SEARCH RESULTS FOR: renal

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" />

Upper Urinary Tract infection (UUTI): Pathogenesis and Clinical Findings

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Central Adrenal Insufficiency - Pathogenesis and Clinical Findings

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

Pathogenesis of Anxiety Disorders

Yu, Y - Pathogenesis of Anxiety Disorders FINAL.pptx Stress hormones interact with brain and body in various complicated mechanismsAnxiety Disorders: Pathogenesis of AnxietyPhysiological arousalAuthor: Yan YuReviewers:Sara Meunier JoAnna FayDex ArnoldMargaret Oakander* MD at time of publicationLegend:Published October 28, 2013 on www.thecalgaryguide.comMechanismPathophysiologySign/Symptom/Lab FindingComplicationsGenetics (Positive family history)Sense of foreboding or apprehensionActivation of hypothalamus-pituitary-adrenal cortex axisPredisposition to anxiety: Imbalance and/or abnormal functioning of norepinephrine, serotonin, dopamine, and gamma-aminobutyric acid (GABA) Female gender (may be related to hormonal factors, less internal locus of control, greater reporting rates)Other biological theories (under investigation)Prefrontal Cortex modulation of amygdala impairedUnpleasant tensionAmygdala maladaptively activates fear response? Cortisol releaseChronic activation of stress hormones over time causes death of neurons in the hippocampusAnxiety Disorders:A maladaptive emotional state causing fear, worry, and excessive stress, characterized by:Perceived environmental threatHippocampus and Cingulate Gyrus abnormally process threatActivation of autonomic nervous system and adrenal medulla? Epinephrine releaseHippocampus shrinks in sizeAbility of hippocampus to normally integrate environmental stimuli is further compromisedMood dysregulationMemory impairmentStrong association between anxiety disorders and depressionMeasurable ? in Brain-Derived Neurotrophic factor (BDNF)BDNF value correlates with the degree of neuronal loss in the hippocampus 97 kB / 173 words

Pre-Renal Acute Kidney Injury Pathogenesis

Pre-Renal Acute Kidney Injury Pathogenesis

Hyperosmolar Hyperglycemic State

Hyperosmolar Hyperglycemic State (HHS) Note: HHS is only seen in Type II DM patients! Note: In patients with either DKA or HHS, always look for an underlying cause (i.e. an infection) Author: Yan Yu Reviewers: Peter Vetere Gill Goobie Hanan Bassyouni* * MD at time of publication Alters total body water & ion osmosis Inadequate insulin production, insulin resistance, non- adherence to insulin Tx Relative Insulin deficit Stresses that ↑ Insulin demand: infections, pneumonia, MI, pancreatitis, etc) Hyperglycemia (Very high blood [glucose], higher than in DKA) When blood [glucose] > 12mmol/L, glucose filtration > reabsorption, ↑ urine [glucose] Glucosuria Glucose in filtrate promotes osmotic diuresis: large- volume urine output Polyuria Dehydration (↓ JVP, orthostasis: postural hypotension/ postural tachycardia, ↑ resting HR) Some insulin still present, but not enoughsome glucose is utilized by muscle/fat cells, some remain in the blood Cells not “starved”, but still need more energy ↑ release of Catabolic hormones: Glucagon, Epinephrine, Cortisol, GH Body tries to ↑ blood [glucose], to hopefully ↑ cell glucose absorption Hypothalamic cells sense low intra-cellular glucose, triggering feelings of hunger Polyphagia Note: the presence of some insulin directly inhibits lipolysis; thus, in HHS there is no ketone body production, and no subsequent metabolic acidosis and ketouria (unlike in DKA). If ketones are detected in an HHS patient it’s likely secondary to starvation or other mechanisms. ↓ ECF volume, ↑ ECF osmolarity (i.e. hypernatremia) ↑ Gluconeogenesis ↑ Glycogenolysis (in liver) ↓ Protein synthesis, ↑ proteolysis (in muscle) ↑ Gluconeogenic substrates for liver If the patient doesn’t drink enough water to replenish lost blood volume If pt is alert and Electrolyte imbalance water is accessible Water osmotically leaves neurons, shrinking them Neural damage: delirium, lethargy, seizure, stupor, coma ↓ renal perfusion, ↓ GFR Renal Failure (pre-renal cause; see relevant slides) Polydipsia Note: in HHS, body K+ is lost via osmotic diuresis. But diffusion of K+ out of cells may cause serum [K+] to be falsely normal/elevated. To prevent hypokalemia, give IV KCl along with IV insulin as soon as serum K+ <5.0mmol/L. But ensure patient has good renal function/urine output first, to avoid iatrogenic hyperkalemia! Note: Electrolyte imbalances (i.e. hyperkalemia, hypernatremia) are worsened by the acute renal failure commonly coexisting with DKA/HHS Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 3, 2016 on www.thecalgaryguide.com

chronic-hypertensive-retinopathy-pathogenesis-and-clinical-findings

Chronic Hypertensive Retinopathy: Pathogenesis and clinical findings Risk Factors for 1° HTN (ex. 1` Age, FHx, Ethnicity, Diet, Smoking, 1` Alcohol use, Stress, 1` Salt intake, 1` BMI, 1, Exercise) • 1° HTN Retinal Detachment Vitreous Hemorrhage Central/Branch Retinal Artery/Vein Occlusions Risk Factors for 2° HTN (ex. Hyperaldosterone, Cushing's, Acromegaly, Chronic Kidney Disease, Obstructive Sleep Apnea, Diabetes Mellitus, Hypo/Hyper-thyroid, Adrenal Hyperplasia, Renal Artery Stenosis) 2° HTN Ophthalmic Artery Hypertension ,17 Stage 1: Mild/vasoconstrictive Stage 2: Moderate/sclerotic Stage 3: Severe/exudative Stage 4: Malignant Abbreviations: • HTN — Hypertension • BRB — Blood-retinal barrier • RPE — Retinal pigment epithelium Legend: Pathophysiology Mechanism Acute and chronic vasospasm Authors: Graeme Prosperi-Porta Reviewers: Stephanie Cote Usama Malik Johnathan Wong* * MD at time of publication Diffuse and focal arterial narrowing and vascular tortuosity Atherosclerosis and hyalinization causes arteriolar wall thickening resulting in a diffuse light reflex appearing red-brown coloured Thickening of the arteriolar wall and/or sclerotic thickening at the arteriole/venule crossing compresses the underlying venule BRB breakdown causes dot/blot hemorrhages in the inner retina and flame hemorrhages in the nerve fiber layer Serum proteins and lipids leakage from damaged BRB appears as white or yellow areas with sharp margins Occlusion of the terminal retinal arterioles causes fluffy white ischemic lesions in the inner retinal nerve fiber layer Hyper-pigmented patches surrounded by a hypo-pigmented ring due to RPE clumping around atrophic areas in the choroid Sign/Symptom/Lab Finding lschemia of optic disc arterioles causes optic nerve swelling and blurred disc margins. Leakage of optic disc arterioles causes hemorrhage and disc edema. Complications Copper Wiring AV nicking Retinal Hemorrhages Yellow Hard Exudates Cotton-wool Spots Elschnig's Spots Papilledema

Serotonin Syndrome Pathogenesis and Clinical Findings

Serotonin Syndrome: Pathogenesis and Clinical Findings Serotonergic Agents SSR1s, SNRIs, MOAIs, TCAs, atypical antidepressants, antibiotics, mood stabilizers (valporate, lithium), opioids, antiemetic agents, triptans, weight loss agents, drugs of abuse (e.g. cocaine, amphetamines) Therapeutic drug use • Drug interactions (esp. combo of serotonergic agents) Serotonin Syndrome Variable combination of mental status changes, autonomic instability, and neuromuscular hyperactivity ranging from mild to life-threatening with an abrupt onset (within minutes to hours) after medication ingestion and most cases resolving within 24 hours of cessation of offending medication Intentional self-poisoning Excessive serotonergic activity at 5-HT receptors centrally (brainstem) and peripherally serotonin synthesis and release serotonin reuptake and metabolism IN receptor agonism and sensitivity 4, Drug-induced changes in the relative ratio of non-serotonergic neurotransmitters (e.g. increase in noradrenaline) Altered Mental Status Anxiety, confusion, agitation, hypervigilance, pressured speech, delirium, coma Autonomic Instability Shivering, diaphoresis, fever, diarrhea, tachycardia, mydriasis, hypertension Authors: Preeti Kar Reviewers: Erika Russell Usama Malik Aaron Mackie* * MD at time of publication Notes: The Hunter Serotonin Toxicity Criteria is used to make a clinical diagnosis • History of serotonergic agent taken within past 5 weeks + any of the following clinical features: • Spontaneous clonus • Inducible clonus and either agitation or diaphoresis • Ocular clonus and either agitation or diaphoresis • Tremor and hyperreflexia • Hypertonia, temperature > 38 °C, and either ocular clonus or inducible clonus Neuromuscular Hyperactivity Hyperreflexia, muscle rigidity (esp. lower extremities), myoclonus, tremor, incoordination, trismus*, opisthotonus*, ocular clonus*, seizures *Notes: • Trismus or lockjaw, is the reduced opening of the jaw • Opisthotonus is an abnormal body position where the person is usually rigid and arches their back, with their head thrown backwards • Ocular Clonus is rhythmic or equal movements of both eyes; should be distinguished from nystagmus which has a fast and slow component Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Abbreviations: • 5-HT = serotonin • SSRI = selective serotonin reuptake inhibitors • SNRI = selective noradrenaline reuptake inhibitors • MOAI = monoamine oxidase inhibitors • TCA = tricyclic antidepressants

2nd gen antipsychotics (Slovenian translation) - FINAL VERSION

Antipsihotiki druge generacije: mehanizem delovanja in neieleni utinki antipsihotiki druge generacije (atipibi antipsihotiki): primeri: klozapin, olanzapin, kvetiapin, risperidon, paliperidon itd. antagonisti dopaminskih D2 receptorjev zavirajo delovanje DA na D2 receptorjih po celotnih mo2ganih antagonisti serotoninskih 2A receptorjev zavirajo delovanje 5-HT na 5-HT2A receptorjih po celotnih mo2ganih antagonisti serotoninskih 2C receptorjev klozapin, olanzapin, kvetiapin antagonisti ACh M1 receptorjev zavirajo delovanje ACh po telesu (v ustih, prebavilih, o6eh, mo2ganih) antagonisti aradrenoceptorjev v oiilju dilatacija gladkih migic v stenah arteriol antagonisti histaminskih H1 receptorjev zavirajo delovanje histamina po telesu sano-presnovni kink' mehanizem neznan Legenda: patofiziologija mehanizem Pomni: posledica velikih razlik v afiniteti za receptorska vezavna mesta so svojevrstni terapevtski in varnostni profili atipicnih a nti psi hoti kov. Kloza pi n med vsemi velja za najud nkovitejSega, a i ma tudi najve6 neZelenih uC'inkov, vkljUuja agranulocitozo (0,5-2 %). Tako predstavlja terapijo drugega izbora, potrebno je red no spremljanje bolnikove krvne slike. mezolimbiEna pot DA blokada > 5-HT blokado nigrostriatna pot 5-HT blokada > DA blokado 4, pozitivnih simptomov terapevtski ueinek blokada 5-HT vodi v sprokanje DA v striatumu tubero- blokada 5-HT zavre sprokanje infundibularna pot prolaktina v adenohipofizi mezokortikalna pot blokada 5-HT2c receptorjev stimulira sprokanje DA in NA v prefrontalni skorji zamegljen vid kognitivna upolasnjenost sposobnost vzdrievanja krvnega tlaka omotica apetit T tel. tee ortostatska hipotenzija tveganje za debelost trigliceridi na tee inzulinska odpornost —■ diabetes tipa 2 znak/simptom/laboratorijska najdba 4, halucinacii blodeni avtorica: Sara Meunier pregledala: Yan Yu, Aaron Mackie* * dr. med. ob objavi prevedel in priredil: Jan KejZar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. 4, ekstrapiramidnih simptomov (EPS)* 4, hiperprolaktinemije* prokognitivni in antidepresivni ainki 4, kognitivnih simptomov* 4, negativnih simptomov* * Glede na anti-psihotike prve generacije, glej ustreznogradivo! okrajgave: 5-HT - serotonin DA - dopamin NA - noradrenalin ACh - acetilholin visoko presnovno tveganje: klozapin, olanzapin zmerno presnovno tveganje: risperidon, kvetiapin nizko presnovnotveganje:antipsihotikitretjegeneracije 1 tveganje za diabeti6no ketoacidozo pri bolnikih z visokim tveganjem tveganje za srbo-iilne dogodke tveganje za prezgodnjo smrt zaplet Objavljeno 15. junija 2017 na www.thecalgaryguide.com.

BMR (Slovenian translation) - FINAL VERSION

Bipolarna motnja razpoloienja: patogeneza in kliniene najdbe genetika 85-% tveganje pri enojagnih neravnovesja iivenih prenagalcev dvoj6kih, 5- do 12-% tveganje zlasti serotonina, noradrenalina pri sorodnikih v prvem kolenu in dopamina nepravilnosti v moig. poteh deregulacija frontalnih in limbi6nih poti maniEna epizoda najmanj 1 teden ali indikacija za sprejem • ( A privzdignjeno/ekspanzivno/razdrailjivo razpoloienje k cilju usmerjenega vedenja/agitacija potrebe po spanju odkrenljivost vrveiavost pospegen govor evforije velilavosti I` razdrailjivosti tveganja Legenda: patofiziologija mehanizem inhibicije nadzora custvenih poti bipolarna motnja razpoloienja motnje homeostaze custev 4, nihanja razpoloienjskih stanj raznolik potek bolezni pri razliCnih bolnikih evtimi'a o6itna obdobja normalnega razpolo2enja Primarni cilj zdravljenja je vzdr2evati to fazo! okoljski dejavniki (travmatski dogodki, 2ivljenjski stresorji) ) Pomni: • Bipolar motnja tipa 1: maniba epizoda in/ali depresivna epizoda: priblrino 10 epizod manije in depresije v 2ivljenju bolnika v primeru nezdravljene bolezni • Bipolar motnja tipa 2: hipomaniba epizoda in depresivna epizoda • hipomaniba epizoda predstavlja bla2jo obliko manije, tj. brez funkcionalne okrnjenosti, brez psihotibih simptomov, brez hospitalizacije in v trajanju vsaj 4 zaporednih dni znak/simptom/laboratorijska najdba avtorici: Briana Cassetta, Sara Meunier pregledali: Yan Yu, Alexander Arnold, Philip Stokes* * dr. med. ob objavi prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. depresivna epizoda najmanj 2 tedna depresivno razpoloienje socialnega urriika obEutkov krivde, tesnobe brezupa samomorilnih misli in vedenja anhedonija teiave s pozornostjo A v spanju, utrujenost A tel. teie, apetita psihomotorna agitira nost ali upolasnjenost zaplet Objavljeno 30. junija 2017 na www.thecalgaryguide.com.

Bupropion (Slovenian translation) - FINAL VERSION

Bupropion (atipiEni antidepresiv): Mehanizem delovanja in neieleni utinki potenten antidepresiv v monoterapiji all kot dodatno zdravilo pri zdravljenju razpoloienjskih motenj okrajgave: 5-HT - serotonin DA - dopamin DAT - prenagalec DA NA - noradrenalin NAT - prenagalec NA SSRI - selektivni zaviralec ponovnega privzema 5-HT Legenda: bupropion farmakologija antidepresivni udnki uporaben pri zdravljenju NAT), ki proizvaja aktivne metabolite. Natan'6en mehanizem delovanja (se) ni znan. znak/simptom/laboratorijska najdba DA in NE posledi6no ostaneta v sinapsah dlje Casa in okrepita 2iv6ni prenos neieleni udnki glavobol suha usta 4, tel. tee nespeEnost slabost zaprtie tahikardija epileptiEni napadi faringitis omotica hipertenziia agitacija prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. eliminacija poteka preko jeter in ledvic prilagoditev odmerka v primeru bolezni jeter in/ali ledvic bupropion lahko inhibira jetrni citokrom P4502D6 in povzrod interakcije med zdravili kontraindiciran pri boleznih, ki zmanIgajo epileptogeni prag: anoreksija/bulimija nervoza, epilepsija, odtegnitev alkohola, odtegnitev benzodiazepinov zaplet Objavljeno 30. junija 2017 na www.thecalgaryguide.com. " title="Bupropion (atipiEni antidepresiv): Mehanizem delovanja in neieleni utinki potenten antidepresiv v monoterapiji all kot dodatno zdravilo pri zdravljenju razpoloienjskih motenj okrajgave: 5-HT - serotonin DA - dopamin DAT - prenagalec DA NA - noradrenalin NAT - prenagalec NA SSRI - selektivni zaviralec ponovnega privzema 5-HT Legenda: bupropion farmakologija antidepresivni udnki uporaben pri zdravljenju "zmaniganega pozitivnega afekta" nima pomembnelgih 5-HT udnkov povzraa spolne disfunkcije v primerjavi s SSRI; lahko celo odpravi omenjeni neieleni udnek (povzraen s strani SSRI) dodatek pri zdravljenju odvisnosti od nikotina preko T iive'nega prenosa DA v nagrajevalni poti energije preko T 2ivbega prenosa NA patofiziologija mehanizem farmakokinetika farmakodinamika avtorica: JoAnna Fay, Sara Meunier pregledala: Jojo Jiang, Alexander Arnold, Aaron Mackie* * dr. med. ob objavi Nizkoafiniteten zaviralec ponovnega privzema DA in NA (DAT>NAT), ki proizvaja aktivne metabolite. Natan'6en mehanizem delovanja (se) ni znan. znak/simptom/laboratorijska najdba DA in NE posledi6no ostaneta v sinapsah dlje Casa in okrepita 2iv6ni prenos neieleni udnki glavobol suha usta 4, tel. tee nespeEnost slabost zaprtie tahikardija epileptiEni napadi faringitis omotica hipertenziia agitacija prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. eliminacija poteka preko jeter in ledvic prilagoditev odmerka v primeru bolezni jeter in/ali ledvic bupropion lahko inhibira jetrni citokrom P4502D6 in povzrod interakcije med zdravili kontraindiciran pri boleznih, ki zmanIgajo epileptogeni prag: anoreksija/bulimija nervoza, epilepsija, odtegnitev alkohola, odtegnitev benzodiazepinov zaplet Objavljeno 30. junija 2017 na www.thecalgaryguide.com. " />

Left Heart Failure: Pathophysiology (Neurohormonal Activation)

Left Heart Failure: Pathophysiology (Neurohormonal Activation) Frank Starling Mechanism • The Frank Starling mechanism of the heart represents the relationship between preload (EDV) and SV • As preload (EDV) increases, SV increases, because higher volumes of blood in the ventricles stretch the cardiac fibers and increases cardiac contraction during systole. However, volume overload causes reduced SV. Myocardial Dysfunction: • Left ventricular Compensatory 4, SV 4A, CO 4 Mechanisms 4, BP Important equations: • BP = CO x SVR • CO = SV x HR Cardiac hemodynamics: • Stroke volume is affected by three factors 1) Preload (end-diastolic volume (EDV)) 2) Afterload (resistance to LV ejection) 3) Contractility (inherent strength of contraction of LV myocytes) Definition of heart failure: • Myocardial dysfunction (systolic or diastolic) results in decreased CO, such that the heart cannot meet the body's metabolic demands or can only do so at elevated filling pressures Anti-diuretic hormone (ADH) activation: Arginine 4, BP 4 carotid sinus Vasopressin --• and aortic arch (V2) receptor baroceptors activation activation 4 I` ADH release RAAS System: 4, BP 4 t release of renin from the juxtaglomerular kidney cells due to renal hypoperfusion SNS System: In response to CO, 4 SNS t release of (catecholamines) norepinephrine and epinephrine Adrenal Glands: Aldosterone release Angiotensin II Type 1 receptor activation al receptor activation 13, receptor activation —• Renal Collecting Ducts: t H2O retention Renal Distal —• Tubules: t Na+ & H2O retention Heart: Activation of fibroblasts 4 collagen synthesis and hypertrophy Blood Vessels: Peripheral vasoconstriction 4 SVR Heart: Chronic p, receptor activation 4 Ca2+ overload myocyte apoptosis Heart: Increase HR to maintain normal CO Maladaptive Response: t preload (EDV), —• volume overload Abbreviations: • SV — Stroke volume • CO — Cardiac output • SVR — Systemic vascular resistance • BP — Blood pressure • RAAS — Renin-Angiotensin-Aldosterone System • SNS — Sympathetic nervous system tin systemic and pulmonary congestion via the Frank-Starling Mechanism Maladaptive 1` resistance Response: t BP, —• against LV afterload ejection 4 4, SV Maladaptive Response: Adverse LV remodelling Maladaptive Response: t myocardial oxygen demand and 4, diastolic time 4, contractility —• of the heart 4, coronary blood flow 4 myocardial ischemia Physical signs and symptoms of congestive heart failure (see relevant slide) Authors: Sunny Fong Reviewers: —• I Jack Fu Usama Malik Dr. Jason Waechter* *MD at time of publication

Anksiozne motnje: patogeneza tesnobe

Anksiozne motnje: patogeneza tesnobe ienski spol (morda v povezavi s hormonskimi dejavniki, manj notranjega „lokusa

