogenesis Unclear mechanism → Primary defect in subset of angioblasts or other vascular supporting cells Facial vascular malformations (VMs) Localized abnormal vasculogenesis & vascular function Ocular vascular malformations (VMs) Port-wine stain (flat, red or purple birthmark caused by dilated blood vessels) → commonly affects trigeminal nerve (ophthalmic/maxillary) Intracranial vascular malformations (VMs) Choroidal Heterochromi Episcleral & hemangioma a conjunctival VMs (benign tumor (different (abnormal blood Leptomeningeal of blood vessels colored eyes) vessels on the capillary-venous in the choroid eye's surface) Overgrowth of Overgrowth of malformation layer of the eye) underlying soft cutaneous (abnormal blood tissue & bone vasculature vessel cluster in the ↑ episcleral brain/spinal (eye’s outer Nodularity Gingival/palatal covering) layer) venous angiomatosis pressure (abnormal blood Gingival Glaucoma vessel growth in hyperplasia Venous hypertension gum tissue & (overgrowth of gum palate) tissue) Chronic tissue ischemia Thrombosis Hemiparesis (weakness on one side of body) Venous stasis Unclear mechanism → disruption of hypothalamic-pituitary axis Focal cortical dysplasia (abnormal brain tissue in specific areas) Intraparenchymal calcification (calcium deposits in brain tissue) Stroke-like events Hemiatrophy (loss of tissue or shrinkage on one side of body) Hypothyroidism Growth hormone deficiency Seizures Visual field defects Intellectual disability Behavioral problems Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com Brain atrophy

Rickets and Osteomalacia Pathogenesis and Clinical Findings

Nutritional PO₄³⁻ deficiency Rickets and Osteomalacia: Pathogenesis and clinical findings **See corresponding Calgary Guide slide Direct inhibition of bone mineralization Phosphopenic rickets (insufficient phosphate (PO₄³⁻)) Medications (i.e., bisphosphonates) Hereditary hypophosphatasia Medication act as pyrophosphate (PPi) analogue Renal tubular defects (e.g., Faconi syndrome, distal renal tubular acidosis) Chronic use of Tumor- phosphate binders induced (e.g., calcium osteomalacia carbonate) Hereditary hypophosphatemic rickets Calcipenic rickets (insufficient calcium (Ca2+)) ↓ Sunlight exposure ↓ Intestinal absorption of fat- soluble vitamins (A, D, E & K) (e.g., in GI or liver disease) ↓ Intake through food Vitamin D- dependent rickets type 1 Vitamin D- dependent rickets type 2 Osteoblasts secrete ↓ alkaline phosphatase (ALP) (cleaves PPi to create sites forCa2+ & PO₄³⁻ deposition) ↑ Fibroblast growth factor 23 (FGF23) Mutation in CYP27B1 or CYP2R1 gene Mutation in vitamin D receptor gene ↑ PPi binds to growing hydroxyapatite crystals in bone & prevents further deposition of Ca2+ & PO₄³⁻ ↑ Renal losses of PO₄³⁻ FGF23 ↑ breakdown of FGF23 ↑ 24- 1α-hydroxylase (converts Hydroxylase Vitamin D deficiency (most common cause) calcidiol (inactive vitamin activity D) to calcitriol (active (catabolizes calcitriol) vitamin D) ↓ Calcidiol Mutations prevent conversion of calcidiol to calcitriol End-organ resistance to calcitriol ↓ Cleavage of PPi ↓ Calcitriol ↓ PO₄³⁻ released from PPi ↓ PO₄³⁻ absorption in intestines ↓ Ca2+ absorption from intestines & kidneys Hypophosphatemia (↓ Serum PO₄³⁻) Hypocalcemia** (↓ Serum Ca2+) Ca2+ deficiency ↓ Availability of PO₄³⁻ & Ca2+ impairs formation of hydroxyapatite ((Ca10(PO4)6(OH)2) crystals (deposition of crystals hardens bone) Parathyroid gland releases PTH (secondary hyperparathyroidism) to maintain serum Ca2+ Impaired mineralization of osteoid ↑ Parathyroid hormone** (PTH) Rickets Defective mineralization of new bone formation at growth plate (only occurs in children with open growth plates) Defective mineralization of preformed osteoid Osteomalacia Defective mineralization of existing bone (can occur in individuals with open or closed growth plates) Unmineralized cartilage overgrows at growth plates ↓ Mineralization impairs structural integrity of bone ↓ Calcitriol & PO₄³⁻ impairs dentin & enamel mineralization Unmineralized cartilage overgrows at costochondral junctions ↓ Mineralization of skull bones ↓ Structural integrity & ↓ bone density ↓ PO₄³⁻ disrupts ATP production in muscles Osteoblasts secrete ↑ ALP to compensate for ↓ mineralization ↑ Diameter of growth plate & metaphysis Shear forces bend osteopenic bone during ambulation Delayed dental eruption & enamel hypoplasia Rachitic rosary (palpable bead-like nodules along ribs) ↑ Stress on poorly mineralized bone ↑ Stimulation of periosteal nociceptors Muscle weakness &/or poor tone ↑ALP Metaphyseal cupping on X-ray Widened wrists & ankles Progressive lateral bowing of femur & tibia Abnormal gait Genu varum/valgum Delayed fontanelle closure Craniotabes (softening of skull bones) Fractures &/or pseudofractures Localized bone pain or tenderness ↓ Bone mineral density Authors: Olivia Yung, Payam Pournazari Reviewers: Merry Faye Graff, Yan Yu, Spencer Montgomery, Emily J. Doucette, David Hanley*, Danielle Nelson* * MD at time of publication Sign/Symptom/Lab Finding Complications Published Nov 26, 2012; updated Nov 2, 2025 on www.thecalgaryguide.com ↓ Mineralization impairs growth plate fusion ↓ Linear bone growth Short stature Legend: Pathophysiology Mechanism

Acute Tubular Necrosis

Acute Tubular Necrosis: Pathogenesis & clinical findings Severe systemic volume depletion (e.g., vomiting, diarrhea) Septic shock** Cardiogenic shock** Cholesterol embolization syndrome (rare) Severe hypotension ↓ Mean arterial pressure reduces renal perfusion pressure which ↓ renal blood flow Renal vascular autoregulation fails to maintain renal perfusion Tubular cell hypoxia & depletion of adenosine triphosphate (ATP) (primary energy carrier in cells) Cell ion pump failure, cell swelling, & cell membrane disruption Ischemic tubular necrosis (renal tubular cell injury secondary to ↓ blood flow) Myoglobinuria Hemoglobinuria Aminoglycosides Ethylene glycol Amphotericin Cisplatin ↓ Efficiency of kidney reabsorption & excretion Kidney removes ↓ potassium (K+) from the blood volume Hyperkalemia** (high K+ concentration in the blood) ↑ Serum K+ levels induce abnormal cardiac electrical conduction patterns & excessive cardiac excitability Fatal cardiac dysrhythmia (irregular heartbeat pattern) Kidney removes ↓ urea from the blood volume Kidney removes ↓ creatinine from the blood volume Azotemia (↑ serum urea & creatinine) Uremic toxins systemically impair neutrophil function Uremic toxins (indoxyl sulfate or paracresyl sulfate) induce oxidative stress in the brain through accumulation of reactive oxygen species (ROS) ↑ Risk of infection ROS damage neuronal membranes & ion channels & induce dysfunctional mitochondria in the brain Authors: Adam Bubelenyi Reviewers: Britney Wong Luiza Radu Jessica Revington Veronica Hammer* Braden Manns* * MD at time of publication **See corresponding Calgary Guide slide Dysfunctional brain mitochondria cannot properly metabolize purines & urea Brain cannot use any metabolic or cellular pathways requiring ATP ↓ Cerebral neuronal signaling Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Intravenous (IV) administration of iodinated contrast medium Tumor lysis syndrome Cancer cell apoptosis (cell death) releases ↑ uric acid & phosphate Heme-containing pigments Medications Uric acid & calcium phosphate crystals precipitate in renal tubules Nephrotoxic substances damage renal tubular cells through unique mechanisms Lipid peroxidation (oxidative degradation) of lipid bilayer weakens renal tubular cell membranes Damage to mitochondria in tubular cells causes depletion of ATP Formation of oxygen free radicals in renal tubular cells Impairment of ATP- dependent processes Activation of pro-inflammatory cytokines & enzymes in the kidney ↑ Renal tubular cell permeability Disruption of protein synthesis & enzyme function in renal tubular cells Degradation of tubular cell membrane lipids & proteins Free radicals oxidize tubular