Depresivna epizoda/motnja: patogeneza in klinične najdbe

Depresivna epizoda/motnja: patogeneza in kliniene najdbe Legenda: genetika 10 do 15-% tveganje z obolelim sorodnikom v prvem kolenu, 50-% tveganje z obolelim enojagninn bratom monoaminska hipoteza zni2ani konc. NA in 5-HT v mo2ganih, doka-zani z obdukcijskimi studijami, mehanizmom delovanja antidepresivov in PET slikanjem • Freudova teorija jeza in agresija zaradi medosebne izgube usmerjeni navznoter Beckov kognitivni model triada negativnih misli o sebi, svojem svetu in svoji prihodnosti; ponavljajai se vzorci depresivnega razmigljanja; okrnjena obdelava podatkov v mo2ganih psiholaki in • avtorica: JoAnna Fay pregledali: Sara Meunier, Jojo Jiang, Alexander Arnold, Philip Stokes* * dr. med. ob objavi prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. revkina in dru2bena izklju6enost neugodni 2ivljenjski dogodki (npr. zloraba, izguba, bolezen, laitev) pomanjkanje tesnih, zaupnih odnosov druibeni dejavniki Prevalenca 10-15 % pri 2enskah in 5-12 % pri mogkih. Razmerje med 2enskami in mc&imi 2:1. Pogosteja pri razvezanih, laenih in samskih ter tistih z nizkim druThenoekonomskim stanjem. depresivna epizoda/motnja simptomi (po DSM 5 merilih) prisotni tekom istega dvotedenskega obdobja in pomenijo odklon od premorbidne ravni funkcioniranja drugi simptomi pomanjkanje libida tesnoba razpolo2enje '6ez dan niha (ang. diurnal variation) huje pozimi (sezonska depresivna motnja) halucinacije (psihotiCna depresija) blodnje (psihotiena depresija) anhedonija (izguba zanimanj/u2itkov) depresivno razpolo2enje nejeknost ali povaan apetit s pridrdienimi spremembami telesne te2e (4, ali 1`) anergija (utrujenost) nespanost ali preva spanja okrajgave: 5-HT - serotonin NA - noradrenalin nastop v mesecu po porodu (poporodna depresija) obC'utki niC'vrednosti ali pretirane krivde psihomotorit'na upaasnjenost ali agitiranost upad spoznavnih sposobnosti (zlasti motnje pozornosti) ponavljajae se misli na smrt/samomor

Serotoninski sindrom: patogeneza in klinične najdbe

Serotoninski sindrom: patogeneza in kliniene najdbe serotoninergiEne snovi SSRI, SNRI, MAOI, TCA, atipieni antidepresivi, antibiotiki, stabilizatorji razpololenja (valproat, litij), opioidi, antiemetiki, triptani, zdravila za izgubo tel. te2e, ilegalne psihoaktivne snovi (npr. kokain, amfetamini) terapevtska raba 1 interakcije (se posebej pri kombinacijah serotoninergikov) namerna samozastrupitev serotoninski sindrom raznolika kombinacija sprememb v psihiZnem stanju, vegetativne nestabilnosti in iivZnomigiZne hiperaktivnosti, ki sega od blage do iivljenje ogroiajoL'e z nenadnim nastopom (v nekaj minutah do urah) po administraciji zdravil(a), v vecini primerov pa se razregi v <24 urah po prekinitvi jemanja odgovorne snovi prekomerna serotoninergitha aktivnost 5-HT receptorjev centralno (v moiganskem deblu) in periferno sinteza in privzem in T receptorski agonizem sprogEanje 5-HT presnova 5-HT in ok'utljivost z zdravili povzraene spremembe v relativnem razmerju ne-serotoninergithih nevrotransmitorjev (npr. pove6anje konc. noradrenalina) spremenjeno psihreno stanje tesnoba, zmedenost, agitacija, hipervigilnost, dolgoveznost, delirij, koma vegetativna nestabilnost mrzlica/drgetanje, 6ezmerno potenje, vraina, driska, tahikardija, ra8irjene zenice, hipertenzija avtorica: Preeti Kar pregledali: Erika Russell, Usama Malik, Aaron Mackie* * dr. med. ob objavi prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. Pomni: za klinicno postavitev diagnoze uporabljamo Hunterjeva merila serotoninske toksiZnosti: - zgodovina jemanja serotoninergithih snovi v preteklih 5 tednih + kateri koli od naslednjih pogojev: • spontani klonus • inducirani klonus in bodisi agitacija bodisi L'ezmerno potenje • aesni klonus in bodisi agitacija bodisi L'ezmerno potenje • tremor in hiperrefleksija • hipertonija, tel. temperatura >38 °C in bodisi aesni klonus bodisi inducirani klonus ihgnomigiZna hiperaktivnost hiperrefleksija, mR

Zaviralci privzema serotonina in noradrenalina (SNRI): mehanizem delovanja in neželeni učinki

Zaviralci privzema serotonina in noradrenalina (SNRI): mehanizem delovanja in neieleni utinki zaviralci privzema serotonina in noradrenalina predstavnika: venlafaksin, duloksetin konc. 5-HT in NA v 02S/P2S farmakologija farmakokinetika farmakodinamika nenadna prekinitev jemanja zdravila ali vnos avtorici: JoAnna Fay, Sara Meunier pregledali: Jojo Jiang, Alexander Arnold, Jessica Asgarpour, Aaron Mackie* iz krvnega obtoka jih odstranijo jetra zavirajo prenagalec za privzem NA (NET) in prenaalec za privzem 5-HT (SERT) 5-HT in NA ostaneta v sinapsah dlje in podaVata oz. okrepita iiv6ni prenos odtegnitev namerno predoziranje nenamerno povzrocene interakcije nepri6akovan odziv na terapevtski odmerek prekometna v aktivnost 02S/P2S sindrom 1` 5-HT omotica 5-HT serotoninski omotica driska nejegZnost nespeEnost nespanost slabost utrujenost glavobol vegetativna * iivEnomiKiEne kognitivne hiperaktivnost nepravilnosti spremembe vrtoglavica potencialno iivljenje ogroiajoE spolne hipertenzija olesni klonus agitacija motn'e porast tahikardija tremor akatizra tel. tee raigir-ene hiperrefleksija zenice migiEni klonus Legenda: patofiziologija mehanizem znak/simptom/laboratorijska najdba 1` NA slabost Zezmerno potenie * dr. med. ob objavi prevedel in priredil: Jan Kejiar, dr. med., specializant psihiatrije pregledala: doc. dr. Brigita Novak Sarotar, dr. med., spec. psih. v primeru ietrnih bolezni in/ali saasne rabe zaviralcev/sproncev CYPD26 ie potrebna prilagoditev odmerka izboljganje depresivne in anksiozne simptomatike 1 blokada ponovnega privzema 5-HT in NA v sinapsah pa u6inka SNRI ne pojasni v celoti posredno SNRI povzro6ijo sproManja nevrozaMitnih proteinov, denimo BDNF, ki bi naj imel po podatkih §tudij protivnetno delovanje za dosego kliniEnega uZinka ie potrebnih 3-8 tednov all veZ zdravlienia okralgave in opombe: 5-HT— serotonin NA— noradrenalin BDNF — mo2ganski nevrotrofiEni faktor 025 — osrednji 2ivEni sistem P2S — periferni 2ivEni sistem *vegetativen — nanagajoE se na avtonomni 2ivEni sistem

Socialna anksiozna motnja: patogeneza in klinične najdbe

Socialna anksiozna motnja: patogeneza in kliniene najdbe nevrobiologki dejavniki 1

Impetigo Pathogenesis and clinical findings

Impetigo: Pathogenesis and clinical findings Early: Single erythematous macule developing into vesicle or pustule Late: vesicular lesion and pustules with

Fisiologi sistem Renin-Angiotensin-Aldosteron (RAAS)

Angiotensinogen \*. Renin • Angiotensin I LACE • Angiotensin II Fisiologi sistem Renin-Angiotensin-Aldosteron (RAAS) Hipoperfusi Ginjal Regangan baroreseptor pada dinding arteriol aferen Hipotensi/ Hipovolemia 9 Pengiriman NaCI ke Makula Densa 9 Tekanan dirasakan oleh Baroreseptor Jantung & Arteri Katekolamin di sirkulasi Aktivitas saraf simpatis pada arteriol aferen Stimulasi reseptorn-adrenergik pada arteriol aferen Keseimbangan Glomerulotubuler (Mekanisme intrinsik ginjal diluar RAAS) *Hanya sebagian dari mekanisme tersebut Angiotensin II 4 konstriksi arteriol eferen 01% Tekanan hidrostatik glomerulus Jumlah cairan yang disaring + Konsentrasi sisa protein darah di glomerulus Darah kental bergerak dari glomerulus menuju kapiler peritubuler it pada kapiler peritubuler 9 Tekanan hidrostatik peritubular Legenda: Patofisiologi Mekanisme Pelepasan Renin oleh sel-sel Jukstaglomerular pada arteriol aferen 4 berujung pada T Angiotensin II Sekresi aldosterone dari korteks adrenal 1 Insersi KNaE pada Sel Prinsipal di DK ■ Aktivitas transporter NHE3 di dalam PCT Reabsorpsi Na ke dalam darah, menarik H2O ke dalam darah melalui osmosis Reabsorpsi H2O langsung ke dalam sirkulasi darah (via aliran gradien tekanan onkotik dan hidrostatik H2O) Tanda/Gejala/Penunjang Komplikasi Author: David Waldner Reviewers: Yan Yu Sean Spence Sophia Chou* Penerjemah: M Harmen Reza S* * MD (dokter) pada saat publikasi Hati secara normal mensintesis angiotensinogen dengan laju basal, melepaskannya ke dalam sirkulasi darah: Vasokonstri ksi arteri sistemik Tekanan darah Daftar singkatan: • ACE: Angiotensin Converting Enzyme (disintesis oleh Ginjal dan Paru) • DK: Duktus Kolektivus • PCT: Tubulus Konturtus Proksimal • NHE3: Sodium Hydrogen Exchanger (Antiport) 3 • KNaE: Kanal Natrium (Sodium) Epitel • n:Tekanan onkotik

Acetylcholinesterase Inhibitors

1 .1-- ► Hypotension ► Nausea/ Vomiting Authors: Sunny Fong Reviewers: Joseph Tropiano Billy Sun Melinda Davis, MD Quick Facts Primary indication in the OR = Used as a reversal agent against non-depolarizing neuromuscular blockers post-surgery Route of Administration = IV Metabolism & Excretion = hepatic clearance and renal excretion See Anticholinerqics slide for reversal of parasympathetic effects due to acetylcholinesterase inhibitors Abbreviations ACh — Acetylcholine NDNMBs — Non-depolarizing neuromuscular blockers Acetylcholinesterase Inhibitors E.g. Neostigmine, Pyridostigmine, Physostigmine 4, Breakdown of ACh in neuromuscular junctions ACh available to compete with NDNMBs to bind to post-synaptic nicotinic receptors on muscles Reversible enzymatic inhibition of acetylcholinesterase ACh available to compete with NDNMBs to bind to pre-synaptic nicotinic receptors on neurons Normal neuromuscular junction function re-established 1` Positive feedback for continued ACh release Reversal of neuromuscular block 1 Excess dose leads to depolarizing block of the nicotinic receptors Flaccid skeletal muscle paralysis Respiratory paralysis & failure 1 4, Breakdown of ACh in rest of body 1` Stimulation of muscarinic receptors various organ systems Muscarinic (parasympathetic) effects Salivation Peristalsis ► Bradycardia Bronchoconstriction Bronchial Secretions Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications I Published March 3, 2018 on www.thecalgaryguide.com 0€3,0 BY NC SA

non-depolarizing-neuromuscular-blocks-ndnmbs

Authors: Sunny Fong Reviewers: Joseph Tropiano Billy Sun Melinda Davis, MD Non-Depolarizing Neuromuscular Blockers (NDNMBs) Eg. pancuronium, rocuronium, atracurium, vecuronium Abbreviations NDNMBs — Non-Depolarizing Neuromuscular Blockers ACh — Acetylcholine Quick Facts 1° Indication = Skeletal muscle paralysis to facilitate tracheal intubation, and used during indicated surgeries or mechanical ventilation Route of Administration = IV Metabolism & Excretion = Redistribution, hepatic clearance/renal excretion (extent varies greatly by drug). NOT degraded by acetylcholinesterase or pseudocholinesterase See Acetylcholinesterase Inhibitors slide for reversal of NDN M Bs Competitive antagonism at post-synaptic nicotinic receptors on muscles Competitive antagonism at the pre-synaptic nicotinic receptors on neurons Vagolytic effect (esp. pancuronium) Anaphylactic/ anaphylactoid reactions 4, Binding sites for ACh at post-synaptic nicotinic receptors on muscles 4, Binding sites for ACh at pre-synaptic nicotinic receptors on neurons Blockage of vagal muscarinic receptors in sinoatrial nodes IgE antibodies attach to ammonium ion components of NDNMBs Non-immunologic mast cell degranulation (esp. atracurium) 4, Muscle cell depolarization 4, Positive feedback for continued ACh ► release in response to high frequency stimulation Skeletal muscle paralysis Tetanic fade, Train-of-Four fade 4, —• Parasympathetic Tachycardia effects on heart Release of histamine from mast cells and basophils Bronchospasm Hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications I Published March 3, 2018 on www.thecalgaryguide.com 0€3,0 BY NC SA

Propofol

Authors: Ryden Armstrong Reviewers: Billy Sun Joseph Tropiano Melinda Davis, MD Propofol Abbreviations GABA – Ga mma-a minobutyric acid Quick Facts 1° Indication = Induction and maintenance of general anesthesia, sedation Route of Administration = IV Metabolism & Excretion = Redistribution, hepatic conjugation/ renal clearance Legend: Pathophysiology Mechanism Allosterically increases binding affinity of inhibitory neurotransmitter GABA for GABAA receptor i Prolonged opening of chloride channel 1 Hyperpolarization of nerve membrane Inhibitory effect on CNS I Induction/maintenance of general anesthesia Sign/Symptom/Lab Finding Injection site pain Can pre-treat with intravenous local anesthetic (lidocaine) 4, Cerebral metabolic rate CNS —÷ 4, Cerebral oxygen consumption 4, Intra-cranial pressure 4, Systemic vascular resistance Hypotension ► Cardiovascular --■ —■ (with no change 4, Preload in heart rate) 4, Contractility Respiratory / ♦ Hypercapnia 4, Hypoxic and --■ hypercapnic Hypoxia respiratory drive ♦ Apnea 4, Upper airway reflexes Complications I Published MARCH 3, 2018 on www.thecalgaryguide.com Lac.).T2

non-depolarizing-neuromuscular-blocks-ndnmbs

Authors: Sunny Fong Reviewers: Joseph Tropiano Billy Sun Melinda Davis, MD Non-Depolarizing Neuromuscular Blockers (NDNMBs) Eg. pancuronium, rocuronium, atracurium, vecuronium Abbreviations NDNMBs — Non-Depolarizing Neuromuscular Blockers ACh — Acetylcholine Quick Facts 1° Indication = Skeletal muscle paralysis to facilitate tracheal intubation, and used during indicated surgeries or mechanical ventilation Route of Administration = IV Metabolism & Excretion = Redistribution, hepatic clearance/renal excretion (extent varies greatly by drug). NOT degraded by acetylcholinesterase or pseudocholinesterase See Acetylcholinesterase Inhibitors slide for reversal of NDN M Bs Competitive antagonism at post-synaptic nicotinic receptors on muscles Competitive antagonism at the pre-synaptic nicotinic receptors on neurons Vagolytic effect (esp. pancuronium) Anaphylactic/ anaphylactoid reactions 4, Binding sites for ACh at post-synaptic nicotinic receptors on muscles 4, Binding sites for ACh at pre-synaptic nicotinic receptors on neurons Blockage of vagal muscarinic receptors in sinoatrial nodes IgE antibodies attach to ammonium ion components of NDNMBs Non-immunologic mast cell degranulation (esp. atracurium) 4, Muscle cell depolarization 4, Positive feedback for continued ACh ► release in response to high frequency stimulation Skeletal muscle paralysis Tetanic fade, Train-of-Four fade 4, —• Parasympathetic Tachycardia effects on heart Release of histamine from mast cells and basophils Bronchospasm Hypotension Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications I Published March 3, 2018 on www.thecalgaryguide.com 0€3,0 BY NC SA

Celiac Disease: Pathogenesis and clinical findings

Celiac Disease: Pathogenesis and clinical findings Associated with other autoimmune disorders (i.e. DM1, thyroiditis, RA, SLE, Addison's) Genetic predisposition -■ (Northern European, Down's syndrome, Associated with HLA DQ 2,8) Note: *The anti-TTG antibody is an IgA anti-body, therefore if the patient is IgA-deficient, absence of anti-TTG does not rule out celiac Anti-TTG in serum* Anti-TTG reacts with TTG in skin Deposition of anti-TTG in renal glomeruli Dermatitis herpetiformis Chronic Kidney Disease Small Bowel Biopsy: Crypts of bowel become enlarged (hyperplasia) with architectural change, villous shortening Legend: Pathophysiology Mechanism Exposure to prolamins (proteins found in wheat, rye, oats, barley) TTG alters prolamin Altered protein fits more easily into HLA HLA activates adaptive immunity IgA generated against prolamin-TTG Wheat prolamin (gliandin) interacts with and activates zonulin signalling Gut epithelium becomes more porous Large dietary proteins in epithelium disrupt tight junctions Author: Matthew Harding Yan Yu Peter Bishay Reviewers: Dean Percy Jason Baserman Usama Malik Kerri Novak* * MD at time of publication Inflammation of Intestinal epithelium Inflammation disrupts structure of bowel mucosa Mechanism Unknown Lymphocytes migrate to site of inflammation Extraintestinal Complications: Arthropathy Ataxia (gluten associated) Infertility Mild Hepatitis Villi of intestine atrophy Risk of Microscopic Colitis (50x) Malabsorption Extraintestinal manifestations: Chronic watery Fatigue Failure to thrive, weight loss Anemia (Fe, B12, folate) Peripheral neuropathy (B12, Ca) Ataxia (Ca) Dysrhythmia (Ca, K) Osteoporosis (Vit D, Ca) diarrhea + Intestinal manifestations steatorrhea: Pale, foul-smelling Abdominal bloating Steatorrhea (fat in stool) Diarrhea

Kallmann Syndrome and Normosmotic Idiopathic Hypogonadotropism: Pathogenesis and Clinical Findings

Kallmann syndrome (KS) and Normosmic Idiopathic Hypogonadotropic Hypogonadism (nIHH): Pathogenesis and clinical findings Authors: Danielle Lynch Reviewers: Nicola Adderley Josephine Ho* * MD at time of publication Abbreviations: GnRH – gonadotropin- releasing hormone LH – luteinizing hormone FSH - follicle stimulating hormone Notes: • 4 male : 1 female • KS, nIHH, and isolated anosmia exist on a spectrum • KS has X-linked recessive, autosomal dominant, autosomal recessive, oligogenic, and idiopathic forms • KS and nIHH are also associated with gene- specific features such as cleft lip/palate, oculomotor synkinesis, hearing loss, and unilateral renal aplasia • Diagnosis typically occurs around pubertal age, but may be earlier in males if micropenis and cryptorchidism are present at birth Mutations in KAL1, NELF, and PROKR2 Abnormal olfactory bulb development Mutations in FGFR1, FGF8, PROK2, PROKR2, HS6ST1, CHD7, WRD11, and SEMA3A or idiopathic Mutations in GNRH1, KISS1, KISS1R, TAC3, TACR3 Impaired migration of olfactory neurons from olfactory bulb to hypothalamus Impaired migration of GnRH neurons from olfactory bulb to hypothalamus Impaired GnRH neuron activity Kallmann syndrome (idiopathic hypogonadotropic hypogonadism with anosmia) Normosmic idiopathic hypogonadotropic hypogonadism Anosmia Olfactory bulb aplasia Abnormal /absent olfactory bulb on MRI ↓ GnRH ↓LH and ↓FSH Delayed or absent puberty Infertility ↓estrogen In males: ↓testosterone Cryptorchidism Delayed epiphyseal plate closure Micropenis (5-10%) Uninhibited long bone growth ↑ length hands, arms, legs Delayed bone age (hand/wrist x-ray) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 29, 2018 on www.thecalgaryguide.com

Feedback Loop: Adrenocorticotropic Hormone (ACTH)

Feedback Loop: Adrenocorticotropic Hormone (ACTH) Authors: Rhiannon Brett Reviewers: Andrea Kuczynski Bernard Corenblum* * MD at time of publication Posterior Pituitary Gland ADH - - - Hypothalamus CRH + Anterior Pituitary Gland ACTH, MSH, other hormones produced from POMC ACTH + Adrenal Cortex Activate ACTHR Activate cAMP Activate PKA Activate Zona Fasciculata Cortisol Abbreviations: CRH: Corticotropin Releasing Hormone ADH: Anti-diuretic Hormone ACTH: Adrenocorticotropic Hormone MSH: Melanocyte Stimulating Hormone POMC: Pro-Opiomelanocortin ACTHR: ACTH Receptor cAMP: Cyclic Adenosine Monophosphate PKA: Protein Kinase A DHEA(S): Dehydroepiandrosterone (sulfonated form) F: Female M: Male Excess: hirsutism, acne, oily skin, oligo- or amenorrhea, virilization in F Deficiency: symptoms not typically seen due to gonadal production Note: Activate Zona Reticularis Activate Zona Glomerulosa (minor effect) Excess: central obesity, hirsutism, violaceous striae, weakness Deficiency: weight loss, fatigue, weakness, nausea/vomiting, diarrhea DHEA(S) Aldosterone Specific to primary adrenal insufficiency: ↑ pigmentation, hyperkalemia • Virilization is a red flag for an androgen- secreting tumor Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 2, 2018 on www.thecalgaryguide.com

intrauterine-growth-restriction-iugr-pathogenesis

Intrauterine Growth Restriction (IUGR): Pathogenesis Authors: Ricki Hagen Reviewers: Jaimie Bird Sarah McQuillan* * MD at time of publication Abbreviations: • DM: diabetes mellitus • HTN: hypertension • IUGR: intrauterine growth restriction • SGA: small for gestational age • SLE: systemic lupus erythematosus • TORCH: Toxoplasmosis, Others, Rubella, CMV, HSV Maternal Factors Maternal-Fetal Factors Placental malformations (Ex. previa, accreta, infarction, abnormal implantation, ischemia) Gestational HTN/ Preeclampsia Multiple gestation Gestational DM Fetal Factors Structural anomalies (often comorbid with cytogenetic disorders) Congenital infections (Ex. TORCH) Inborn errors of metabolism Chromosomal disorders/ genetic syndromes Multiple unclear intrinsic fetal mechanisms Note: Teratogenic medications (Ex. Warafin, Valproic Acid, Folic Acid Antagonists) High altitude living Smoking, ETOH and/or drug use Malnutrition/ Low pre-gestational weight Multiple unclear extrinsic fetal mechanisms Medical conditions (Ex: chronic HTN, cyanotic heart disease, severe chronic anemia, kidney disease) Autoimmune conditions (Ex. Type 1 DM, SLE) Decreased uteroplacental blood flow Nutrient supply to fetus compromised Reduction of total body mass, bone mineral content, and muscle mass Blood flow redirected away from vital organs to brain, placenta, heart and adrenal glands Reduction of overall fetal size to increase survival IUGR Failure to reach genetically determined growth potential • IUGR is not synonymous with SGA • Constitutional SGA is due to paternal and maternal factors such as height, weight, ethnicity, and parity; it is not associated with increased risk for infant mortality or morbidity Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October, 30, 2018 on www.thecalgaryguide.com

fetal-alcohol-spectrum-disorder-pathogenesis-and-clinical-findings

Fetal Alcohol Spectrum Disorder: Pathogenesis and clinical findings Authors: Preeti Kar Reviewers: Nicola Adderley Chandandeep Bal* Danielle Nelson* * MD at time of publication Genetic Factors Disadvantaged prenatal and/or postnatal environment Maternal factors (age, metabolism, stress, other substance use) Maternal alcohol consumption during pregnancy (greatest risk with binge drinking and daily/chronic intake) Prenatal alcohol exposure to fetus via placenta-umbilical transport Notes: Fetal Alcohol Spectrum Disorder with Sentinel Facial Features (confirmed or unknown PAE) Fetal Alcohol Spectrum Disorder without Sentinel Facial Features • There is no known safe amount of prenatal alcohol exposure (PAE). Although PAE below the threshold of >7 drinks/week or > 2 binge episodes (one binge episode is >4 drinks in one sitting) has not been associated with neurodevelopmental effects, there is insufficient objective evidence to deem this level of alcohol exposure safe. Sentinel Facial Features (confirmed PAE) Alcohol exposure between Alcohol acts directly as a teratogen Vasoconstriction of placental-umbilical unit ̄ blood flow and ̄ oxygen delivery to fetus Notes (continued): • A multidisciplinary team is necessary for an accurate and comprehensive diagnosis and subsequent recommendations. Canadian Guidelines for diagnosis, 4-digit code, the APP Toolkit, University of Washington Lip- Philtrum Guide are different methods of assessing and diagnosing patients. • While not specific to FASD, congenital abnormalities (e.g. heart defects, renal problems, auditory/visual impairments, skeletal defects) and growth deficits (prenatal and/or postnatal height or weight ≤ 10th percentile) are often associated with this disorder. Smooth philtrum Thin upper lip day 15 and 22 of & indirectly via its metabolites pregnancy (most often) Neuronal cell death & disruption of migration & proliferation Altered signaling, neurotransmitter imbalance, & neural connectivity Evidence of impairment in 3+ neurodevelopmental domains Small palpebral fissures (≥2 SDs below the mean for age & sex or < 3rd percentile) Language Memory Attention Motor skills Cognition Affect regulation Academic achievement Executive function (including hyperactivity & impulsivity) Neuroanatomy/ Neurophysiology (e.g. seizure disorder, abnormal brain structure as seen on brain imaging, microcephaly (head circumference ≤ 10th percentile)) Adaptive behavior, social skills, or social communication Failure to reach age-appropriate milestones, challenges at school, aggression, delinquency, mental health challenges, substance use disorders Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 30, 2018 on www.thecalgaryguide.com

Vesicoureteric reflux (VUR): Pathogenesis and clinical findings

Vesicoureteric reflux (VUR): Pathogenesis and clinical findings Authors: Nicola Adderley Reviewers: Emily Ryznar *Lindsay Long * MD at time of publication Abnormal function Abnormal anatomy Neurogenic bladder (e.g. cerebral palsy, constipation, spinal injury, iatrogenic) Non-neurogenic bladder (neuropsychological) Lower urinary tract abnormality (posterior urethral valves, meatal stenosis) Bladder outlet obstruction ↑ pressure distorts UVJ Upper urinary tract abnormality (ureters) UVJ abnormality Incomplete closure of UVJ during bladder contraction Abbreviations • UVJ - ureterovesicular junction • UTI – urinary tract infection Failure of bladder sphincter to relax during bladder contraction Vesicoureteric reflux (VUR): Back flow of urine from the bladder into one or both ureters +/- kidneys Migration of lower urinary tract bacteria to kidneys Bacterial invasion of renal parenchyma Upper UTI (pyelonephritis) Incomplete emptying of bladder during Abnormal ↑ pressure in bladder Bladder dilates Dilated bladder on U/S urination Bacteria in bladder are not cleared during urination voiding habits ↑ bladder capacity Renal scarring ↓ functional renal tissue *Chronic kidney disease (↓ GFR, hypertension, proteinuria) Flank tenderness Fever, dysuria, urgency, frequency Lower UTI (cystitis) Urinary stasis Cloudy, foul- smelling urine Urethral stricture Notes Urgency, dysuria, frequency • First febrile UTI in an infant should trigger a work-up for VUR • High likelihood of spontaneous resolution • *Late complication of severe VUR Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 19, 2018 on www.thecalgaryguide.com

Anticonvulsants as Mood Stabilizers: Mechanism and Side-effect

Anticonvulsants as Mood Stabilizers: Mechanism and Side-effect Anticonvulsants as Mood Stabilizers Examples: Valproate, Carbamazepine, Lamotrigine Pharmacology Mild anticholinergic effect Drowsiness, dry mouth, blurred vision, constipation Allergic reaction Benign rash Pharmacokinetics —■ Cleared from circulation by liver —■ Pharmacodynamics Block voltage sensitive sodium channels Failure to clear reactive metabolites • T-cell mediated cytotoxic reaction to drug antigens Potentially life threatening –Stevens-Johnson Syndrome • NI, Glutamate and aspartate release or I` GABA neurotransmission Authors: Usama Malik Reviewers: Sina Marzoughi Aaron Mackie* * MD at time of publication Dose adjustments needed in setting of liver disease and specific CYP450 inhibitors/inducers Excessive blockage of VSSCs Abrupt discontinuation or 4, intake Inhibition of dopaminergic activity Neurologic effect Systemic effect 1 1 • Withdrawal seizure, relapse of bipolar disorder Notes: • Valproate relies on CYP450 2C9/2C19, Carbamazepine relies on CYP450 34A, and Lamotrigine relies on glucuronidation • Lamotrigine and Carbamazepine are excreted renally • Valproate act on nonspecific VSSCs while lamotrigine and carbamazepine mostly act on alpha unit VSSC • Exact mechanism for some of the side-effects is unknown Legend: Pathophysiology Mechanism Dose-dependent tremor, ataxia, asthenia Sedation, dose-Nausea, vomiting, dependent tremor, diarrhea, dizziness, diplopia, hyponatremia, rash, ataxia, asthenia, pruritus, weight gain, headache alopecia (unusual), thrombocytopenia Abbreviations: • VSSCs: Voltage-Sensitive Sodium Channels

Microangiopathic Hemolytic Anemia: Pathogenesis and clinical findings

Microangiopathic Hemolytic Anemia: Pathogenesis and clinical findings Authors: Jocelyn Law Reviewers: Naman Siddique Emily Ryznar Lynn Savoie* * MD at time of publication Atypical HUS Mutation or antibody attack of complement proteins HELLP Anti-angiogenic factors in maternal blood Damaged placental vasculature Typical HUS STEC releases Shiga Toxin Malignant Hypertension DIC (See DIC Slide) ↓ Inhibition of complement Immune inflammatory ↑ Pressure in ↑ Extrinsic clotting pathway activation TTP (See TTP-HUS Slide) Disruption of endothelial cell activation perfusion/ischemia response metabolism vasculature ↑Thrombin Deficient Placental under- renal afferent ↑ Complement pathway activation MAC-mediated cell lysis Cytokine release Endothelial injury Shear stress on endothelium production ↑ Fibrin clot production and deposition in small vessels ADAMTS13 protease enzyme ↓ Cleavage and ↑ accumulation of VWF multimers Abbreviations: • HELLP - Hemolysis, Elevated Liver Enzymes, Low Platelets • HUS - Hemolytic-Uremic Syndrome • DIC - Disseminated Intravascular Coagulation • TTP - Thrombotic Thrombocytopenic Purpura • MAC - Membrane Attack Complex • STEC - Shiga Toxin-Producing Escherichia coli • VWF - Von Willebrand Factor Pro-thrombotic Environment (see Virchow’s Triad Slide) Platelet aggregation Mechanical obstruction of the vessel lumen Hypercoagulable state Thrombocytopenia ↑ RBC production in bone marrow ↑ Reticulocytes Hemoglobin released from damaged RBCs Shearing of RBCs Anemia Binds to haptoglobin Conversion to bilirubin in liver ↓ Free haptoglobin ↑Indirect bilirubin Shistocytes Jaundice Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 13, 2018 on www.thecalgaryguide.com

Hypernatremia Physiology

Hypernatremia: Physiology Unreplaced H2O loss Hypodipsia H2O shift into cells Severe exercise, electroshock induced seizures Transient ↑ cell osmolality Na+ overload Inappropriate IV hypertonic solution, salt poisoning Abbreviations: H2O: Water GI: Gastrointestinal DM: Diabetes Mellitus DI: Diabetes Insipidus Na+: Sodium ion IV: Intravenous ADH: Antidiuretic Hormone LOC: Level of Consciousness Skin Sweat, burns GI Vomiting, bleeding, osmotic diarrhea Fluid [Na+] < serum [Na+] ↑ H2O loss compared to Na+ loss Renal DM, Mannitol, Diuretics Absent thirst mechanism Hypothalamic lesion impairs normal drive for H2O intake Nephrogenic ↑ renal resistance to ADH H2O Deprivation Test + no AVP response ↓ access to H2O DI Central ↓ ADH secretion H2O Deprivation Test + AVP response ↑ [Na+] 10- 15 mEq/L within a few minutes Weakness, irritability, seizures, coma ↑ thirst, ↓ urinary frequency and volume Note: Hypernatremia Serum [Na+] > 145 mmol/L Intracranial hemorrhage Headache, vomiting, ↓ LOC • Plasma [Na+] is regulated by water intake/excretion, not by changes in [Na+]. • Effects on plasma [Na+] of IV fluids or loss of bodily fluids is determined by the tonicity of the fluid, not the osmolality. Authors: Mannat Dhillon Reviewers: Andrea Kuczynski Kevin McLaughlin* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 11, 2019 on www.thecalgaryguide.com

Hyponatremia- Physiology

Hyponatremia: Physiology Authors: Mannat Dhillon Reviewers: Andrea Kuczynski Kevin McLaughlin* * MD at time of publication Abnormal Renal H2O Handling (hypo-osmolar serum) AKI/CKD Heart failure ↓ renal blood flow ↓ glomerular filtration GFR < 25 mL/min, ↓ urine dilution ↑ H2O retention Note: • Plasma [Na+] is regulated by water intake/excretion, not by changes in [Na+]. • Artifactual hyponatremia can be differentiated by a normal or hyperosmolar serum. Appropriate ADH secretion ↓ EABV Hypovolemia: losses via GI, renal, skin, 3rd spacing, bleeding Hypervolemia: heart failure, cirrhosis ↑ Na+/H2O absorption at PCT ↓ EABV, ↑ H2O retention Urine [Na+] < 20 mmol/L Hereditary: tubular disorders (Bartter, Gitlemann syndromes). Thiazide diuretics Inappropriate: SIADH, hypothyroidism, AI Normal EABV Anti-diuresis Primary polydipsia, eating disorder ↑ H2O or ↓ solute intake ↓ Osmoles Impaired desalination Block NCC ↑ H2O retention ↑ Na+/K+ excretion Hyponatremia Serum [Na+] < 135 mmol/L Urine osmolality > 100 mmol/L Urine osmolality < 100 mmol/L Cerebral edema, ↑ intracranial pressure, vasoconstriction If hypovolemic: ↓ JVP, ↓ blood pressure Lethargy, altered mental status Abbreviations: AKI: Acute Kidney Injury CKD: Chronic Kidney Disease GFR: Glomerular Filtration Rate H2O: Water PCT: Proximal Convoluted Tubule EABV: Effective Arterial Blood Volume NCC: Na+/Cl- Co-Transporter SIADH: Syndrome of Inappropriate ADH Secretion AI: Adrenal Insufficiency Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 11, 2019 on www.thecalgaryguide.com

adrenergic-agonists-for-treating-hypotensionlow-blood-pressure

Side effects Authors: Arsalan Ahmad, Lance Bartel, Yan Yu* Reviewers: Billy Sun, Mackenzie Gault, Melinda Davis* *MD at time of publication Legend: Published February 19, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding thecalgaryguide.com Epinephrine Norepinephrine High Dose Low Dose Adrenergic Agonists for Treating Hypotension/Low Blood Pressure (BP) β1-receptor activation on cardiac myocytes ↑ contractility α1-receptor activation on the smooth muscle of blood vessel walls ↑ intra-cellular Ca2+ in these cells, ↑ their contraction Ephedrine Direct effect Indirect effect ↑ release of endogenous norepinephrine from the adrenal medulla (see above) Mimics epinephrine (see above) Primary Indications: anaphylaxis, cardiac arrest Primary Indications: Hypovolemic states (e.g. blood loss), Low systemic vascular resistance states (e.g. sepsis, Anesthesia-induced hypotension) Primary Indications: mainly used in Anesthesiainduced hypotension ↑ intracellular Ca2+ ↑ rate of myocyte contraction Phenylephrine ↑ Cardiac Output ↑ heart rate ↑ strength of myocyte contraction ↑ arterial wall tone ↑ stroke volume Pushes more blood to flow back to heart (↑ preload) ↑ systemic vascular resistance (SVR) More blood in ventricles stretch myocytes more optimally for ↑ contractility (Frank Starling Law) ↑ venous wall tone ↑ Blood Pressure Nonspecific activation of α and β receptors on other areas of the body (e.g. on the autonomic nervous system) as well as on cardiac myocytes Hypertension Cardiac Dysrythmias: e.g. palpitations, ventricular fibrillation Tremors Cardiac arrest All four drugs

Hyperkalemia- Physiology

Hyperkalemia: Physiology ↓ Renal Excretion ↑ Intake ↓ Intracellular Shift Acute and chronic kidney disease; CHF Principal Cell Dysfunction (TTKG < 7) ACEi/ARB; AI; heparin Hypovolemia (TTKG > 7) ↓ EABV ↓ distal flow of Na+ and H2O Urine [Na+] < 20 mmol/L Cell lysis ↑ osmolarity H2O efflux Solvent drag β2 inhibition α1 stimulation Digoxin ↓ A NAGMA ↓ insulin ↓ NHE1 activity Diabetic nephropathy; NSAIDs ↓ A: ↓ R K+ sparing diuretics; voltage- dependent RTA ↓ Na+/K+ ATPase activity ↓ GFR ↓ A: ↑ R ↑ A: ↑ R ↓ CCD K+ secretion ↑ K+ availability ↑ K+ release ↓ intracellular K+ influx Chronic: Desensitize voltage- gated Na+ channels and ↓ membrane excitability ECG: Peaked T-waves, ↑ PR interval, flat/absent P-wave, ↑ QRS, QRST “sine wave” Hyperkalemia Serum [K+] > 5.1 mmol/L Acute: ↑ extracellular [K+] makes the RMP less (-) Abbreviations: A: Aldosterone AI: Adrenal Insufficiency CCD: Cortical Collecting Duct CHF: Congestive Heart Failure EABV: Effective Arterial Blood Volume H+: Hydrogen ion K+: Potassium ion Na+: Sodium ion NAGMA: Normal Anion Gap Metabolic Acidosis NSAIDs: Non-steroidal anti-inflammatory drugs Note: Muscle weakness or paralysis, ↓ urinary acid excretion R: Renin RTA: Renal Tubular Acidosis RMP: Resting Membrane Potential TTKG: Transtubular Potassium Gradient • Pseudohyperkalemia should always be excluded; can be caused by thrombocytosis, leukocytosis or improper blood withdrawal technique. Authors: Mannat Dhillon Joshua Low Reviewers: Andrea Kuczynski Kevin McLaughlin* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 6, 2019 on www.thecalgaryguide.com

autosomal-dominant-polycystic-kidney-disease-adpkd

Autosomal Dominant Polycystic Kidney Disease (ADPKD): Pathogenesis, Clinical Findings, and Complications Author: Yan Yu* Reviewers: David Waldner* Sean Spence* Andrew Wade* * MD at time of publication Legend: Published April 14, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com One theory (mechanism unclear): these mutations in the polycystin gene result in dysfunctional Ca2+ channels on epithelial cells PKD1 mutation (~78%) Abnormal Ca2+ entry disrupts intracellular Ca2+ signaling In the Kidney: all segments of the nephron develop cysts: sacs of flattened epithelium filled with proteinaceous fluid, replacing normal parenchyma with dysfunctional tissue PKD2 mutation (~15%) Expansive cell proliferation Low urine Osmolality (< 500 mmol/kg) Abnormally expandable basement membranes PKD3 mutation (rare) ↑ fluid secretion 95% inherited, autosomal dominant mutations 5% spontaneous mutations In adults, the same pathophysiology occurs in epithelial tissue throughout the body When pH of urine <5.5, uric acid is in its protonated form & is less soluble àprecipitates uric acid stones Nephrolithiasis Urine accumulates within cysts Cyst growth Pyelonephritis Damaged tubules leak proteins into filtrate Proteinuria Flank pain Inability to concentrate urine Low urine specific gravity (<1.010) ¯ NH3 production, ↑ acidity of renal tubule (¯ pH) Activates nociceptors Cyst hemorrhage Urine stasis à precipitation of CaOxalate stones within cysts Multiple Renal Cysts (bilaterally, in cortex and medulla, on Ultrasound) In the Brain: expansion & weakening of cerebral arterial walls “Berry Aneurysms” 9- 12% (ask about this on Family Hx!) In many organs: epithelial tissue expansion & fluid secretion In the Heart: abnormal valve collagen matrix Valve prolapse & regurgitation Liver (90%), spleen/pancreas (5-10%), thyroid (rare) cysts In seminal vesicles: Cyst formation disrupts sperm motility Infertility In GI tract: Cyst formation Herniations, diverticuli Dysfunctional collecting ducts Abdominal mass (enlarged kidneys) (may be palpable) Blood leaks into renal tubules Hematuria (isomorphic) Bacteria accumulate in the static urine Dysfunctional proximal tubules Unknown mechanisms à ¯ urine citrate àmore urine Ca2+ binds to oxalate than to citrate à↑ Ca- Oxalate stones Note: PKD1 mutations have more severe prognosis than PKD2 mutations (earlier disease onset, larger cysts) Vessels tear more easily Stretches renal capsule Cysts compress renal vasculature ¯ Glomerular perfusion To ↑ perfusion à kidneys activate RAAS Hypertension

Rickets and Osteomalacia: Pathogenesis and Clinical Findings

Hypocalcemia Rickets and Osteomalacia: Pathogenesis and clinical findings Abnormal Vitamin D Metabolism: Deficiency, hereditary disorders of synthesis or vitamin D receptor Fractures Proximal muscle weakness, manifesting often as gait disturbances Osteomalacia: Occurs after epiphyseal closure Bone mineralization defect (Osteopenia with reduced mineralization) Shear forces bend the osteopenic bone Short stature Diffuse skeletal pain (bone tenderness) Osteopenia reduces bone density and cause fractures with minimal force applied If hypophosphatemic, production of ATP and other high energy molecules declines Unequally distributed forces and muscle/tendon tension stimulate nociceptors Legend: Published November 26, 2012 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Calcification inhibitors (excess exposure to Al, Fluoride, etidronate) Lack, or reduced function, of mineralization enzymes (like ALP) Lack of bone mineral components: 1. Phosphate: renal tubule disorders, vit D or Phosphate deficiency, ↑FGF23 2. Calcium: severe deficiency (infants) Rickets: Occurs before epiphyseal closure Epiphyseal plates do not fuse, impairing bone growth Bowed legs Cartilage in epiphyseal plates cannot become ossified Disruption in calcium ion homeostasis ↓ GI absorption of Ca2+ into blood ↓ Kidney reabsorption of Ca2+ into blood ↓ energy available to muscle Author: Payam Pournazari Reviewers: Yan Yu Spencer Montgomery David Hanley* * MD at time of publication

Polyarteritis Nodosa (PAN): Pathogenesis and Clinical Findings

Polyarteritis Nodosa (PAN): Pathogenesis and clinical findings Environmental triggers Infectious/viral agents (commonly Hepatitis B) Medical Comorbidities Malignancies (most commonly hairy-cell leukemia) Immunogenetic Predisposition: patient is genetically predisposed to a dysregulated immune response Fever ↑ ESR and CRP Postulate 1 Viral antigen-antibody complexes deposit in vasculature, causing lesions and activating cellular inflammatory response Authors: Nela Cosic, Yan Yu* Reviewers: Sean Doherty Martin Atkinson* * MD at time of publication Palpable or necrotic purpura Malignant Hypertension Renal Insufficiency Myocardial ischemia Heart failure Diffuse myalgias Postulate 2 Viral replication causes direct injury to vascular endothelial cells ↑ Anti- endothelial cell autoantibodies (AECA) Altered cytokine profile (↑TNF-α, IL-1β, IFN-α, IL- 2)à↑ T-cell mediated immune response Weight metabolism Loss Autoimmune attack on various areas of the body Malaise and/or Arthralgias (knees, ankles, elbows, wrists) Orchitis: Testicular pain, erythema and/or swelling Small intestine perforation GI Manifestations Non-specific abdo pain GI hemorrhage Peripheral sensory changes: Distal mononeuropathy multiplex Polyarteritis Nodosa (PAN) Focal segmental necrotizing leukocytoclastic vasculitis of medium or small-sized arteries Inflammation of arteries damages the vascular endothelium of those arteries Inflammation predisposes formation of arterial thromboses Blockage of arteriesà tissue ischemia and possible necrosis (tissue cell death) ↑ basal Arterial aneurysms Inflamed subcutaneous arteries Inflamed renal artery àluminal narrowing and reduced blood flow to kidneys Inflamed coronary artery à luminal narrowing, occlusion, thromboses Segmental inflammation of muscular arteries, stimulating surrounding nociceptors. Muscle ischemia develops long-term. Ischemia/necrosis of the testicles Ischemia/necrosis of the small intestine Ischemic vasculitic nerve damage: Immune complex deposition within vessel walls of arteries traveling with nerves leads to persistent vascular inflammation and ischemia of associated nerve Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 18, 2019 on www.thecalgaryguide.com