cell proteins & impair structure & function Toxic tubular necrosis (renal tubular injury due to nephrotoxic substances) Acute Tubular Necrosis Acute kidney injury via renal tubular cell damage & cell death Denudation (removal of surface tissue layers) & erosion of the tubular basement membrane Kidney removes ↓ sodium (Na+) & water from the blood volume ↓ Bicarbonate reabsorption from the proximal tubule of the kidney Necrotic tubular cells fall into tubular lumen Ongoing tubule damage ↓ ability to concentrate urine solutes ↓ Bicarbonate neutralization of acids in the blood Necrotic tubular cells release intracellular contents Obstruction of tubular lumen impedes glomerular filtration ↓ Urine osmolality (low urine solute concentration) ↑ Water in blood volume dilutes Na+ serum concentration Metabolic acidosis (blood pH <7.35) Muddy brown granular casts ↓ Glomerular filtration rate (GFR) Hyponatremia** (low Na+ concentration in the blood) ↑ Na+ retention in the circulatory blood volume & ↓ Na+ excretion in the urine ↓ Urine output Accumulation of ROS activates microglia & releases pro-inflammatory cytokines ↑ Fluid retention in the circulatory system Aggressive IV fluid rehydration in septic shock or cardiogenic shock patients Cerebral inflammation ↑ oxidative damage to neurons & glial cells Fluid overload Uremic encephalopathy Pulmonary edema (excess fluid accumulation in lung alveoli & interstitium) Published November 15, 2025 on www.thecalgaryguide.com Complications Disruption of DNA & RNA synthesis within renal tubular cells Tubular epithelial cells in urine Epithelial cell casts in urine (cast composed of epithelial cells embedded in a matrix) ↓ Ability to clear bacteria in urine ↑ Risk of urinary tract infection

Peripheral Vestibular Dysfunction

Peripheral Vestibular Dysfunction: Pathogenesis, mechanisms, & clinical findings Preceding viral illness or bacterial infection Vestibular structure pathologies Impaired resorption of endolymph (inner ear fluid involved in hearing & balance) in the membranous labyrinth (fluid-filled chambers & ducts in the inner ear) ↑ Humoral & cellular immune responses in the inner ear cause nerve inflammation Otoconia (calcium carbonate crystals in the inner ear) dislodge & migrate into the ear’s semicircular canals Direct entry of pathogens via oval or round window (membrane-covered openings between the middle & inner ear) Hematogenous (through blood) or subarachnoid space infection ↑ Accumulation of endolymph distends the membranous labyrinth & produces ↑ pressure on inner ear structures Dislodged otoconia cause differences in endolymph flow & subsequent asymmetric hair cell movement Ménière’s disease Endolymphatic hydrops (abnormal endolymph buildup in the inner ear) Vestibular hyperactivity & mismatched visual sensory input activates the histaminergic neuronal system in the hypothalamus Histaminergic neurons send activation signals to histamine H1 receptors in the brain’s vomiting centre Activation of H1 receptors stimulates the chemoreceptor trigger zone in the vomiting centre Nausea** Vomiting** Legend: ↑ Cytokines (immune chemical messengers) ICAM-1 & IL-1β recruit additional immune cells to the inner ear & further ↑ immune responses Activation of immune cells within inner ear Benign paroxysmal positional vertigo** Breakdown of the inner ear blood-labyrinth barrier Autoimmune inner ear disease (e.g., Cogan’s syndrome, granulomatosis with polyangiitis, systemic lupus erythematosus) Systemic manifestations of autoimmune disease (e.g., rash, joint pain, eye inflammation) Labyrinthitis (membranous labyrinth inflammation) Vestibular neuritis (inflammation of the vestibular nerve) Peripheral Vestibular Dysfunction Pathology of the inner ear & vestibular portion of the vestibulocochlear nerve Central nervous system receives dysregulated visual inputs, vestibular inputs, & proprioceptive (body positioning) inputs ↑ Damage to the hair cells (sensory receptors) in the inner ear ↑ Damage to the vestibulocochlear nerve Loss of nerve input from the vestibulocochlear nerve causes abnormal neuronal activity in the auditory cortex Asymmetric, mismatched, or contradictory sensory inputs cannot be properly interpreted by the brain Damaged hair cells cannot convert sound or movement into appropriate electrical signals for vestibulocochlear nerve transmission Brainstem & auditory cortex receive ↓ or no auditory signal input from the vestibulocochlear nerve Abnormal neuronal activity & nerve signals may be misinterpreted by the auditory cortex as sound Sensorineural hearing loss Dizziness Vertigo (abnormal sensation of spinning or movement) Subjective tinnitus** (continuous or intermittent perception of ringing or buzzing without an acoustic stimulus) Published November 23, 2025 on www.thecalgaryguide.com Vestibulocochlear nerve pathologies NF2 gene encodes for functional schwannomin (cell structure protein involved in suppressing tumour growth) Point mutations & loss of heterozygosity in the NF2 gene result in ↓ or absent schwannomin Schwann cells (cells protecting nerve fibres) form a protective myelin sheath on the vestibulocochlear nerve Schwann cells malfunction in the absence of schwannoma & the myelin sheath is compromised Vestibular schwannomas (benign tumours on the vestibulocochlear nerve) develop in the absence of functional schwannomin Asymmetric vestibular input disrupts the nerve inputs sent to the oculomotor nuclei (brainstem nerve cells responsible for muscles involved in eye movement) Triggers an abnormal vestibulo-ocular reflex (normal reflex keeps vision steady while the head moves) Authors: Nystagmus (repetitive & uncontrolled eye movements) Fariha Rahman Farah Ali Reviewers: Vaneeza Moosa Jessica Revington Gabrielle Juliet French* * MD at time of publication **See corresponding Calgary Guide slide Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS): Pathogenesis and clinical findings Initiation or ↑ dose of dopamine receptor (D2) antagonist medication (typical antipsychotics more common than atypical; antiemetics eg. metoclopramide) Medication blocks dopamine D2 receptors in the central nervous system Genetic risk factors including DRD2 A1 allele (TaqI A1 polymorphisms) & CYP2D6 deficiency Sudden ↓ in central dopamine activity Rapid withdrawal of dopaminergic medications (eg. Levodopa) Abrupt withdrawal of D2 receptor stimulation in the central nervous system Depolarization blockade of the nigrostriatal pathway & basal ganglia (mechanism not fully understood) Disinhibition of striatal indirect pathway Hyperactive subthalamic nuclei drives excitation of globus pallidus internus (GPi) Overactive GPi strongly inhibits thalamus & ↓ cortical motor output ↓ Cortical motor output produces sustained muscle contraction ↑Peripheral calcium release from myocyte sarcoplasmic reticulum Continuous depolarization & sustained contraction ↑ Metabolic demand & heat production Dopamine depletion in mesolimbic & neocortical pathways (mechanism not fully understood) Altered mental status (e.g. delirium) Hypothalamic dysregulation & autonomic instability (mechanism not fully understood) Disinhibition of posterior hypothalamus sympathetic premotor neurons Dysregulated thermogenesis & impaired cooling mechanisms in the anterior pre-optic area Strong neuronal excitation in the paraventricular nucleus amplifies signals along descending autonomic tracts Persistent sympathetic tone & suppressed parasympathetic tone Diaphoresis Tachycardia Fluctuating blood pressure Severe “lead-pipe” muscle rigidity ↑ Serum creatine kinase Myoglobinuria Hyperthermia (fever ≥40◦C) Acute renal failure Prolonged illness promotes skeletal muscle damage & breakdown, immobilization, & dehydration Rhabdomyolysis Author: Amena Thraya Reviewers: Emily J. Doucette, Rupang Pandya* * MD at time of publication Legend: Pathophysiology Mechanism Published Feb 24, 2026 on www.thecalgaryguide.com Sign/Symptom/Lab Finding Complications