Secondary Polycythemia

Secondary Polycythemia: Pathogenesis Authors: Noriyah Al Awadhi, Yan Yu, Peter Duggan* Reviewers: Crystal Liu, Kara Hawker, Paul Ratti, Man-Chiu Poon*, Lynn Savoie* * MD at time of initial publication Chronic lung disease (ILD, COPD) Poor lung function Renal artery stenosis ↓ blood flow to kidney Kidney senses ↓ O2 High affinity Hb or CO poisoning Hb does not easily unload O2 Tissues become hypoxic Tumors (e.g. renal, hepatic, lung) Secretes EPO in an unregulated way, as a “paraneoplastic syndrome” High altitude Obstructive sleep apnea Episodic airway obstruction during sleep Intermittent hypoxia Cyanotic heart disease Shunting of blood Venous and arterial blood mixes Poorly oxygenated blood ↓ O2 partial pressure ↑ EPO production independent of O2 (inappropriate response) ↑ EPO production due to hypoxia (appropriate response) Abbreviations: • Hb- Hemoglobin • EPO- Erythropoietin • ILD- Interstitial Lung Disease • COPD- Chronic Obstructive Pulmonary Disease “Endogenous causes” of high EPO Secondary Polycythemia “Exogenous causes” of high EPO Testosterone therapy Iatrogenic EPO (results in ↑ EPO synthesis administration within the body) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published May 5, 2019 on www.thecalgaryguide.com

Appendicitis

Appendicitis: Pathogenesis and Clinical Findings Authors: Yan Yu Wayne Rosen* Reviewers: Wendy Yao Laura Craig Noriyah AlAwadhi* * MD at time of publication Dull, crampy, diffuse peri- umbilical pain Pt may develop fever, diarrhea, constipation, vomiting or anorexia as inflammation worsens Focal, intense, persistent RLQ pain, abdominal guarding and peritoneal signs (i.e. percussion and rebound tenderness Epidemiology Dx of healthy adults: • Men > women • Commonly 10-30 years old, can present at any age • Most common cause of acute abdomen (5% prevalence in all ethnicities) The appendix is anatomically located in the RLQ; appendicitis may be confused with disorders of surrounding structures: Gynecological Diseases • RuleoutpregnancywithHCG pregnancy test • Rupturedovariancyst • Ectopicpregnancy • Mittelschmerz(mid-cycle pain) Gastro-intestinal Diseases • Meckel’sdiverticulum (presents identically to appendicitis; surgically located 2 feet from ileocecal valve; mostly seen in children) • Diverticulitis(presentsasleft sided appendicitis) Non-GI Abdominal Issues • Mesentericadenitisinkids <15: swollen mesenteric lymph nodes • Renalcolic Obstruction of appendiceal lumen (by fecalith, fibrosis, neoplasia, foreign bodies or lymph nodes in kids) Appendix distension and spasms ↑ lumen pressure, ↓ blood flow to appendix Ischemia, tissue necrosis, loss of appendix structural integrity Bacterial invasion of the appendix wall, causing transmural inflammationandnecrosis Stretching of visceral peritoneum, stimulation of autonomic nerves T9-T10 Progression of inflammation over several days (variable length of time) Irritation of parietal peritoneum, stimulation of somaticnerves If appendix not surgically removed Perforation of colon wall, causing peritonitis, abscesses or death Note: Symptoms hugely variable. Only 30% present with classic history. Diagnosis is mostly clinical. Further investigations: CBC: Leukocytosis (due to inflammatory response) CT: Gold standard test. Thickened visceral membrane with enhancing (white) rim due to ↑ blood flow Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published July 27, 2019 on www.thecalgaryguide.com

Diverticulosis and Angiodysplasia

Diverticulosis and Angiodysplasia: Pathogenesis and Clinical Features Diverticulosis Author: Yan Yu Reviewers: Jason Baserman, Jennifer Au Paige Shelemey, Tony Gu Kerri Novak* * MD at time of publication Abnormal Angiogenesis vWF Deficiency Older Ageà weakening the circular muscles strutting the colon High intracolonic pressure (i.e. from peristalsis pushing against colonic waste that’s low in fiber and harder to move) Angiodysplasia Autoimmune Diseases Unclear Mechanisms These patients tend to have “arterial-venous malformations” that rise up to the mucosa of the lower GI tract Irritation of these malformations leads to bleeding into the GI tract lumen Lower GI bleed (occult, slow, asymptomatic, large- volume blood loss, usually associated with iron deficiency anemia) Renal Failure Older Age Gradual expansion over time thins the diverticular wall Capillaries within diverticuli burst and leak blood into the colon lumen Lower GI bleed (usually stops by itself) Colon wall forms little outpouchings (diverticuli) Stretching of colonic serosa stimulates somatic sensory nerves innervating the colon Bloating, cramping (But most often PAINLESS) Trapping of feces in the colonic diverticuli Bacteria have more time to metabolize the undigested materials, producing gas Flautulence Irregular defecation Both conditions share similar features: • Both are common, and their prevalence increases with age • Are relatively benign and most are easy to treat (80% stop w/o intervention) • Both present without pain in a previously-well patient • Together, account for 50-80% of lower GI bleeds (diverticulosis > angiodysplasia) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published August 4, 2019 on www.thecalgaryguide.com

iga-vasculitis-henoch-scholein-purpura-pathogenesis-and-clinical-findings

IgA Vasculitis (Henoch-Schönlein purpura) : Pathogenesis and clinical findings Authors: Mia Koegler Nela Cosic Reviewers: Crystal Liu Yan Yu* Martin Atkinson* * MD at time of publication Infectious Agents 50% have preceding upper respiratory tract infections, i.e., influenza virus or Group A Strep Drugs I.e., antibiotics (penicillin, erythromycin), NSAIDs and biologics (tumor necrosis factor α inhibitors) Immunogenetic and cellular predisposition Various genetic polymorphisms alter cell- mediated immune response, IgA levels elevated in 50% of people ↑ Circulating galactose-deficient IgA1 (GD-IgA1). Deficiency in galactosylation of IgAà↓ IgA serum clearanceàadhesion of IgA complexes, which then deposit into the endothelial lining of blood vesselsàattraction of various inflammatory cells to the area: Formation of Secretion of Interleukin 8 (IL8) - cytokine that induces Neutrophils infiltrate Activation of complement immune complexes neutrophilic chemotaxis and macrophage phagocytosis the tissue site factors (C3, C4) Leukocytoclastic vasculitis (histopathologic term for small vessels inflamed by neutrophilic autoimmune response) Inflamed cutaneous vessels become enlarged in clusters Symmetrical palpable purpura (red/purple, non- blanchable papules) distributed on lower limbs and buttocks areas Cutaneous small vessel vasculitis (100%) Inflamed gastric vessels - hemorrhage and edema within bowel wall Gastrointestinal (85%) Colicky abdominal pain (commonly in the periumbilical region), nausea, vomiting Gastrointestinal GI bleeding (hematemesis, melena), Intussusception Glomerular mesangial proliferation and inflammation ↑ mast cell deposition in joints Joints (60-85%) Arthralgia's (common), arthritis (especially knees and ankles) Arthralgia often transient. No permanent sequelae Sympathetic nervous system activation Glomerulosclerosis, tubulointerstitial and podocyte damage Renal tissue ischemia ↑ Na sensitivity in renal tubules (↑ Na and water retention) Renal (10-50%) Increased renin secretion HTN, nephrotic/nephritic syndrome, renal insufficiency Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 1, 2019 on www.thecalgaryguide.com

Varicocele

Varicocele: Pathogenesis and clinical findings Authors: Luc Wittig Ryan Brenneis Reviewers: Alec Mitchell Darren Desantis* * MD at time of publication Notes: • 90% present as left sided. • Primary varicocele ache and scrotal venous distention can be relieved by superincumbent positioning (increases venous return). • Small varicoceles can be identified by preforming the Valsalva maneuver (decreases venous return). • Unilateral right varicoceles are uncommon and should be investigated for underlying pathology causing obstruction. Primary Anatomically: the left spermatic vein drains into the left renal vein Nutcracker Effect: The left renal vein can get pinched by the abdominal aorta and superior mesenteric artery Backup of blood in left renal vein ↑ pressure in left spermatic vein Secondary Renal cell carcinoma or retroperitoneal masses Inferior vena cava thrombus External compression of spermatic vein Obstruction of blood flow ↑ spermatic vein pressure Vein valve leaflet failure & retrograde bloodflow back towards testicle Dilation of pampiniform plexus and scrotal vein plexus Varicocele ↑ scrotal blood volume ↑ volume in a closed space ↑ pressure and distension of scrotal layers ↑ scrotal vein plexus pressure Compliant veins distend, becoming visible through scrotum Blood heats up the structures it flows through Scrotal hyperthermia Unsuitable environment for spermatogenesis Loss of germ cell mass Bag of Worms Sign Dull ache/heaviness Decreased fertility Testicular atrophy Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 26, 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

Diabetic-Nephropathy

Diabetic Nephropathy: Pathogenesis Type I or Type II Diabetes ↑ Glucose uptake & glycolysis in glomerular & tubular cells Poor glycemic control = ↑ Glucose load ↑ Proximal tubule reabsorption of Na via Na/glucose co-transporter ↓ NaCl to distal tubule Activation of tubulo- glomerular feedback at macula densa to kidney ↑ Activation of renin- angiotensin system (RAS) ↑ Intrarenal angiotensin II ↑ Advanced glycation end products (AGE) Shunting of glucose through non- glycolytic pathways (e.g. polyol) Activation of Protein Kinase C (PKC) pathway Excessive production and accumulation of glycolytic intermediates (e.g. sorbitol, hexosamine, succinate) hyperglycemia Succinate via GPR91 ↑ Free radical production (oxidative stress) Activation of cellular signalling, transcription factors and cytokines (e.g. TGF-β-Smad-MAPK, IGF-1, NF-κB) ↑NADPH oxidase activity ↑Blood volume ↑ Blood pressure ↑ Renal perfusion Relative afferent arteriole dilatation, efferent arteriole constriction Initial ↑ in glomerular filtration rate (GFR) Podocyte loss/injury Authors: Steven Chen Shannon Gui Yan Yu* Reviewers: Julia Heighton Ryan Brenneis Sophia Chou* * MD at time of publication Initial glomerular hyperfiltration at time of diagnosis ↓ Production of matrix metallo- proteinases Aberrant extracellular matrix (ECM) protein expression and accumulation Sheer stress to glomeruli à pressure-induced damage ↑ Glomerular basement membrane permeability to proteins like albumin ↓ Extracellular matrix regulation “Metabolic Pathway” Mesangial matrix expansion Kimmelstiel- Wilson lesions (pink hyaline nodules due to accumulation of damaged proteins) Tubular fibrosis Scarred glomeruli are less able to effectively filter blood ↓ in glomerular filtration rate (GFR) Albuminuria Usually occurs after ~5 years from time of diagnosis in T1DM; can occur at time of diagnosis in T2DM Abbreviations IGF: Insulin-like growth factor MAPK: Mitogen-activated protein kinases NADPH: Nicotinamide adenine dinucleotide phosphate NF-κB: Nuclear factor kappa-light-chain- enhancer of activated B cells TGF-β: Transforming growth factor-β Protein endocytosis into tubular cells causing inflammation “Hemodynamic Pathway” Diabetic Nephropathy Overt diabetic nephropathy may take upwards of 15-25 years to develop Note: The mechanisms presented here have been simplified. The cross- talk and signaling between the metabolic and hemodynamic factors do not manifest in a step-wise fashion, but rather occur in parallel. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 3, 2020 on www.thecalgaryguide.com

GU-changes-in-pregnancy

Physiologic Changes in Pregnancy: Renal & Genitourinary Pregnancy ↑ estrogen ↑ angiotensin synthesis in liver Renin-angiotensin- aldosterone system activation ↑ aldosterone ↑ plasma volume ↑ glomerular filtration rate (GFR) Mechanism unclear, possibly 1) ↑ circulating anti- angiogenic factorsà ↑ permeability of glomerular basement membrane, or 2) ↑ plasma volumeà↓ oncotic pressure of plasma at the glomerulus Proteinuria > 300 mg/day, abnormal in pregnancy ↑ hCG level Dilation of renal vasculature ↑ renal vascular & interstitial volume ↑ filtration surface area Overwhelming load of glucose to proximal tubule ↑ urine output ↑ relaxin secreted by placenta Mechanism not well understood ↓ osmotic threshold for ADH release & thirst ↑ ADH secretion & ↑ oral hydration Incomplete reabsorption of glucose Glucosuria Encourage bacterial growth in the urine Urinary tract infection (e.g. cystitis, pyelonephritis) ↑ serum progesterone Uterine rotation as uterus enlarge due to presence of large bowel Ureter compression (R > L) Ureterovesical reflux (back-flow of urine into the ureters/kidneys) Dilatation of ureters (R > L) (hydroureter) & renal pelvis (hydronephrosis) Progesterone competes with aldosterone ↓ sodium reabsorption ↓ plasma sodium concentration Hyponatremia of pregnancy* (pathological if < 130 mEq/L) *Despite factors favoring sodium excretion, there is a net retention of sodium during pregnancy from adaptation of the renal tubules ↑ urinary stasis ↑ excretion of creatinine and urea in urine ↓ serum creatinine and urea ↓ ureteral toneà ↑potential for ureter dilation Mechanism not well understood ↓ peristalsis of ureters ↑ urinary frequency (voiding > 7x/day) ↑ nocturia (voiding ≥ 2x/night) ↓ oncotic pressure of plasma intra-vascularly àwater leaves blood, enters interstitial tissue, and stays there in gravity-dependent regions of the body Pedal +/- ankle edema Author: Simonne Horwitz Reviewers: Claire Lothian, Crystal Liu, Ronald Cusano*, Candace O’Quinn*, Yan Yu* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published June 28, 2020 on www.thecalgaryguide.com

acute-pancreatitis-complications

Acute pancreatitis: Complications Inflammation causes vasodilation and vasculature leakage Mild, (85%): Interstitial edematous pancreatitis Local accumulation of fluid in the pancreas <2 weeks after onset Acute peripancreatic fluid collection (not encapsulated) Walled off by fibrous & granulation tissue >2 weeks after onset Pancreatic pseudocyst (completely encapsulated) Peritoneal irritation à pain Large cyst can (very rarely) compress surrounding bowel Acute Pancreatitis Inflammatory cytokines are released from damaged pancreas If recurrentàchronic pancreatitis (see relevant slide) Inflammation damages pancreatic exocrine cellsàInappropriate release of pancreatic enzymes into surrounding tissue & vasculature àdigesting pancreatic parenchyma Authors: Nissi Wei, *Yan Yu Reviewers: Dean Percy, Miles Mannas, Varun Suresh, Brandon Hisey, *Kerri Novak, *Sylvain Coderre * MD at time of publication complete resolution (most cases) Necrotic tissue is vulnerable to infection (esp. Gram neg GI bacteria) inflammation & necrosis activate cytokine cascade Severe, necrosis (15%): Necrotizing pancreatitis Local infection Severe pancreatic inflammation shifts body fluid into retroperitoneal spaceàintravascular volume depletion Systemic Inflammatory Response Syndrome (SIRS) (see relevant slide) Organ failure (may be sole feature on presentation) Stagnant fluid can more easily become infected Infection spreads to bloodstream Cardiac failure Hypovolemic shock Renal failure Local accumulation of fluid & necrosis in the pancreas < 4 weeks after onset: Acute necrotic collection (not encapsulated) Walled off by fibrous & granulation tissue > 4 weeks after onset walled-off necrosis (completely encapsulated) When treated with excess fluid resuscitation: Intra- abdominal hypertension Respiratory failure (ARDS) Disseminated intravascular coagulation (DIC) Bowel obstruction Gastric outlet (see relevant slide) obstruction Infected pancreatic necrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 20, 2016, updated September 7, 2020 on www.thecalgaryguide.com

insuffisance-cardiaque-gauche-les-resultats-de-lexamen-physique

Insuffisance cardiaque gauche: les résultats de l’examen physique Lesoreillettes cardiaques se contractent contre un ventricule gauche rigide en fin de diastole Dysfonction diastolique ̄Débit cardiaque: Insuffisance ventriculaire gauche Il y a une augmentation de la quantité de sang dans le ventricule gauche suivant la systole, avec ­ pression télédiastolique du ventricule gauche Le sang reflue au niveau des poumons, ­ la pression vasculaire pulmonaire B4 Si le ventricule gauche est dilaté (i.e. en cas de cardiomyopathie dilatée) Dysfonction systolique ̄ Perfusion tissulaire (au niveau cerebral, renal etc.) Vasoconstriction périphérique àdetournement limité du volume d’ejection systolique vers les organes principaux Extrémités froides, cyanose périphérique ̄ Du débit urinaire ̄ De l’état de conscience Hypoxie tissulaire ­ la respiration anaérobique, ­ production d’acide lactique (acidose) Les centres respiratoires tentent de compenser Expulsion des fluides des capillaires vers les alvéolesà oedème pulmonaire transudatif La congestion vasculaire et les alvéoles oedématiées compriment les voies respiratoires, provoquant une turbulence du flux d'air Un flux d'air turbulent est entendu lors de l'auscultation Respiration sifflante (wheezing) Flux turbulent dans le ventricule gauche distendu au début de la diastole B3 Choc de la pointe diffuse ̄ Du flux sanguin artériel pendant la systole ̄ Tension artérielle en systole ­ De la tension artérielle lors de la diastole ̄ Pouls cardiaque Fermeture des valves pulmonaires avec une force supérieure à la normale ­ B2 pulmonaire ̄ De l’oxygenation sanguine Le transsudat obstrue les petites voies aériennes et alvéolaires Si le ventricule gauche est en surcharge de pression ou si hypertrophié (i.e. sténose aortique, hypertension sévère) Choc de la pointe soutenue ­ De l'activité du système sympathique (pour tenter de rétablir le débit cardiaque) Pendant l'inspiration, de petites zones de compartiments aériennes s'ouvrent Crépitements pulmonaires (ils sont généralement bilatéraux et surtout au niveau de la base pulmonaire) Auteur: Yan Yu Editeurs: Sean Spence, Jason Baserman, Nanette Alvarez* Traductrice/Traducteur: Emma Hofland-Burry, Jean-François Lemay* *MD au moment de la publication ­ Activité des glandes sudoripares Diaphorèse ­ Activité cardiaque Tachycardie ­ Fréquence respiratoire Tachypnée Remarque: l'insuffisance cardiaque gauche étant la cause principale de l'insuffisance cardiaque droite, elle peut également se présenter par des signes d'insuffisance cardiaque droite. Les autres caractéristiques de l'insuffisance cardiaque gauche dépendent de la cause sous-jacente. Si la pression vasculaire artérielle pulmonaire est chroniquement élevéeàporvequera un surmenage prolongé de la function du ventricule droit: Insuffisance cardiaque droite: Le patient présente des conséquences directes de sa congestion veineuse systémique: œdème périphérique (i.e.cheville), épanchements pleuraux, congestion hépatique/ascites (s.v.p. voir la diapositive correspondante) Publié le 10 Janvier 2013 à www.thecalgaryguide.com

Pathogenesis-of-Female-Infertility

Pathogenesis of Female Infertility Author: Simonne Horwitz Reviewers: Claire Lothian, Hannah Yaphe, Yan Yu*, Nicole Paterson* * MD at time of publication Extreme stress, eating disorder, excessive exercise, intracranial tumor, or hyperprolactinemia* ↓ Gonadotropin releasing hormone (GnRN) from hypothalamus ↓ release of Luteinizing hormone (LH) & Follicle stimulating hormone (FSH) by pituitary ↓ release of estrogen by ovaries Anovulation (oocyte is not released) Fewer follicles available to ovulate * Causes of Hyperprolactinemia include: prolactinoma (prolactin-producing tumor), hypothalamic infiltrate or mass, chest wall irritation, hypothyroidism, renal or liver disease (↓ prolactin clearance), dopamine antagonists that ↑ prolactin secretion (antipsychotics, anti- depressants, anti-emetics) Polycystic ovary syndrome (see PCOS: Pathogenesis and Clinical findings) ↑ androgen production & ↑ estrogen earlier in the menstrual cycle ↓ FSHà↓ follicle growth ↑ rate of follicle depletion Oocyte not available every month for fertilization Premature ovarian insufficiency due to unexplained causes, chemotherapy, radiation, autoimmune ovarian destruction, Turner’s & Fragile X Syndromes Damage in germ cells that accumulates over a woman’s lifetime Age-related changes in quality of granulosa cells surrounding oocyte Genetic damage accumulates, such as ↑ rates of meiotic nondisjunction (failure of chromosomes to separate during gamete cell division) Tubal occlusion or ↓ transport of oocyte tubal cilia dysfunction through fallopian tube ↓ quality of oocytes Normal transport of oocyte & sperm through fallopian tube is impaired ↓ facilitation of sperm transportation Inhibits normal zygote implantation Chlamydial or gonorrhoeal pathogens Previous tubal surgery or ectopic pregnancy surgery tissue removal ↓ transport of oocyte through fallopian tube Female Infertility Previous abdominal infection or surgery Endometriosis Congenital malformations or trauma / surgery to cervix Uterine leiomyomata (benign smooth muscle monoclonal tumor) or polyp Intrauterine procedures Pelvic adhesions (scar-like tissue that tether together abdominal organs) may distort the shape and normal anatomy of the fallopian tube Ectopic endometrial cells implant & Local inflammatory response grow along pathway of egg/sperm further ↓ egg/sperm mobility Inability of cervix to produce normal mucus, and/or sperm physically unable to enter the cervix Submucosal or intracavitary component disrupts uterine lining Trauma to basalis layer of endometrium Intrauterine scarring or synechiae (adhesions) ↓ vascularization & endometrial regrowth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications 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

Primary-Aldosteronism

Primary Aldosteronism: Clinical findings Note: This condition is also known as “Primary Hyper-Aldosteronism” or “Conn’s Syndrome” Authors: Samin Dolatabadi Reviewers: Amanda Henderson, Hannah Yaphe, Yan Yu*, Hanan Bassyouni* Juliya Hemmett* * MD at time of publication ↑ Expression of Cl-/HCO3- exchanger in the basolateral membrane of intercalated cell of cortical collecting duct ↑ HCO3- reabsorption into bloodstream ↑ Autonomous aldosterone secretion from zona glomerulosa of adrenal cortex (e.g. aldosterone producing adenoma) ↑ Serum aldosterone level ↑ Circulating aldosterone activates mineralocorticoid receptors on cardiac myocytes ↑ Transcription of proinflammatory and profibrotic genes in cardiac myocytes Cardiac fibrosis and hypertrophy In the rest of the body, K+ moves from intracellular to extracellular environment (down it's concentration gradient) to compensate for decreased serum K+ Loss of positively charged K+ànegative intracellular chargeàcells take up H+ to remain electrostatically neutral ↑ Expression of epithelial sodium channels in principal cells of cortical collecting duct ↑ Na+ reabsorption from cortical collecting duct into blood vessels + Water follows Na into the blood vessels to balance the osmotic pressure between the blood and the renal tubules ↑ blood volume within the volume- constrained space of blood vessels ↑ Activation of Na+/K+ ATPase in principle cells of cortical collecting duct Removal of positively charged Na+ from tubular lumenà lumen becomes electronegative versus the interstitial space & inside tubular epithelial cells Positively charged K+ follows the electrical gradient and is secreted into tubular lumen ↓ Serum K+ concentration ↑ Expression of H+ ATPase in the apical (luminal) membrane of intercalated cell of cortical collecting duct H+ is secreted into cortical collecting duct → renal loss of H+ from the body Metabolic Alkalosis (blood becomes more basic; ↑ serum pH) Hypertension Muscle weakness, fatigue, polyuria ↓ pH in intercalated cell ↓ pH in cells of proximal convoluted tubule ↑ loss of H+ through kidneys H+ secretion into cortical collecting duct ↑ H+ ATPase activity in intercalated cell Activation of glutaminase in proximal convoluted tubule HCO3- pumped into blood ↑ production of HCO3- (product of glutamine breakdown) ↑ breakdown of glutamine Hypokalemia (See Hypokalemia: Clinical Findings slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2020 on www.thecalgaryguide.com

Beta-Blockers-Mechanism-of-Action-and-Side-Effects

Beta-Blockers: Mechanism of Action and Side Effects Two classes of “Beta-Blockers” are used clinically: Non-cardio-selective: binds Cardio-selective: binds largely beta-1 and beta-2 receptors to beta-1 receptors Authors: Tegan Evans, Davis Maclean, Yan Yu* Reviewers:, Amanda Nguyen, P. Timothy Pollak*, Sean Spence* * MD at time of publication Beta blockers bind to beta 1 and/or beta 2-receptors of various tissues throughout body, and thus competitively inhibit binding of sympathetic adrenergic molecules (such as catecholamines from the adrenal medulla, e.g. epinephrine) to these receptors, ↓ their normal adrenergic tone Beta-2 receptor antagonism Beta-1 receptor antagonism Lungs Eyes Central nervous system Heart Kidneys ↓ cAMP (intracellular messenger) productionàcomplex, tissue-specific intracellular mechanisms resulting in a variety of effects in different tissues: Throughout body tissue Epinephrine (via cAMP) indirectly ↑ the activity of the Na+/K+ pump on cell membranes (a pump that moves 3 Na+ out of cells per 2 K+ moved into cells) Blocking epinephrine from binding the beta-2 receptor and producing cAMPà↓ activity of Na+/K+ pump à↓K+ moved into cells ↑ proportion of K+ now resides in extracellular fluid, detectable in serum (total body K+ remains the same) Hyperkalemia (see Calgary Guide: Hyperkalemia – Clinical findings) Blocking sympathetic hormonesà↓ relaxation of smooth muscle circumferentially wrapped around airways ↑ resting airway muscle toneà bronchoconstriction ↑ resistance to airflow Wheezing, dyspnea, chest tightness Exacerbation of underlying airway disease (e.g. asthma) ↓ ciliary epithelium’s production of aqueous humor (fluid that fills anterior chamber of the eye) Reduced intraocular pressure Blocking adrenergic response mediated by epinephrine and norepinephrine (e.g. the physiologic “fight- or-flight” response to stress) ↓ tremor, irritability, anxiety ↓ ability to produce adrenergic symptoms in response to hypoglycemia Hypoglycemia unawareness Coronary perfusion pressure = diastolic blood pressure in aorta – LV end diastolic pressure ↓ inotropy (contractility of cardiac muscle) ↓ chronotropy (heart rate and conduction velocity) ↓ renin releaseà↓ creation of angiotensin II & aldosterone + ↓ reabsorption of Na and H2O in nephron ↑ urinary Na+ & H2O loss ↓ total blood volume Decompensation of acute heart failure Dizziness and fatigue Hypotension (Blood pressure = cardiac output x systemic vascular resistance) ↓ O2 demand of myocardial tissue Bradycardia Inability to ↑ heart rate in response to stress (e.g. shock, sepsis) ↓ stroke volume ↓ cardiac output Beta blockers ↓ diastolic blood pressure, & thus may ↓ coronary perfusion pressure Before giving beta blockers, ensure blood pressure isn’t too low Otherwise, may worsen acute myocardial ischemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 14, 2021, updated Feb 7, 2021 on www.thecalgaryguide.com

Potassium-Sparing-Diuretics-Mechanism-of-Action-and-Side-Effects

Potassium-Sparing Diuretics: Mechanism of Action and Side Effects Potassium-Sparing Diuretics Authors: Samin Dolatabadi, Yan Yu* Reviewers: Jessica Krahn, Timothy Fu, Juliya Hemmett* * MD at time of publication Epithelium Sodium Channel Blockers (Amiloride and Triamterene) Inhibit Na+ channels (involved in Na+ reabsorption) in the luminal membrane of the principal cells in the cortical collecting duct Aldosterone Antagonists (Spironolactone and Eplerenone) Competitively blocks mineralocorticoid receptors and ↓ aldosterone effect in the renal tubules and throughout the body ↓ aldosterone effectà↓ expression of basolateral Na+/K+ pumps & luminal epithelium Na+ channels on the principal cells of cortical collecting duct Spironolactone’s molecular structure is similar to that of steroid hormonesàspironolactone can also block androgen receptors Anti-androgenic effects (due to ↓ androgen function in reproductive organs, skin, and on brain centers) Triamterene can form triamterene crystals and granular casts (unclear mechanism) ↓ Na+ reabsorption by principal cells ↓ in serum Na+ concentration: Hyponatremia ↓ K+ pumped out into the tubule by principal cells Crystals & casts obstruct tubular lumen → inflammation (unclear mechanism) Triamterene crystals are directly cytotoxic to tubular cells Only ~2-5% of Na+ filtered by the glomerulus is normally reabsorbed in the cortical collecting ductàthe ↑ in Na+ retained in cortical collecting duct is mild Water follows Na+ to maintain a balanced osmotic pressureà↑ in water in cortical collecting duct available for excretion ↑ positive charges in lumen relative to surroundings generates an electropositive tubular lumen Unfavorable electrical gradient ↓ secretion of positive charged ions into electropositive lumen ↓ libido Menstrual abnormalities (in women) ↓ acne Gynecomastia (in men) ↓ secretion of K+ ↑ in serum K+ concentration: Hyperkalemia Cardiac Arrythmias (See relevant slide on Hyperkalemia: Clinical Findings) Interstitial inflammation and tubular injury Drug-induced Nephrotoxicity Mild Diuresis ↓ blood volume ↓ Blood pressure/ Hypotension ↓ secretion of H+ ↑ in serum H+ concentration: Metabolic Acidosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 15, 2021 on www.thecalgaryguide.com

AAA-Pathogenesis

Abdominal Aortic Aneurysm (AAA): Pathogenesis Different parts of the aorta have different embryologic origins Atherosclerosis Hypertension Age > 65 Progressive deterioration of aorta structural integrity over life span Connective Tissue Disease Structurally abnormal protein or protein organization in aorta Autoimmunity Infection (e.g Chlamydia, Mycoplasma pneumoniae, Helicobacter pylori, human cytomegalovirus, herpes simplex virus) Antigens (substance that causes immune response) on virus or bacteria resemble local proteins in abdominal aorta Antibodies produced in response to infection inappropriately target host cells in the aorta Antibodies tag cells in the abdominal aorta for destruction by T-lymphocytes Immune-mediated destruction of aorta Smoking Genetics Unclear mechanisms Subacute (not clinically detectable) inflammation of aortic tissue Inflammatory cytokines are released and immune cells are recruited ↑ pressure on aorta and other vessel walls Infiltration of vessel wall by lymphocytes and macrophages Production of enzymes that break down elastin & collagen proteins (which provide most tensile strength to aorta) Aorta susceptible to damage Degradation of aortic connective tissue Biomechanical stress on vessels Authors: Olivia Genereux Davis Maclean Reviewers: Jason Waechter* Amy Bromley* Yan Yu* *MD at time of publication The exact mechanisms are complex, debatable, and an area of intensive research – the 3 mechanisms and associated pathophysiology presented here are generally thought to be the main causes of abdominal aortic aneurysms Infrarenal aorta has poorly developed vaso vasorum (dedicated blood supply to vessel wall) Infrarenal aorta relies solely on nutrient diffusion from aortic blood that crosses abdominal aorta Infrarenal aortic wall has fewer “lamellar” units (fibromuscular units) than other regions of the aorta Infrarenal aorta is less elastic & less able to distribute stress Loss of smooth muscle cells & thinning of tunica media Destruction of elastin in tunica media Normal layers of the aortic wall ↓ aortic tensile strength (ability to withstand stretching) Aorta expands and dilates due to internal pressure Tunica Intima (inner-most tissue layer of aorta) Tunica Media (layers of elastic tissue (elastin) and muscle fibers) Adventitia (thin outermost collagenous layer) (longitudinal section) Aortic aneurysms are usually infrarenal (85%) Abdominal Aortic Aneurysm Infrarenal aorta more prone to ischemia and has impaired repair potential Abnormal, irreversible dilation of a focal area of abdominal aorta (area of aorta between diaphragm & aortic bifurcation) to twice the diameter of adjacent normal artery segment Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published February 27, 2021 on www.thecalgaryguide.com

VITT

Vaccine Induced Thrombosis and Thrombocytopenia (VITT): Pathogenesis and Clinical Findings Current leading theory: COVID-19 viral vector vaccines (Johnson and Johnson and AstraZeneca) contain an anionic molecule (currently unspecified), which binds to the cationic platelet factor 4 (PF4) molecule in the bloodstream, forming vaccine/PF4 complexes Authors: Brooke Fallis Reviewers: Yan Yu* Katie Lin* * MD at time of publication Spleen macrophages remove antibody/platelet complexes from circulation Fewer unbound platelets in circulation detected on complete blood count (CBC) Thrombocytopenia: Platelets <150x!

disseminated-intravascular-coagulation

Disseminated Intravascular Coagulation (DIC): Pathogenesis and clinical findings Authors: Emily Wildman Mehul Gupta Sean Spence Yan Yu* Reviewers: Kiera Pajunen Wendy Yao Tristan Jones Man-Chiu Poon* Lynn Savoie* * MD at time of publication Sepsis Microorganisms express pathogen- associated molecular patterns (PAMPs) Severe Trauma Damaged endothelial cells release damage- associated molecular patterns (DAMPs) Solid and Hematologic Malignancies Cancer cells express tissue factor and release procoagulants Immune cells recognize DAMPs and PAMPs and begin expressing tissue factor and releasing procoagulants Systemic activation of coagulation cascade Activation of coagulation cascade results in the factor X mediated conversion of large quantities of prothrombin (factor II) to its active form, thrombin (factor IIa) Thrombin cleaves fibrinogen (factor I) circulating in blood to an activate form known as fibrin (factor 1a) ↓ Serum fibrinogen Diffuse coagulation causes imbalances between coagulation and anticoagulation pathways Consumption of coagulation factors (including platelets, fibrinogen, prothrombin, factor V, factor VIII) exceeds rate of production Fibrin, in conjunction with platelets, form widespread thrombi within vasculature Fibrin thrombi accumulate in the microvasculature and shear transiting red blood cells Microangiopathic hemolytic anemia (MAHA) ↑ thrombi formation ↑ fibrinolysis, a parallel process that naturally degrades fibrin thrombi Relative deficiency of coagulation factors leads to a bleeding diathesis (tendency to bleed) despite widespread clots ↑ Prothrombin time (PT) ↑ Partial thromboplastin time (PTT) ↑ D-dimer Fibrin thrombi ↑ Fibrin degradation products Platelets are used up forming thrombià less free platelets in circulation ↓ Platelets on Complete Blood Count accumulate in microvasculature of major organs Deposition of thrombi occlude blood flow resulting in ischemia of organ parenchyma Lack of coagulation factors can predispose spontaneous hemorrhage in various organs Multiple organ dysfunction syndrome (MODS) - (renal failure, hepatic dysfunction, stroke, pulmonary disease) Clinical manifestations of bleeding, including petechiae (pinpoint red spots on skin), ecchymoses (bruising), weeping wound sites, bleeding mucous membranes Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published Aug 7, 2012, updated July 27, 2019 & Aug 29, 2021 on www.thecalgaryguide.com

Primary-Adrenal-Insufficiency

Primary Adrenal Insufficiency: Clinical findings Infection (fungal or tuberculosis) Note: “Primary” refers to pathology in the gland that produces the functional hormone (in this case, the adrenal gland), as opposed to “secondary” or “tertiary” which refers to pathology in glands that indirectly control the primary gland. Bilateral adrenal Autoimmune damage (cancer, ↓ Androgen levels in women (in whom adrenal glands are the primary source) ↓ Libido ↓ Axillary and pubic hair Muscle/joint pain Anorexia, weight loss Abdominal pain, nausea, vomiting Diseases bleeding, etc) ↓ Androgen production from the zona reticularis ↓ Cortisol production from the zona fasciculata ↓ Serum cortisol Patients could present with many severe symptoms of adrenal insufficiency, e.g. low blood pressure refractory to fluid resuscitation Significant bilateral damage to the adrenal glands Entire adrenal cortex function impaired ↓ Serum levels of adrenal steroid hormones exert positive feedback effect on pituitary gland, ↑ pituitary gland’s production of adrenocorticotropic hormone (ACTH) ↑ Serum levels of ACTH The same gene that encodes ACTH also encodes melanocyte stimulating hormone (MSH) Coincidental ↑ in MSH production by the pituitary ↓ Serum DHEAS, testosterone and androstenedione Unknown mechanism(s) Malaise Adrenal Crisis ↓ Cortisol mediated gluconeogenesis and glycogenolysis ↑ Cortisol Releasing Hormone (CRH) from the hypothalamus Lack of cortisol-driven vasoconstriction of blood vesselsà↑ Vasodilation ↓ Blood pressure, postural dizziness Water follows sodiumà ↑ excretion of water ↓ Sodium resorbed from kidney tubulesà↑ Sodium excretion ↓ Potassium pumped into kidney tubules à↑ potassium retained in serum Hypoglycemia (↓ blood glucose) ↑↑ Antidiuretic hormone (ADH) release Kidneys reabsorb water à↑ total body water Hyponatremia (↓ serum sodium) ↑ Salt craving Hyperkalemia (high serum potassium level) ↓ Aldosterone production from the zona glomerulosa ↓ Serum aldosterone MSH triggers ↑ production of melanin by the melanocytes in skin ↓ Excretion of hydrogen ions from kidneys (See type IV RTA slide for full mechanism) Metabolic acidosis (low pH, low bicarbonate) ↓ Sodium channel and Na/K ATPase expression on principle cells of the kidney Hyperpigmentation of the skin and mucosal surfaces Authors: Jaye Platnich, Brooke Fallis, Yan Yu* Reviewers: Mark Elliott, Alexander Arnold, Hanan Bassyouni*, David Campbell* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 13, 2013, updated October 1, 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

Diabetische Ketoazidose (DKA)

Diabetische Ketoazidose (DKA) Betrifft hauptsächlich Patienten mit Diabetes Mellitus Typ 1: Bestimmte Situationen (z.B. Infektionen) erhöhen den Insulinbedarf, welcher durch fehlende Produktion/unzureichende Substitution nicht gedeckt werden kann Autor: Yan Yu Rezensenten: Peter Vetere, Gill Goobie, Sean Spence, Hanan Bassyouni* Übersetzung: Sarah Schwarz Übersetzungsprüfung: Dr. Gesche Tallen * MD zum Zeitpunkt der Veröffentlichung Hyperglykämie (erhöhter Blutzucker) Bei >12mmol/L, Glukosefiltration > - resorption, Glukose verbleibt im Urin Glukosurie Glukose ist osmotisch wirksam und zieht große Mengen Wasser mit sich (Osmotische Diurese) Polyurie Schwere Dehydrierung(bis zu 4-5L) (ZVD↓, Orthostase: posturale Hypotension/ posturale Tachykardie, Ruhepuls ↑ ) Insulinmangel enthemmt die Lipolyse, sodass der Körper Energie aus Triglyceriden produziert Freisetzung von freien Fettsäuren aus Fettgewebe Absoluter Insulinmangel Hypothalamische Zellen induzieren bei geringem intrazellulären Glukosespiegel ein starkes Hungergefühl Glukose bleibt im Blut & kann nicht durch Muskel- /Fettgewebe verstoffwechselt werden “Ausgehungerte” Zellen triggern die Freisetzung kataboler Hormone: Glucagon, Katecholamine, Cortisol, Somatotropin Damit intrazellulärer Glukosespiegel ↑, erhöht der Körper den Blutzucker Hydrolyse von freien Fettsäure in der Leber (Ketogenese) Polyphagie ↓ Proteinsynthese, ↑ Proteolyse (in Muskelgewebe) ↑ Gluconeogenese, ↑ Glykogenolyse (in der Leber) Acetyl Co-A Energiequelle für “ausgehungerte” Zellen Beachte: Neben Glukose sind Ketonkörper die einzigen Energieträger die von Nervenzellen metabolisiert werden können. Deshalb werden sie vom Körper bei geringem Glukoseangebot produziert. Ketonkörper ( β-Hydroxybutyrat, Acetoacetat, Aceton, akkumulieren im Blut) Ketonurie Metabolische Azidose (↑Anionenlücke: Ketonkörper verbrauchen den HCO3--Puffer) Substrate der Gluconeogenese↑ Durch ↓ Extrazellulärflüssigkeit, werden Ketonkörper konzentriert → Azidose Stört das enterische Nervensystem, Magenentleerung ↓, Ileus Bauchschmerzen, Übelkeit, Erbrechen (Dehydration↑) Abatmen von CO2 um Azidose auszugleichen Kussmaul- Atmung (Tiefe, schnelle Züge) Abatmen von Keton- körpern Azeton- geruch der Atemluft Beeinträchtigung elektrischer Signale zum Gehirn, Rücken- mark und Nervenzellen Perfusion des Gehirns, Rückenmark, Nervenzellen↓ Verschiebung des Wasser- und Elektrolythaushalts Falls Trinkwasser vorhanden Polydipsie Beachte: Während der DKA verliert der Körper K+ durch Elektrolytstörung Schwäche, Delirium +/- Koma osmotische Diurese und Erbrechen. Da gleichzeitig allerdings K+ aus den Zellen diffundiert, kann das Serumkalium unauffällig/erhöht sein. Um Hypokaliämien zu verhindern sollte bei K+ <5.0mmol/L KCl zusammen mit Insulin i.v. verabreicht werden. Cave: gute Nierenfunktion des Patienten Therapie: 1) +++ Flüssigkeit. 2) Insulin + KCl. 3) Auffüllen der Anionenlücke. 4) Auslösende Faktoren identifizieren. 5) Wenig PO4 (typischerweise wenige Stunden bis einen Tag nach der Ketoazidose durch ↑ ATP-Produktion.) Legende: Pathophysiologie Mechanismen Symptome/Klinische Befunde Komplikationen Publikationsdatum: 17 Juni 2013 auf www.thecalgaryguide.com Hyperosmolares/ Hyperglykämisches Koma (HHS) Beachte: betrifft nur Patienten mit Diabetes mellitus Typ II Beachte: Es sollte stets nach auslösenden Faktoren z.B. einer Infektion gesucht werden Autor: Yan Yu Rezensenten: Peter Vetere Gill Goobie Hanan Bassyouni* Übersetzung: Sarah Schwarz Übersetzungsprüfung: Dr. Gesche Tallen * MD zum Zeitpunkt der Veröffentlichung Verschiebung des Wasser- und Elektrolythaushalts Elektrolytstörung Unzureichende Insulin- produktion, Insulinresistenz, Nichtansprechen auf Insulintherapie Relativer Insulinmangel Situationen mit ↑Insulinbedarf: Infekt, Pneumonie, Herzinfarkt, Pancreatitis, etc.) Hyperglykämie (Stark erhöhter Blutzucker, höher als bei der DKA) Bei >12mmol/L, Glukosefiltration > - resorption, Glukose verbleibt im Urin Glukosurie Glukose ist osmotisch wirksam und zieht große Mengen Wasser mit sich (Osmotische Diurese) Polyurie Dehydration (ZVD↓, Orthostase: posturale Hypotension/posturale Tachykardie, Ruhepuls ↑ ) Durch das wenige noch vorhandene Insulin, wird ein Teil der Glukose von Muskel- /Fettgewebe verstoffwechselt, ein Teil verbleibt im Blut Körperzellen brauchen eine weitere Energiequelle Freisetzung kataboler Hormone: Glucagon, Katecholamine, Cortisol, Somatrotropin Damit intrazellulärer Glukosespiegel ↑, erhöht der Körper den Blutzucker Hypothalamische Zellen induzieren bei geringem intrazellulären Glukosespiegel ein starkes Hungergefühl Polyphagie Beachte: Durch das wenige noch vorhandene Insulin wird die Lipolyse gehemmt und werden keine Ketonkörper produziert. Es kommt nicht zur Azidose und Ketonurie (Gegensatz zur DKA). Sollte es doch zur Ketourie kommen, ist das meist Folge von Hungerzuständen oder anderen Mechanismen Extrazellulärflüssigkeit ↓ mit erhöhter Osmolarität (z.B. Hypernatriämie) ↑ Gluconeogenese, ↑ Glykogenolyse (in der Leber) ↓ Proteinsynthese, ↑ Proteolyse (in Muskelgewebe) Substrate der Gluconeogenese ↑ Sollte der Patient nicht ausreichend trinken um das Volumendefizit auszugleichen Falls Trinkwasser vorhanden Polydipsie Wasser verlässt Zellen entlang des osmotischen Gradienten, Neuronen schrumpfen Neuronaler Schaden: Delirium, Krampfanfall, Benommenheit, Koma Renale Perfusion↓, GFR ↓ Nierenversagen (prä-renal, siehe entsprechende Folie) Beachte: Während der DKA verliert der Körper K+ durch osmotische Diurese. Da gleichzeitig allerdings K+ aus den Zellen diffundiert, kann das Serumkalium unauffällig/erhöht sein. Um Hypokaliämien zu verhindern sollte bei K+ <5.0mmol/L KCl zusammen mit Insulin i.v. verabreicht werden. Cave: gute Nierenfunktion des Patienten Beachte: Elektrolytstörungen (z.B. Hyperkaliämien, Hypernatriämien) verschlechtern sich bei akutem Nierenversagen, welches bei der DKA &HK häufig auftritt Legende: Pathophysiologie Mechanismen Symptome/Klinische Befunde Komplikationen Veröffentlicht: 3. November 2016 auf www.thecalgaryguide.com

Hyperosmolares/ Hyperglykämisches Koma (HHS)

Diabetische Ketoazidose (DKA) Betrifft hauptsächlich Patienten mit Diabetes Mellitus Typ 1: Bestimmte Situationen (z.B. Infektionen) erhöhen den Insulinbedarf, welcher durch fehlende Produktion/unzureichende Substitution nicht gedeckt werden kann Autor: Yan Yu Rezensenten: Peter Vetere, Gill Goobie, Sean Spence, Hanan Bassyouni* Übersetzung: Sarah Schwarz Übersetzungsprüfung: Dr. Gesche Tallen * MD zum Zeitpunkt der Veröffentlichung Hyperglykämie (erhöhter Blutzucker) Bei >12mmol/L, Glukosefiltration > - resorption, Glukose verbleibt im Urin Glukosurie Glukose ist osmotisch wirksam und zieht große Mengen Wasser mit sich (Osmotische Diurese) Polyurie Schwere Dehydrierung(bis zu 4-5L) (ZVD↓, Orthostase: posturale Hypotension/ posturale Tachykardie, Ruhepuls ↑ ) Insulinmangel enthemmt die Lipolyse, sodass der Körper Energie aus Triglyceriden produziert Freisetzung von freien Fettsäuren aus Fettgewebe Absoluter Insulinmangel Hypothalamische Zellen induzieren bei geringem intrazellulären Glukosespiegel ein starkes Hungergefühl Glukose bleibt im Blut & kann nicht durch Muskel- /Fettgewebe verstoffwechselt werden “Ausgehungerte” Zellen triggern die Freisetzung kataboler Hormone: Glucagon, Katecholamine, Cortisol, Somatotropin Damit intrazellulärer Glukosespiegel ↑, erhöht der Körper den Blutzucker Hydrolyse von freien Fettsäure in der Leber (Ketogenese) Polyphagie ↓ Proteinsynthese, ↑ Proteolyse (in Muskelgewebe) ↑ Gluconeogenese, ↑ Glykogenolyse (in der Leber) Acetyl Co-A Energiequelle für “ausgehungerte” Zellen Beachte: Neben Glukose sind Ketonkörper die einzigen Energieträger die von Nervenzellen metabolisiert werden können. Deshalb werden sie vom Körper bei geringem Glukoseangebot produziert. Ketonkörper ( β-Hydroxybutyrat, Acetoacetat, Aceton, akkumulieren im Blut) Ketonurie Metabolische Azidose (↑Anionenlücke: Ketonkörper verbrauchen den HCO3--Puffer) Substrate der Gluconeogenese↑ Durch ↓ Extrazellulärflüssigkeit, werden Ketonkörper konzentriert → Azidose Stört das enterische Nervensystem, Magenentleerung ↓, Ileus Bauchschmerzen, Übelkeit, Erbrechen (Dehydration↑) Abatmen von CO2 um Azidose auszugleichen Kussmaul- Atmung (Tiefe, schnelle Züge) Abatmen von Keton- körpern Azeton- geruch der Atemluft Beeinträchtigung elektrischer Signale zum Gehirn, Rücken- mark und Nervenzellen Perfusion des Gehirns, Rückenmark, Nervenzellen↓ Verschiebung des Wasser- und Elektrolythaushalts Falls Trinkwasser vorhanden Polydipsie Beachte: Während der DKA verliert der Körper K+ durch Elektrolytstörung Schwäche, Delirium +/- Koma osmotische Diurese und Erbrechen. Da gleichzeitig allerdings K+ aus den Zellen diffundiert, kann das Serumkalium unauffällig/erhöht sein. Um Hypokaliämien zu verhindern sollte bei K+ <5.0mmol/L KCl zusammen mit Insulin i.v. verabreicht werden. Cave: gute Nierenfunktion des Patienten Therapie: 1) +++ Flüssigkeit. 2) Insulin + KCl. 3) Auffüllen der Anionenlücke. 4) Auslösende Faktoren identifizieren. 5) Wenig PO4 (typischerweise wenige Stunden bis einen Tag nach der Ketoazidose durch ↑ ATP-Produktion.) Legende: Pathophysiologie Mechanismen Symptome/Klinische Befunde Komplikationen Publikationsdatum: 17 Juni 2013 auf www.thecalgaryguide.com Hyperosmolares/ Hyperglykämisches Koma (HHS) Beachte: betrifft nur Patienten mit Diabetes mellitus Typ II Beachte: Es sollte stets nach auslösenden Faktoren z.B. einer Infektion gesucht werden Autor: Yan Yu Rezensenten: Peter Vetere Gill Goobie Hanan Bassyouni* Übersetzung: Sarah Schwarz Übersetzungsprüfung: Dr. Gesche Tallen * MD zum Zeitpunkt der Veröffentlichung Verschiebung des Wasser- und Elektrolythaushalts Elektrolytstörung Unzureichende Insulin- produktion, Insulinresistenz, Nichtansprechen auf Insulintherapie Relativer Insulinmangel Situationen mit ↑Insulinbedarf: Infekt, Pneumonie, Herzinfarkt, Pancreatitis, etc.) Hyperglykämie (Stark erhöhter Blutzucker, höher als bei der DKA) Bei >12mmol/L, Glukosefiltration > - resorption, Glukose verbleibt im Urin Glukosurie Glukose ist osmotisch wirksam und zieht große Mengen Wasser mit sich (Osmotische Diurese) Polyurie Dehydration (ZVD↓, Orthostase: posturale Hypotension/posturale Tachykardie, Ruhepuls ↑ ) Durch das wenige noch vorhandene Insulin, wird ein Teil der Glukose von Muskel- /Fettgewebe verstoffwechselt, ein Teil verbleibt im Blut Körperzellen brauchen eine weitere Energiequelle Freisetzung kataboler Hormone: Glucagon, Katecholamine, Cortisol, Somatrotropin Damit intrazellulärer Glukosespiegel ↑, erhöht der Körper den Blutzucker Hypothalamische Zellen induzieren bei geringem intrazellulären Glukosespiegel ein starkes Hungergefühl Polyphagie Beachte: Durch das wenige noch vorhandene Insulin wird die Lipolyse gehemmt und werden keine Ketonkörper produziert. Es kommt nicht zur Azidose und Ketonurie (Gegensatz zur DKA). Sollte es doch zur Ketourie kommen, ist das meist Folge von Hungerzuständen oder anderen Mechanismen Extrazellulärflüssigkeit ↓ mit erhöhter Osmolarität (z.B. Hypernatriämie) ↑ Gluconeogenese, ↑ Glykogenolyse (in der Leber) ↓ Proteinsynthese, ↑ Proteolyse (in Muskelgewebe) Substrate der Gluconeogenese ↑ Sollte der Patient nicht ausreichend trinken um das Volumendefizit auszugleichen Falls Trinkwasser vorhanden Polydipsie Wasser verlässt Zellen entlang des osmotischen Gradienten, Neuronen schrumpfen Neuronaler Schaden: Delirium, Krampfanfall, Benommenheit, Koma Renale Perfusion↓, GFR ↓ Nierenversagen (prä-renal, siehe entsprechende Folie) Beachte: Während der DKA verliert der Körper K+ durch osmotische Diurese. Da gleichzeitig allerdings K+ aus den Zellen diffundiert, kann das Serumkalium unauffällig/erhöht sein. Um Hypokaliämien zu verhindern sollte bei K+ <5.0mmol/L KCl zusammen mit Insulin i.v. verabreicht werden. Cave: gute Nierenfunktion des Patienten Beachte: Elektrolytstörungen (z.B. Hyperkaliämien, Hypernatriämien) verschlechtern sich bei akutem Nierenversagen, welches bei der DKA &HK häufig auftritt Legende: Pathophysiologie Mechanismen Symptome/Klinische Befunde Komplikationen Veröffentlicht: 3. November 2016 auf www.thecalgaryguide.com

Nephrotisches Syndrom: Pathogenese und klinische Befunde

Nephrotisches Syndrom: Pathogenese und klinische Befunde Membranoproliferative Glomerulonephritis (MPGN) Lupus-Nephritis Postinfektiöse Glomeruloneprhitis IgA Nephropathie Membranöse Glomerulonephritis Antikörper greifen Podozyten an, Verdickung der glomerulären Basalmembran Fokal-segmentale Glomerulosklerose (FSSGN) Schädigung des glomerulären Endo- und Epithels Minimal Change Glomerulo- nephritis (MCNG) Diabetes mellitus Autor: Yan Yu Rezensenten: Alexander Arnold David Waldner Sean Spence Stefan Mustata* Übersetzung: Sarah Schwarz Übersetzungsprüfung: Gesche Tallen* * MD zum Zeitpunkt der Veröffentlichung Podozyten-Schädigung auf der epithelialen Seite des Glomerulums (Abflachung der Podozytenfortsätze) Glomeruläre Immunkomplex- ablagerungen Chronische Hyperglykämien schädigen das Glomerulum Geschädigter Proteinfilter (v.a. für geladene Proteine) Ablagerungen von Immunglobulin-Leichtketten im Glomerulum Amyloidose Geschädigte Glomeruli --> gestörte Filterbarriere v.a. für Proteine --> übermäßige Filtration von Plasmaproteinen Vermehrte renale Ausscheidung von Immunglobulin-Leichtketten (Filtration>Resorption) Hypoalbuminämie* Übermäßiger Verlust an Albumin über den Urin Proteinurie >3.5g/Tag* Verlust an Antikoagulationsproteinen (Antithrombin, Plasminogen, Protein C & S) über den Urin Koagulations- /Gerinnungsfaktoren (z.B. 1,7,8, 10) sind in Überzahl Proteinurie >3.5g/Tag* Thrombophilie Anasarka (Generalisiertes Ödem) Lidödem (klassisches Frühzeichen) Lipidurie (zeigt unter gekreuztem polarisiertem Licht eine Malteserkreuz- form) 50% des Serumkalziums sind an Albumin gebunden, sodass Serumkalzium- spiegel ↓ Serum- Ca2+ repräsentiert nicht mehr das Gesamt-Ca2+ Beachte: • DerklassischeSymptomkomplex(*)desnephrotischen Syndroms besteht aus: Proteinurie (>3,5g/Tag), Ödemen, Hypoalbuminämie,Hyperlipidämie • Fürjede10g/LmitAlbumin<40: ➔ Addiere 2.5 zur errechneten Anionenlücke um dessen “wahren” Wert zu bekommen ➔ Addiere 0,2mmol/L zum Gesamt-Ca um den Wert des ionisierten Kalziums zu errechnen Blut neigt zur Bildung von Thromben Ödeme* ↑ Renale Filtrationder Lipide und Ausscheidung über den Urin Die Anionenlücke ergibt sich hauptsächlich aus negativ geladenem Serumalbumin Anionenlücke↓ Kolloid- osmotischer Druck ↓ Flüssigkeit kann nicht mehr in den Blutgefäßen gehalten werden und diffundiert ins Gewebe Signalisiert der Leber die Albuminproduktion zuerhöhen,Albumin wird aber weiterhin über die Nieren verloren Synthese- arbeit der Leber↑, auch ↑ Lipoprotein- synthese Hyperlipidämie*: (Serum-LDL, -VLDL, - TG ↑ ) Legende: Pathophysiologie Mechanismen Symptome/Klinische Befunde Komplikationen Veröffentlicht: 19. August 2013 auf www.thecalgaryguide.com

impetigo-patogenesis-y-hallazgos-clinicos

Impétigo: Patogénesis y hallazgos clínicos Infección de la epidermis superficial Autor: Taylor Woo Revisores: Gurleen Chahal Usama Malik Laurie M. Parsons* * MD en el momento de la publicación Traducción: Anagabriela Duarte María Rosario Talavera* Temprano: pequeñas vesículas que progresan hacia ampollas superficiales Tardío: ampollas flácidas grandes de base eritematosa con

Psuedocholinesterase Deficiency

Pseudocholinesterase Deficiency: Pathophysiology and Anesthetic Considerations Drugs (anticholinesterases) Break down or inhibit the pseudocholinesterase enzymeà↓ pseudo- cholinesterase activity Note: Pseudocholinesterase has many synonymous names including butyrylcholinesterase, BChE, BuChE, plasma esterase, plasma cholinesterase, and serum cholinesterase Malignancy Abnormal gene expressionà↓ protein synthesis Acquired Liver disease ↓ liver’s ability to synthesize proteins Malnutrition ↓ molecular precursors for protein production Renal Disease Mechanism unclear Fluid Overload Hemodilution of circulating proteins Hereditary BChE (Butyrylcholinesterase) gene mutation ↓ production or production of non-functional pseudo- cholinesterase by the liver ↓ synthesis of pseudocholinesterase by the liver Pseudocholinesterase Deficiency: reduced levels of functional pseudocholinesterase in plasma and tissues Impaired ability to hydrolyze ester linkages of substrates like neuromuscular blocking agents (e.g. succinylcholine, mivacurium, diamorphine, acetylsalicylic acid, methylprednisolone, cocaine, heroin ) Prolonged binding of neuromuscular blocking agent to nicotinic cholinergic receptors in neuromuscular junctions ↑ patient’s susceptibility to side effects from drugs with ester linkages Mivacurium administered to produce muscle paralysis Succinylcholine administered to produce muscle paralysis Competitively binds to acetylcholine nicotinic receptor Irreversibly binds to acetylcholine nicotinic receptor Active site of post-synaptic acetylcholine receptor is blocked Continuous depolarization of skeletal muscle Acetylcholine cannot act on receptor = skeletal muscle can’t depolarize Skeletal muscle unable to repolarize Skeletal muscle paralysis Acetylcholine released cannot trigger an action potential ↑ duration of muscle fiber paralysis Since respiratory muscles are affectedà Apnea requiring sedation and respiratory assistance for up to several hours Extended paralysis and/or anesthesia Authors: Evan Allarie Yan Yu* Reviewers: Stephen Chrusch Brooke Fallis Melinda Davis* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2021 on www.thecalgaryguide.com

Primary Aldosteronism Pathogenesis

Primary Aldosteronism: Pathogenesis and clinical findings Unilateral aldosterone producing adenoma Benign tumours of the adrenal glands develop ion channel mutations ↑ Na+ movement into adrenal gland cellsàcell depolarizationà↑ Ca+ entry into zona glomerulosa Bilateral adrenal hyperplasia Unknown mechanisms cause bilateral adrenal hyperplasia of the zona glomerulosa ↑ Ca+ leads to cellular replication and hyperplasia of the zona glomerulosaà ↑aldosterone release Adrenocortical carcinoma Abnormal and excessive growth of the zona glomerulosa (neoplasia)à↑ aldosterone Overproduction of aldosterone, independent from renin-angiotensin- aldosterone system (RAAS) Ectopic aldosterone secreting tumor adrenocortical tissue outside of the adrenal glands produce aldosterone Familial hyperaldosteronism (FH) Type I Rare mutation causing ACTH- sensitive aldosterone production in the zona fasciculata Aldosterone binds its receptor on the principal cells located in the collecting duct of the kidney ↑ Na+ and K+ channel insertion on luminal surface of the principal cell and ↑ Na/K ATPase activity on basolateral surface Na+ follows the concentration gradient and moves into the principal cell cytoplasmàK+ moves into the collecting duct to maintain electroneutrality Aldosterone binds its receptor on the alpha intercalated cells located in the late distal tubule and collecting duct of the kidney ↑ H+ ATPase and Na/H+ ATPase activity on the luminal surface of alpha intercalated cellsà↑ H+ excretion H+ loss permits HCO3- to move down the electrochemical gradient across the luminal surfaceà↑ HCO3- resorption into peritubular capillaries Metabolic alkalosis K+ efflux (or hypokalemia of any etiology) is counterbalanced by influx of H+ into tubular cells to maintain electroneutrality ↓ pH in tubular cells activates glutaminase (a pH dependent enzyme) generating glutamate from glutamine Glutamate within renal tubules dissociates into NH4+, HCO3- Intracellular acidosis within tubular cells Disrupted cellular signaling within the collecting duct results in reduced APQ2 translocation to luminal surface Authors: Kyle Moxham Reviewers: Emily Wildman Austin Laing Yan Yu* Matthew Harding* * MD at time of publication Hypertension ↑ Na+ reabsorption H2O follows active reabsorption of solute into circulationà ↑ effective arterial blood volume (EABV) Chronic EABV expansion resets hypothalamic osmotic sensitive ADH releaseàdecreased ADH production ↑ K+ excretion Hypokalemia (see our Hypokalemia: Clinical Findings Slide) ↓ Na+ delivery to macula densa in the distal convoluted tubule ↓Endogenous renin secretion by juxtaglomerular apparatus while aldosterone continues to be independently produced Polydipsia & Polyuria Mild hypernatremia ↓ Renin: Aldosterone ratio Nephrogenic diabetes insipidus: ↓ urinary concentrating ability Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2021 on www.thecalgaryguide.com

Normal anion gap metabolic acidosis

Normal Anion Gap Metabolic Acidosis: Pathogenesis and Laboratory Findings Authors: Wazaira Khan Reviewers: Jessica Krahn, Timothy Fu, Emily Wildman, Austin Laing, Yan Yu*, Juliya Hemmett* * MD at time of publication GI Loss ↑ gut motility and secretion ↑ HCO3- loss through stool Distal nephron is unaffected and continues to secrete excess acid into the urine in the form of NH4+ For every major urine cation (Na+, K+, NH4+), the distal nephron secretes one corresponding urine Cl- anion Urine NH4+ cannot be measured, so measured urine Cl- exceeds measured urine (Na+ + K+) Negative urine net charge (Urine (Na+ + K+) - Urine Cl-) Type II RTA RTA: renal tubular acidosis ↓ activity of proximal Type I RTA ↓ activity of H+ ATPase on luminal surface of ⍺- intercalated cell in the collecting duct Impaired ⍺-intercalated cell function ↓ H+ secretion into urine by ⍺- intercalated cell ↑ H+ concentration in plasmaà↓ in blood pH Activation of blood bicarbonate buffer system Compensatory ↓ in plasma HCO3- (in response to ↑ in plasma H+) Type IV RTA ↓ aldosterone production or aldosterone resistant state ↓ Na+ channels on luminal surface of principal cell in the collecting duct Impaired principal cell function ↓ Na+ reabsorption by principal cell ↑ Na+ remains in collecting duct lumen ↓ negative charge in collecting duct lumen ↓ K+ secretion into urine by principal cell ↑ K+ in plasma Hyperkalemia Normal anion gap tubule transporters, pumps or enzymes Impaired proximal tubule cell function reabsorption Complex and Incompletely understood mechanisms Hypokalemia Distal nephron function is impairedàdistal nephron is unable to secrete excess acid into the urine in the form of NH4+ ↓ in urinary NH + 4 secretion is accompanied by corresponding ↓ in urinary Cl- secretion Measured urine (Na+ + K+) exceeds measured urine Cl- Positive urine net charge (Urine (Na+ + K+) - Urine Cl-) ↓ HCO3 - in proximal tubule ↑ HCO3- loss through urine ↓ HCO3- concentration in plasma Relative ↑ in plasma H+ compared to plasma HCO3- Compensatory ↑ in CO2 exhalation by lungs (since CO2 is acidic once metabolized in the blood) Since Anion gap = Na+ - Cl- - HCO3-, 1 to 1 replacement of Cl- for HCO - in the 3 plasma results in anion gap unchanged ↓ ability to buffer excess acid Activation of the membrane Cl-/HCO3- exchanger in the collecting duct Exchanger works to ↑ Cl- levels in the plasma by one Cl- for each ↓ of one HCO3- in the plasma Metabolic Acidosis ↓ Plasma partial pressure of CO2 Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 21, 2021 on www.thecalgaryguide.com

Renal Artery Stenosis

Renal Artery Stenosis: Pathogenesis and clinical findings Atherosclerosis: A collection of inflammatory cells, lipids, & Fibromuscular Dysplasia: A rare vascular condition characterized by fibrous connective tissue deposits on the renal artery wall abnormal cellular growth in arterial walls, especially renal & carotid arteries Narrowing (stenosis) of the renal artery Renal Artery Stenosis can be unilateral or bilateral Authors: Samin Dolatabadi, Yan Yu* Reviewers: Meena Assad, Jessica Krahn Timothy Fu, Brooke Fallis, Juliya Hemmett* * MD at time of publication ↓ Pressure perfusing the kidney ↑ RAAS (renin-angiotensin- aldosterone system) activation ↓ pressure gradient in glomerulus ↓ Glomerular filtration rate (GFR) ↑ Secretion of aldosterone Turbulent blood flow through area of stenosis Abdominal bruit on side of affected kidney(s) ↑ Secretion of Angiotensin IIà ↑ Systemic vasoconstriction Hypertension ↑ Expression of epithelial sodium channels in cortical collecting duct ↑ Blood volume within volume- constrained space of blood vessels ↓ Renal blood flowà ischemic renal injury Atrophy and fibrosis of affected kidney(s) Unilateral stenosis à Kidney size asymmetry (≥1.5cm difference) ↓ Positively charged Na+ in lumen à Electronegative lumen compared to the interstitial/tubular epithelial cells K+ follows the electrical gradient and is secreted into the electronegative tubular lumen ↓ Serum K+ concentration Hypokalemia *Note: In unilateral renal artery stenosis, the contralateral (normal) kidney can compensate for the increase in renal perfusion pressure caused by hypertension by increasing sodium excretion (pressure natriuresis), preventing flash pulmonary edema. ↑ NHE3 (Sodium Hydrogen Exchanger 3) activity in proximal collecting tubule ↑ Na+ and water reabsorption from renal tubular lumen into blood vessels Chronic left ventricle pressure overload àLeft ventricle hypertrophy (see Left Heart Failure: Pathogenesis Slide) Systolic dysfunction → ↓ left ventricle stroke volume Normally, ↑ in renal perfusion pressureà↑ Na+ excretion and water loss (pressure natriuresis) In bilateral renal artery stenosis*, ↓ GFRàinability for kidney to ↑ renal Na+ & water excretion à volume overload Acute increase in afterload or preload → sudden ↑ in left ventricular filling pressures → blood backup into lungs Pulmonary vasculature hypertension → ↑ fluid filtration across the pulmonary endothelium into interstitium and alveolar spaces Flash (rapid onset) pulmonary edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 30, 2021 on www.thecalgaryguide.com

Membranous Nephropathy

Authors: Jessica Krahn Membranous Nephropathy: Pathogenesis and clinical findings Reviewers: Brooke Fallis, Yan Yu*, Juliya Hemmet* * MD at time of publication Primary (Idiopathic) Membranous Nephropathy Secondary Membranous Nephropathy Drugs, infections, auto-immune diseases, and malignancies make antigens Blood tests for Anti- PLA2R antibodies are positive in ~70% of cases Autoantibodies are made to antigens expressed near or on podocyte surfaces or planted in the glomerular capillary wall (ie. PLA2R; THSD7A; NELL-1) IgG antibodies filter through the glomerulus Autoimmune: (e.g. Systemic Lupus Erythematous, thyroiditis) Drugs: (e.g. NSAIDs, gold, penicillamine, captopril) Malignancies: (ie. Prostate, Colon) Infections: (e.g. Hepatitis B, Syphilis) Circulating antigens filter through the glomerulus and between the GBM and podocytes Antibodies & antigens form immunocomplexes, which lodge Immunofluorescence shows diffuse “granular” between the glomerular basement membrane & podocytes deposits of immunocomplexes throughout GBM Basement membrane is formed between and around immunocomplex deposits Immunocomplexes activate complement and the assembly of the Membrane attack complex (MAC) MAC creates holes in podocyte plasma membranes Stimulates the release/activation of proteases and oxidases from glomerular podocytes and mesangial cells GBM appears thick on light microscopy “Spike and dome” pattern appears with silver stain Podocyte effacement Damage to negatively charged foot processes damages the charge barrier of the glomerulus that repels negatively charged molecules Increased filtration of large negatively charged molecules, especially albumin Induces ↑ hepatic lipoprotein synthesis and ↓ lipoprotein catabolism Hyperlipidemia (↑ serum LDL, VLDL, and triglycerides) ↑ lipid filtration through glomerulus Lipiduria (fatty casts) *Hypo-albuminemia ↓ oncotic pressure in capillaries Fluid leaks into interstitial space ↑ Filtration of Proteins C and S and antithrombin Hypercoagulable state Thrombosis *Edema (especially *Proteinuria ↑ Filtration of immunoglobulins Immunosuppression Infections ↑ Filtration of Plasminogen Plasminogen converted to plasmin in the cortical collecting duct via urokinase- type plasminogen activator Plasmin activates the epithelial sodium channel ↓ intravascular volume Hypotension Pre-Renal Acute Kidney Injury Underfill edema (see slide) peri-orbital, scrotal, labial, and extremities) Overfill edema (see slide) ↑ Na+ and water reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com

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

Minimal Change Disease

Minimal Change Disease: Pathogenesis and clinical findings Authors: Jessica Krahn Reviewers: Timothy Fu Brooke Fallis Yan Yu* Juliya Hemmet* * MD at time of publication Damage induced by cytokines, not immunocomplexes Lack of abnormal immunocomplexes (antibody-antigen complexes) present in serum Immunofluorescence test negative Idiopathic/Primary Minimal Change Disease No identifiable extraglomerular disease process causes this condition Secondary Minimal Change Disease Infections, NSAIDS, neoplasms via unclear mechanisms Minimal change to glomerulus seen on light microscopy Podocyte effacement seen on electron microscopy Abnormal T Cell activation and release of cytokines (sometimes called permeability factors) that are toxic to podocytes Podocyte foot processes efface (become flattened) or fuse together Damage to negatively charged foot processes damages the charge barrier of the glomerulus that repels negatively charged molecules ↑ filtration of larger negatively charged molecules, such as low-molecular weight proteins like albumin, from the blood into the renal tubular filtrate Induces ↑ hepatic lipoprotein synthesis and ↓ lipoprotein catabolism Hyperlipidemia (↑ serum LDL, VLDL, and triglycerides) ↑ lipid filtration through glomerulus Lipiduria (fatty casts) Hypo-albuminemia ↓ oncotic pressure in capillaries Fluid leaks into interstitial space ↑ Filtration of Proteins C and S and antithrombin Hypercoagulable state Proteinuria ↑ Filtration of immunoglobulins Immunosuppression Infections ↑ Filtration of Plasminogen Plasminogen converted to plasmin in the cortical collecting duct via urokinase- type plasminogen activator Plasmin activates the epithelial sodium channel ↓ intravascular volume Hypotension Pre-Renal Acute Kidney Injury Underfill edema (see slide) Thrombosis Edema (especially peri- orbital, scrotal, labial, and extremities) Overfill edema (see slide) ↑ Na+ and water reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 30, 2021 on www.thecalgaryguide.com

ACE inhibitors

Angiotensin Converting Enzyme (ACE) inhibitors: Mechanism of Action and Clinical Findings Angiotensin Converting Enzyme (ACE) Inhibitors Inhibits the conversion of angiotensin I to angiotensin IIà↓ serum angiotensin II levels Inhibits breakdown of bradykinin ↓ Activation of zona glomerulosa region of the adrenal cortex ↓ Aldosterone secretion from the adrenal cortex ↓ Expression of basolateral Na+/K+ pump and ↓ insertion of luminal Na+ channels in principal cells of the cortical collecting duct in kidney ↓ K+ secretion into urine ↑ Serum K+ concentration Hyperkalemia ↓ Activation of Na+/H+ exchanger in proximal convoluted tubule (PCT) of the kidney ↓ Na+ absorption into PCT and ↓ H+ excretion into lumen ↓ Na+ absorption into the blood ↓ Renal H2O reabsorption via osmosis ↓ Activation of paraventricular nuclei located in the hypothalamus ↓ Secretion of anti- diuretic hormone (ADH) into the capillaries of the posterior pituitary gland ↓ Aquaporin channel insertion at cortical collecting duct in kidney ↓ Renal H2O reabsorption à↑ serum bradykinin levels Vasodilation of efferent arteriole in kidneys ↓ Hydrostatic pressure within the glomerular capillaries ↑ Activation of cyclooxygenase-2 pathway ↑ Prostaglandin production ↓ Activation of angiotensin II type 1 receptors on surface of arteriolar smooth muscle ↓ Activity of G protein-coupled receptor intracellular secondary messenger cascade ↓ Systemic arteriolar vasoconstriction ↓ Total peripheral resistance (resistance to blood flow by systemic vasculature) ↓ Blood Pressure ↓ total blood flow perfusing kidneys Renal hypoxia ↑ Systemic arteriolar vasodilation ↓ Total peripheral resistance ↓ Blood Pressure ↓ Concentration of protein travelling through tubules for excretion ↓ Fraction of H2O filtered from glomerular capillaries into bowman’s capsule (start of the renal tubule) ↓ Filtration of blood contents through glomerular membranes Sensitization of airway vagal afferent receptors Stimulation of the cough center located in the medulla oblongata Cough ↓ Protein in urine High K+ levels surrounding the heart muscle cellsàchronic depolarization of the cardiomyocyte cell membrane àalters cardiomyocyte conduction (complex mechanisms) Cardiac Arrythmias (see relevant slide on Hyperkalemia: Clinical Findings) ↓ Effective arterial blood volume Authors: Nicole Brockman Reviewers: Emily Wildman, Austin Laing Adam Bass*, Yan Yu* * MD at time of publication Renal tubules have relatively less water compared with the peritubular capillaries ↓ H2O reabsorption from the renal tubule back into the blood ↑ Serum creatinine, ↓ estimated glomerular filtration rate Renal nephron injury and dysfunction Acute Kidney Injury (rise in creatinine >26.5umol/L in <7 days) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 10, 2022 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

NSAIDs and the Kidney Nephrotoxicity

NSAIDs and the Kidney: NSAID induced Nephrotoxicity Non-steroidal anti-inflammatory drugs (NSAID) Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* * MD at time of publication Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation) NSAID induced nephrotoxicity: associated with chronic NSAID usage independent of dosage COX inhibition ↑ conversion of arachidonic acid (AA) to leukotrienes, causing systemic T-cell dysfunction (unknown mechanism) Type IV systemic hypersensitivity (delayed T helper cell mediated) reaction to drug exposure T cells release inflammatory cytokines into the bloodstream (see Calgary Guide slide on NSAIDs and the Kidney: Mechanism of Action and Side Effects) T cells infiltrate the renal interstitium, sparing the glomeruli and blood vessels Overproduction of cytokines by T cells causing inflammation, tissue damage, and cell death, of the renal intersitium Drug Induced Acute interstitial nephritis (AIN): a type of immune-mediated tubulointerstitial injury Activated T-cells infiltrate the glomerulus and cause podocyte injury (epithelial cells attached to the glomerular basement membrane) Membranous nephropathy: nephrotic syndrome involving autoimmune glomerular basement membrane thickening & complete podocyte effacement (seen on kidney biopsy) Minimal change disease: nephrotic syndrome caused by autoimmune podocyte effacement (seen on kidney biopsy) Cytokine mediated activation and proliferation of immune cells like macrophages and eosinophils Cytokines travel to hypothalamus, causing change in the body’s thermal set point Fever Podocyte effacement allows for serum proteins to across the glomerulus into the tubular lumen (see Calgary Guide slide on Nephrotic Syndrome for full mechanisms) Repeated NSAID exposure causing recurrent unrecognized AIN and damage of the kidney Chronic interstitial nephritis /analgesic nephropathy Infiltrating immune cells (predominantly neutrophils) are filtered into/enter the renal tubules, and form clumps (“casts”) within the tubulesà casts are then released into urine WBC cast on urinalysis ↑ Blood eosinophils Immune cells infiltrate the dermis and epidermis of the skin Rash Abnormal quantities of protein present in urine Protein present in the blood is improperly filtered into the filtrate at the glomerulus Protein- Creatinine Ratio >3.5mg/mg Proteinuria >3.5g/d Hypo- albuminemia ↓ plasma oncotic pressure resulting in fluid extravasation into the interstitium (see Calgary guide slide on Edema for full mechanisms) Pitting Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 13, 2022 on www.thecalgaryguide.com

Overfill Edema Pathogenesis

Overfill Edema: Pathogenesis Nephrotic Syndrome Damage to the glomeruli of the kidneys (See Nephrotic Syndrome: Pathogenesis and Clinical Findings Slide) Aberrant filtration of proteins including plasminogen (glycoprotein in the systemic circulation involved in the dissolution of fibrin blood clots) ↑ Plasminogen concentration in tubular fluid Conversion of plasminogenà plasmin by urokinase-type plasminogen activator in the cortical collecting tubule Plasmin activates epithelium sodium channels (involved in Na+ reabsorption) in principal cells of the cortical collecting duct Nonsteroidal Anti-inflammatory Drugs Inhibition of cyclooxygenase throughout body (enzyme that converts arachidonic acidàprostaglandins) ↓ Prostaglandins throughout body Thiazolidines ↓ Prostaglandin- mediated inhibition of Na+ and Cl- transport in ascending loop of Henle and collecting ducts ↑ Na+ reabsorption from kidney tubules back into blood ↓ Prostaglandin-mediated vasodilation in kidneys ↓ Pressure of blood perfusing kidneys → ↓ pressure gradient between glomerulus and bowman’s capsule ↓ Glomerular filtration rate ↓ Renal excretion of salt & water ↑ Salt and water retention ↑ Effective arterial blood volume ↑ blood pressure in veins Unclear mechanism but possible theories include upregulation of epithelium sodium channels in the cortical collecting tubule and involvement of other transporters in the proximal tubule and cortical collecting tubule Acute Renal Failure Chronic Renal Failure ↑ Hydrostatic pressure within capillariesàexceeds hydrostatic pressure within interstitial spaceàfluid moves from capillaries into interstitial space Overfill Edema Abnormal accumulation of fluid in the interstitial space where urine Na+ >40meq/L Authors: Samin Dolatabadi Reviewers: Meena Assad, Jessica Krahn, Brooke Fallis, Ran (Marissa) Zhang, Yan Yu*, Juliya Hemmett* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 23, 2022 on www.thecalgaryguide.com

NSAIDs and the Kidney mechanism of action and side effects

NSAIDs and the Kidney: Mechanism of Action and Side Effects Authors: Kyle Moxham Mehul Gupta Reviewers: Emily Wildman Yan Yu* Adam Bass* *MD at time of publication Concurrent use of angiotensin- converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) AECi and ARBs act to ↓ renin- angiotensin-aldosterone system (RAAS) activation Reduced angiotensin (AT) 2 activity at its receptors on efferent arteriole of the nephron Net vasodilation of efferent arterioles ↓ in glomerular pressure ↓ blood perfusing kidney tissueà↑ hypoxemia & renal ischemia Pre-existing ↓effective arterial blood volume (EABV) from dehydration, GI loss, diuretics, CKD, CHF, cirrhosis, etc. Decreased EABV triggers endogenous renal autoregulation, resulting in norepinephrine (NE) mediated vasoconstriction of afferent arteriole of the nephron Net ↓ in renal blood flow and ↓ in glomerular pressure ↓ volume of blood filtered by the glomeruli per unit time Non-steroidal anti-inflammatory drugs (NSAIDs) Inhibition of Cyclooxygenase COX-1 (expressed in kidney) and COX-2 (expressed in kidney and sites of inflammation) ↓ Renal prostaglandin (PG) synthesis: local hormones involved in renal homeostasis NSAID induced nephrotoxicity: associated with chronic usage independent of dosage (see Calgary Guide slide on NSAIDs and the Kidney: NSAID induced nephrotoxicity) ↓ intrarenal PG reduces inhibitory effects of PG over ADH in cortical colleting duct (CCD) of the kidneyà↓ antagonism on ADH activity ↑ ADH activity causes insertion of more aquaporins (water channels) in the collecting duct of renal tubules Net ↑ in volume of water reabsorbed into the blood ↓ vasodilatory effect of PG at the afferent arteriole of the nephron ↓ Glomerular filtration rate (GFR) ↓ PG signalling results in ↓ renin secretion at juxtaglomerular apparatus Low renin levelsà↓ conversion of angiotensinogen into its AT1 form and, by extension, ACE mediated conversion of AT1 to AT2 ↓ ACE 2 signalling leads to ↓ levels of aldosterone in the serum ↓ Na+ and K+ channel insertion on apical surface and ↓ Na/K ATPase activity on basolateral surface of principal cells ↓ K+ excretion into urine, and ↓ Na+ reabsorption back into the blood, at the late DCT and collecting duct of the kidney Pre-renal Acute Kidney Injury (AKI): kidney injury due to renal hypoperfusion Prolonged and/or severe ischemia causes cell death and aggregation of tubular epithelial cells of the kidney with subsequent inability to reabsorb luminal Na+ Renal dehydration predisposes precipitation of uromodulin protein Renal tubules mold uromodulin into cylindrical structures known as “casts”. Casts that contain only uromodulin protein are known as “hyaline casts” Hyaline cast seen on urinalysis Hypoperfusion of the kidney activates the renin- angiotensin- aldosterone system (RAAS) ↑ amount of sodium (Na) reabsorbed from the filtrate (less Na excreted) Fractional excretion of Na <1% Papillary necrosis: ureteral passage of sloughed ischemic tissue causing ureteral obstruction Acute tubular necrosis: a type of kidney injury causing damage to the tubules Hypertension Post-renal AKI: a type of kidney injury due to obstruction of the urinary tract Distal distal obstruction of the urinary tract causes fluid to accumulate within the kidneysàenlarging the kidneys Renal Ultrasound shows hydronephrosis (enlarged kidneys) Damaged tubule epithelial cells slough into the tubular lumen Epithelial cell breakdown in the tubular lumen releases uromodulin & other proteins, which aggregate into “casts” (cylindrical imprints of the renal tubule). The varied protein content of these casts result in them having a coarse, granular appearance Damaged tubular epithelial cells are unable to properly reabsorb sodium ↓ amount of sodium (Na) reabsorbed from filtrate into the blood (more Na excreted) Fractional excretion of Na >2% True excess of free water relative to Na+ in the blood Excess free water ↑ venous hydrostatic pressure (see Calgary Guide slide on edema for full mechanisms) Pitting Edema Hyperkalemia Hyponatremia Coarse granular casts seen on urinalysis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 29, 2022 on www.thecalgaryguide.com

Hypokalemia Physiology

Hypokalemia: Physiology Authors: Samin Dolatabadi, Ran (Marissa) Zhang, Mannat Dhillon Reviewers: Meena Assad, Yan Yu*, Juliya Hemmett* Beta-2 receptor stimulation (e.g. Salbutamol) ↑ Red blood cell production ↑ Na+/K+ ATPase activity in skeletal muscle cells (moves K+ into the cell & Na+ out of cell) ↑ K+ entry into skeletal muscle cells * MD at time of publication Abbreviations: • EABV – Effective Arterial Blood Volume • ENaC – Epithelial Sodium Channel • HCL – Hydrochloric acid • HCO3- –Bicarbonate ion ↑ K+ uptake by new red blood cells ↑ Intracellular shift of K+ into cells Refeeding Syndrome Exogenous insulin ↓ K+ dietary intake (rare cause in isolation) ↑ Insulin in response to carbohydrate load ↑ Na+/K+ ATPase activity in skeletal muscle & hepatic cells ↑ K+ entry into skeletal muscle & hepatic cells ↓ K+ availability for gastrointestinal absorption Hypokalemia (Serum [K+] < 3.5 mmol/L) ↑ Renal K+ secretion K+ follows the electrical gradient into tubular lumen ↑ Electronegativity of tubular lumen ↑ Na+ reabsorptionin principal cellsà Cl- left behind in tubular lumen of kidneys Gastric acid depletionà ↓HCl Loss of H+àShift in bicarbonate buffer system to ↑ plasma HCO3- Plasma HCO3- above reabsorptive capacity of the proximal tubule ↑ HCO3- in the distal tubular lumen of kidneys Vomiting Diarrhea Laxatives Renin secreting tumour Hyperaldosteronism Renal artery stenosis Loop and Thiazide diuretics Bartter’s and Gittelman’s syndrome Liddle syndrome Extracellular fluid volume depletion ↓ EABV ↑ Renin secretion ↓ Afferent arteriole pressure perfusing kidneys Renin-Angiotensin- Aldosterone System (RAAS) activationà ↑ Aldosterone release from the adrenal cortex ↑ Expression of ENaC (Na+ reabsorption) in principal cells of the cortical collectingduct) + ↑Na & water excretion in kidneys ↓ EABV Genetic condition leading to inability to degrade ENaC channels in principal cells of the cortical collecting duct Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 6, 2019, updated Jan 23, 2022 on www.thecalgaryguide.com Hypokalemia: Physiology Authors: Samin Dolatabadi Reviewers: Meena Assad Dr. Juliya Hemmett* * MD at time of publication TTKG > 4 with N/↑ EABV in hypokalemia is inappropriate and a principal cell problem. β2 Stimulation (e.g., Salbutamol) ↑ Na+/K+ ATPase activity ↑ K+ entry into cell ↑ RBC Production ↑ Cell production ↑ K+ uptake by new cells ↓ Extracellular ↑ Insulin in response to H+ carbohydrate load ↑ Na+/H+ antiporter activity (movement of H+ out of cell and Na+ into cell) ↑ Intracellular Na+ ↑ Na+/K+ ATPase activity ↑ K+ entry into cell ↑ Intracellular Shift of K+ Notes: Refeeding Syndrome Insulin Alkalemia • Abbreviations: • CCD – Cortical Collecting Duct • EABV – Effective Arterial Blood Volume • RAAS – Renin-Angiotensin-Aldosterone System • TTKG – Trans-tubular Potassium Gradient • ENaC – Epithelial Sodium Channel ↓ K+ Intake (Rare cause in isolation) ↓ K+ availability Diarrhea, Vomiting, Laxatives ↑ Gastrointestinal loss of K+ Polyuria ↑ Renal loss of K+ (TTKG < 4 as principal cell is working appropriately but small amount of K+ is lost per urination) Hypokalemia (Serum [K+] < 3.5 mmol/L) Liddle Syndrome Hyperaldosteronism Renin Secreting Tumour Renal artery stenosis Loop and Thiazide Diuretics Bartter’s and Gittelman’s Syndrome Genetic condition leading to inability to degrade ENaC channels ↑ Renin ↑ Renal K+ secretion K+ follows the electrical gradient Electronegative lumen ↓ Pressure perfusing the kidney RAAS activation RAAS activation ↑ Aldosterone ↑ Na+ and water excretion ↓ EABV ↑ Expression of ENaC in principal cells of CCD ↑ Na+ reabsorption Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 6, 2019 on www.thecalgaryguide.com

metabolic-alkalosis-pathogenesis

Metabolic Alkalosis: Pathogenesis Authors: Wazaira Khan Reviewers: Jessica Krahn, Emily Wildman, Austin Laing, Huneza Nadeem, Ran (Marissa) Zhang, Adam Bass* * MD at time of publication Primary hyperaldosteronism E.g., aldosterone- secreting mass, adrenal hyperplasia Secondary hyperaldosteronism E.g., renin-secreting mass, renal artery stenosis Pseudo- hypoaldosteronism E.g., Liddle’s Syndrome Unregulated aldosterone production in adrenal cortex Excess aldosterone suppresses renin production Unregulated renin production by juxtaglomerular cells Sustained ↑ in mineralocorticoid (aldosterone) activity Insertion of epithelial sodium channels on principal cells in collecting duct ↑ Water retention by the kidney ↑ Na+ reabsorption by principal cells ↑ EABV • ↑ Jugular venous pressure • Hypertension • Urine Na+ > 40 mEq/L Low renin, high aldosterone state Activation of renin- angiotensin-aldosterone system (RAAS) Release of aldosterone from adrenal cortex High renin, high aldosterone state ↑ Negative charge in collecting duct lumen K+ leaks into collecting duct lumen by principal cell to maintain electroneutrality Hypokalemia Intracellular K+ leaks out of any cell in the body to compensate for low serum K+ levels Extracellular H+ enters cell to maintain electroneutrality Intracellular acidosis Activation of compensatory acid secreting mechanisms in kidney Impaired tubular function E.g., loop/thiazide diuretics, Bartter’s/ Gitelman’s Syndrome Upper GI Loss E.g., vomiting, nasogastric suction Unregulated epithelial sodium channel activity in collecting duct mimicking aldosterone function ↑ in Na+ and water retention à RAAS inhibition ↓ Na+ and Cl- reabsorption in thick ascending limb or distal convoluted tubule Low renin, low aldosterone state ↑ Na+, Cl- and water secretion through kidney RAAS activation See “Physiology of RAAS” slide ↓ EABV • • • Temporary ↑ in mineralocorticoid (aldosterone) activity ↓ Jugular venous pressure Orthostatic hypotension Dry mucous membranes Urine Na+ < 20 mEq/L • Loss of fluid through GI tract ↓ HCl delivery to small intestine ↑ NH + secretion and 4 ↑ HCO3- reabsorption in proximal tubule ↑ H+ secretion in cortical collecting duct Loss of gastric contents, including HCl ↓ HCO3- secretion by pancreas, liver and intestines to neutralize HCl Loss of intrinsic acid to neutralize HCO3- ↑ Plasma [HCO3-] Metabolic Alkalosis Arterial blood gas pH > 7.40 Plasma [HCO3-] > 24 mEq/L Effective Arterial Blood Volume (EABV): component of arterial blood volume that is effectively perfusing organs Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 31, 2022 on www.thecalgaryguide.com

pheochromocytoma-pathogenesis-and-clinical-findings

Pheochromocytoma: Pathogenesis and clinical findings Author: Jaye Platnich Huneza Nadeem Reviewers: Mark Elliott Alexander Arnold Ran (Marissa) Zhang Hanan Bassyouni* * MD at time of publication ↑ Blood pressure results in the activation of neural pain receptors Sustained or paroxysmal 2o hypertension (↑ blood pressure) Pallor Tachycardia (↑ heart rate), palpitations Diaphoresis (excessive sweating) Hyperglycemia Weight loss, fatigue Familial Disorders (10%) E.g., Multiple Endocrine Neoplasm 2 Syndrome (MEN2) types A and B, Neurofibromatosis 1 (NF-1), Von Hippel Lindau Syndrome (VHL), familial pheochromocytoma Dysfunction of various tumor suppressor and/or oncogene proteins Uncontrolled proliferation of the chromaffin cells in the medulla of the adrenal gland(s) Adenoma formation (10% bilateral) Over-production of epinephrine and norepinephrine from the adrenal adenoma(s) or extra- adrenal tumour (10%) Detectable metanephrines (epinephrine/norepinephrine breakdown products) in both plasma and urine Sporadic DNA mutations arising from DNA damage from exposure to mutagens, malignancy (10%), or during DNA replication Detectable mutations on the Von Hippel Linda (VHL), (Rearranged During Transcription) RET, (Succinate Dehydrogenase) SDH, and/or other tumour suppressor or oncogenes Visible adrenal mass on CT scan Heart attack, stroke, or death (Note: These tumors can be fatal therefore screening is essential in patients with adrenal masses or 2o hypertension) Episodic hyper-activity of the sympathetic nervous system Hyper-stimulation of G protein-coupled receptors involved in catabolic metabolic processes Headaches ↑ Vasoconstriction of peripheral blood vessels Hyper-stimulation of adrenergic receptors on cardiac myocytes ↑ Secretion from the eccrine sweat glands Panic, tremor, anxiety ↑ Ability to mobilize glucose into the bloodstream through enhanced lipolysis, glycogenolysis and gluconeogenesis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 20, 2014, updated June 27, 2022 on www.thecalgaryguide.com

Epilepsy Pathogenesis

Epilepsy: Pathogenesis Genetic susceptibility Angelman syndrome, Fragile X syndrome, Tuberous sclerosis, neurofibromatosis Chromosomal abnormalities cause abnormal neural patterns Neural Cerebral palsy, focal cortical dysplasia Malformation of cortical development Cerebrovascular Intracranial hemorrhage, ischemic stroke Other Acquired Head trauma, cerebral infection (i.e., HSV1, VZV, cysticercosis) Neoplasm Metabolic Inborn errors of metabolism Inherited enzyme deficiencies Neurodegenerative Alzheimer’s Disease Protein-rich plaque build-up and brain atrophy Inflammation and formation of scar tissue irritates neural tissue Infiltration of mass, grey matter irritation Damage to the brain and subsequent alteration of neuronal circuitry Neurotransmitter imbalances (i.e. ↑ glutamate, ↓ GABA, ↓ serotonin, ↓ dopamine, ↓ noradrenaline) Abbreviations: • HSV1 – Herpes Simplex Virus 1 • VZV – Varicella Zoster Virus ↑ Inflammatory cytokines (e.g. interleukin-6, tumor necrosis factor-α) Altered neurogenesis and gliosis Ion channel and receptor dysfunction causes imbalance of ion channel charges Authors: Keerthana Pasumarthi Christopher Li Reviewers: Negar Tehrani, Ephrem Zewdie, Ran (Marissa) Zhang, Carlos R. Camara-Lemarroy* * MD at time of publication Neurons fire in burst activity (referred to as paroxysmal depolarization shift) and often in groups (hypersynchrony) Abnormal neural activities eventually create self-reinforcing circuits and transform neural network over time Injuries from falls, bumps, operating heavy machinery Involuntary contractions Loss of consciousness Post-ictal confusion Recurrent seizures Sudden Unexplained Death of Epilepsy Patient (SUDEP) Loss of airway reflexes Aspiration of saliva or food contents Aspiration Pneumonia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 5, 2022 on www.thecalgaryguide.com

etomidate

Etomidate Ultrashort-acting carboxylated imidazole anesthetic administered intravenously to induce unconsciousness, usual dose 0.3 mg/kg IV Directly inhibits adrenal 11-beta- hydroxylase (enzyme responsible for cortisol biosynthesis) ↓ Adrenal cortisol production ↓ Serum cortisol available for stress response Transient adrenal steroid insufficiency ↑ Morbidity & mortality in trauma/critically ill patients (Contraindicated in sepsis) Inhibits nitric oxide signaling Transient cerebral vasoconstriction ↓ Cerebral blood flow ↓ Oxygen delivery to brain ↓ Cerebral metabolic rate Suppression of electrical activity in brain Flat electroencephalogram Binds to GABAA (inhibitory CNS neurotransmitter) receptor Authors: Cindy Chang Ran (Marissa) Zhang Reviewers: Melissa King Brooke Fallis Julia Haber* * MD at time of publication Abbreviations: • CNS - Central Nervous System • GABAA- Gamma- aminobutyric acid type A • TRPA1- Transient receptor potential type A1 Higher selectivity for specific GABAA receptor subtypes compared to other induction agents Positively modulates GABAA receptor (GABAA receptor activated at lower concentrations of GABA ) ↓ Cerebral blood volume Activation of fewer GABAA receptor subtypes in neurons and cardiovascular structures compared to other induction agents ↓ Intracranial pressure ↑ Hemodynamic stability (minimal changes in blood pressure or heart rate) Myoclonus (brief, involuntary, irregular muscle twitch) ↑ Spontaneous CNS neuron firing to skeletal muscle Prolonged opening of GABAA receptors (acts as ion channel for chloride) Inhibits activity of nerve cells in the reticular activating system Activation of peripheral nociceptor receptors ↑ Involuntary muscle contractions Influx of chlorideàHyperpolarization of nerve membranes in reticular activating system (brainstem neuronal network that regulates arousal and sleep- wake transitions) Depression of arousal & loss of consciousness Induction of general anesthesia (no analgesic effect) Direct activation of TRPA1 cation channels (key receptor in pain pathway) Stinging pain with injection (Treat with co-administration of local anesthetic) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 9, 2022 on www.thecalgaryguide.com

complicaciones-de-la-enfermedad-renal-cronica

complicaciones-de-la-enfermedad-renal-cronica

hyperkalemia-↓-renal-excretion-pathophysiology

Hyperkalemia (↓ Renal Excretion): Pathophysiology Non-steroidal anti- inflammatory drugs (NSAIDs) Inhibition of prostaglandins which promote renin secretion (see NSAIDs and the Kidney: Mechanism of Action and Side Effects slide) Diabetic Nephropathy Acute (AIN)and chronic (CIN) interstitial nephritis Immune-mediated damage of the kidney tubule and interstitium Damage to distal tubule leads to aldosterone resistance at principal cell Aldosterone cannot ↑ EnaC insertion on principal cell of CCD Epithelial sodium channel (ENaC) blockers Acute kidney injury and chronic kidney disease ↓ Effective arterial blood volume (volume of blood effectively perfusing tissue) ↓ Oxygen perfusion to renal tissue causing renal ischemia Autonomic neuropathy ↓ sympathetic drive to produce renin Chronic juxtaglomerular cell damage ↓ synthesis of renin Blockage of ENaC on the principal cells of the CCD Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) Angiotensin II is either not formed (ACEi), or blocked at its receptor (ARBs) Angiotensin II cannot stimulate the release of aldosterone from the adrenal cortex Adrenal Insufficiency Adrenal gland cannot produce sufficient amounts of aldosterone ↓ Renin secretion by the afferent arteriole prevents RAAS activation ↓ Aldosterone release from adrenal cortex ↓ ENaC (Na+ reabsorption channel) expression on principal cells of the cortical collecting duct (CCD) Damage to kidney causes renal impairment and ↓ glomerular filtration rate ↓ Glomerular filtrate production means ↓ tubular flow rate ↓ Na+ delivery to the distal tubule ↓ Na+ reabsorption by ENaCs at the principal cell in CCD ↓ Na+ and water reabsorption by ENaCs in CCD ↓ Effective arterial blood volume (EABV) Activates renin-angiotensin-aldosterone system (RAAS) leads to ↑ renin secretion in the afferent arteriole (see Physiology of the renin-angiotensin-aldosterone system (RAAS) slide) ↑ Na+ and water loss in tubular lumen ↑ Positive charge in tubular lumen ↓ Electronegativity gradient in tubular lumen of CCD ↓ K+ excretion by the principal cell in the CCD as there is less of a electronegative gradient ↑ Accumulation of K+ in blood Hyperkalemia Serum [K+] > 5.1 mmol/L See Hyperkalemia: Clinical Findings slide In the case of diabetic nephropathy and NSAIDS ↓ EABV does not stimulate RAAS and therefore aldosterone production ↓ Renin ↓ Aldosterone ↑ Renin secretion activates an ↑ in aldosterone production but aldosterone action at the principal cell is blocked because of ENaCs or resistance in AIN and CIN ↑ Renin ↑ Aldosterone In the case of ACEi, ARBs, or adrenal insufficiency ↑ renin secretion does not lead to ↑ aldosterone ↑ Renin ↓ Aldosterone Note: as described in the above flow chart, measuring serum renin and aldosterone levels can be used to help diagnose the cause of hyperkalemia. Authors: Mannat Dhillon, Joshua Low, Emily Wildman, Huneza Nadeem Reviewers: Andrea Kuczynski, Marissa (Ran) Zhang, Adam Bass*, Kevin McLaughlin* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 2, 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

patellar-tendon-rupture-pathogenesis-and-clinical-findings

Patellar Tendon Rupture: Pathogenesis and clinical findings Author: Molly Joffe Reviewers: Liam Thompson, Alyssa Federico, Tara Shannon, Gentson Leung* *MD at time of publication Chronic disease (e.g. renal failure, gout, rheumatoid arthritis, and diabetes) Repetitive activities involving rapid knee flexion and extension Tendon inflammation and micro-tearing Fluoroquinolone (antibiotic class) use Smoking Immobilization of knee ↓ Muscle and tendon flexibility and strength Steroid use (including intraarticular injections) Changes in collagen fibrils composing tendon (exact mechanism unknown) Disrupted blood supply to tendon and poor healing Compromised integrity and strength of the tendon Sudden heavy load on flexed knee while foot is planted Quadriceps muscles contract while lengthening (eccentric contraction)àforce exceeds tendon strength Patellar tendon innervated by common peroneal (fibular) nerve Nociceptors (pain receptors) within tendon activated by tendon rupture Pain and tenderness below the patella Collagen fibres in tendon tear Tearing or popping sensation at time of injury Patellar Tendon Rupture Tendon/Ligament detaches from bony attachment on patella or tibial tubercle No connection of quadriceps to tibia via patellar tendon ↑ Force on tibial tubercle during tendon detachment Avulsion fracture of tibial tubercle Trauma to tendon ruptures surrounding blood vessels Coagulation cascade and inflammatory mediators released at rupture site Quadriceps muscles unable to stabilize patellar tracking Instability of knee joint Quadriceps muscle tension pulls patella upwards with no resistance from patellar tendon Patellar tendon cannot use distal attachment site for leverage Knee extensor muscles unable to effectively contract Knee buckling Abnormal gait Patella alta (high sitting patella) on X-ray Palpable gap below the patella Bruising below the patella Swelling below the patella ↑ Risk of falls Loss of patellar reflex Inability to perform a straight leg raise (hip flexes and knee cannot remain straight) Hematoma (blood collection under the skin) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 28, 2022 on www.thecalgaryguide.com

quadriceps-tendon-rupture-pathogenesis-and-clinical-findings

Quadriceps Tendon Rupture: Pathogenesis and clinical findings Author: Molly Joffe Reviewers: Liam Thompson, Alyssa Federico, Tara Shannon, Gentson Leung* *MD at time of publication Repetitive activities involving, rapid, active flexion and extension of the knee Quadriceps tendon inflammation and micro-tearing Immobilization of leg/knee Steroid use (including intraarticular injections) Quadricep muscles atrophy ↓ Quadricep muscle strength Smoking Chronic disease (e.g. renal failure, gout, rheumatoid arthritis, and diabetes) Fluoroquinolone (antibiotic class) use Changes in collagen fibrils composing tendonàimpaired tendon strength (exact mechanism unknown) Quadriceps tendon shortens ↓ Quadricep tendon flexibility Disrupted blood supply to quadriceps tendon and poor healing Compromised integrity of the quadriceps tendon and ↓ strength Sudden heavy load on flexed knee while foot is plantedàquadriceps muscles contract while lengthening (eccentric contraction) Force on quadriceps tendon exceeds its strength Quadriceps Tendon Rupture Tendon detaches from bony attachment on patella ↑ Force on patella during quadriceps tendon detachment Collagen fibres in quadriceps tendon tear No connection of quadriceps to tibia via quadriceps tendon Patellar tendon tension pulls patella downwards with no resistance from quadriceps muscles Quadriceps tendon innervated by common peroneal (fibular) nerve Nociceptors (pain receptors) within tendon activated by tendon rupture Pain and tenderness above the patella Trauma to tendon ruptures blood vessels Coagulation cascade and inflammatory mediators released at rupture site Quadriceps muscles unable to stabilize patellar tracking Knee joint instability Patella baja (low sitting patella) on X-ray Palpable gap above the patella Loss of patellar reflex Patellar tendon cannot use proximal attachment site for leverage Knee extensor muscles unable to effectively contract Inability to perform a straight leg raise (hip flexes while knee cannot remain straight) Bruising above the patella Swelling above the patella Avulsion fracture of patella Tearing or popping sensation at time of injury Knee buckling Abnormal gait ↑ Risk of falls Hematoma (blood collection under the skin) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 2, 2022 on www.thecalgaryguide.com

unstable-angina-pathogenesis-and-clinical-findings

Unstable Angina/Unstable Angina Pectoris: Pathogenesis and clinical findings Primary cause: Secondary causes: Coronary artery vasospasm - primary or drug induced (Ex: cocaine, triptans) Coagulopathy (Ex: antiphospholipid antibody syndrome) Vasculitic syndromes (Ex: Takayasu arteritis) Authors: Marisa Vigna Ryan Wilkie Yan Yu* Reviewers: Julena Foglia Davis Maclean Mehul Gupta Andrew Grant* * MD at time of publication Atherosclerosis Fatty plaque accumulates inside the intimal walls of arteries Coronary arterial atherosclerotic plaque rupture or erosion Plaque disruption exposes subendothelial components of damaged vessel wall to platelets, initiating the coagulation cascade and platelet adhesion Aggregation of platelets results in the formation of a thrombus Thrombus partially occludes blood flow through a coronary artery âmyocardial blood supply Congenital anomalies (Ex: myocardial bridge, anomalous coronary) Spontaneous coronary artery dissection Increased blood viscosity (Ex: polycythemia, thrombocytopenia) Factors thatámyocardial (cardiac muscle) oxygen demand (Ex: tachycardia, hypotension, hypertension, anemia, exertion, stress) Coronary embolism (Ex: A. Fib, endocarditis, prosthetic valve thrombus) áheart rate, contractility, and/or wall tension ámyocardial oxygen demand Myocardial ischemia due to imbalance between blood supply and oxygen demand (insufficient blood/oxygen supply) Unstable Angina/Unstable Angina Pectoris Can be new onset angina; typically progressive in frequency, severity, or duration; can occur at rest Subtotal occlusion of a coronary arteryà reduced, but continued, myocardial blood supply Maintained perfusion means cardiomyocytes are still alive and thus do not leak troponin into bloodstream Normal serum troponin Diaphoresis (sweating) Since bloodflow occurs from epicardium to endocardium, myocardial ischemia is more pronounced in the subendocardium (region furthest away from heart’s external surface) Sufficient blood flow is maintained in regions superficial to the subendocardium, resulting in non-transmural (partial thickness) heart wall ischemia Non-inferior wall ischemia triggers a predominantáin sympathetic nervous system activity, given the proximity of cardiac sympathetic nerve innervation Ischemiaâ cardiomyocyte resting membrane potential andâ action potential duration Voltage gradient between normal and subendocardial ischemic zones creates injury currents, shifting the ST- vector on ECG ECG: ST depression and/or T wave inversion Cardiac sensory nerve fibres mix with somatic sensory nerve fibres and enter the spinal cord via the T1-T4 nerve roots Brain perceives increased cardiac sensory nerve signaling as nerve pain coming from the skin of T1-T4 dermatomes (“Referred Pain”) Myocardial ischemia causes hypoxic stress on cardiomyocytesàâaerobic (requiring oxygen) metabolism,áanaerobic (not requiring oxygen) metabolism áanerobic respirationálactic acid production,á[H+], andâcellular pH which impairs cardiomyocyte function Cardiomyocyte dysfunction impairs myocardial relaxation in diastole and/orâ left ventricular contractility in systole âleft ventricular cardiac output àbackup of blood in the left ventricle, atrium, and pulmonary vasculature ápulmonary capillary pressures pushes fluid out of the capillaries into the alveoli in the lungs Fluid filled alveoliâgas exchange andâ oxygenation, triggering harder and faster breathing in order to compensate Dyspnea Activation of sweat glands via acetylcholine release Hormones bind to cardiac β1 receptors Tachycardia (áheart rate) Epinephrine/ Norepinephrine hormone release from the adrenal medulla Hormones bind to arterial smooth muscle α1 receptors ávascular tone (vasoconstriction) Hypertension The Vagus nerve sits in close physical proximity to the inferior wall of the heart àinferior wall ischemia triggers involuntary Vagus nerve activation Since the Vagus nerve coordinates parasympathetic activity,áVagus nerve activity leads to a variety of parasympathetic nervous system responses: Retrosternal discomfort: May present as pain, heaviness, tightness, aching, pressure, burning or squeezing Pain radiation to T1-T4 dermatomes: Left shoulder and arm, lower jaw, neck, abdomen, upper back Syncope (fainting) Bradycardia Nausea Hypotension (âheart rate) (âblood pressure) (áblood pressure) (shortness of breath) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Findings Complications Published Oct 18, 2015, updated Aug 29, 2021 on www.thecalgaryguide.com

type-ii-proximal-renal-tubular-acidosis-pathogenesis-and-laboratory-findings

Type II/Proximal Renal Tubular Acidosis: Pathogenesis and Laboratory Findings Authors: Wazaira Khan* Reviewers: Huneza Nadeem, Ran (Marissa) Zhang, Julian Midgley* * MD at time of publication Overview of bicarbonate reabsorption in the proximal tubule (PT): Serum bicarbonate (HCO3-) is filtered by the glomerulus and enters PT lumen H+ ATPase and sodium- hydrogen exchanger 3 (NHE3) on luminal surface of PT cell secrete H+ into PT lumen H+ combines with HCO3- in PT lumen to form carbonic acid (H2CO3) H2CO3 is broken down to H2O and CO2 by luminal membrane carbonic anhydrase 4 CO2 diffuses into PT cell CO2 reacts with H2O to form H2CO3 in PT cell, catalyzed by cytosolic carbonic anhydrase 2 H2CO3 rapidly breaks down intracellularly to form HCO3- and H+ HCO3- is reabsorbed into plasma by sodium bicarbonate transporter (NBCE1) on basolateral surface of PT cell HCO3- is available for use to buffer plasma H+ H+ is available intracellularly for use by H+ ATPase and NHE3 exchanger Mutation encoding NHE3 exchanger ↓ H+ secretion into PT lumen Galactosemia, Wilson disease, cystinosis, tyrosinemia, glycogen storage disorders Dent disease, Lowe syndrome Infiltrative disorders e.g., amyloidosis, multiple myeloma, monoclonal gammopathies Drugs e.g., tenofivir, ifosfamide, cisplatin Carbonic anhydrase inhibitors ↓ H2CO3 breakdown to H2O and CO2 Mutation encoding CAII enzyme, carbonic anhydrase inhibitors ↓ H2CO3 production in PT lumen ↓ CO2 diffusion into PT cell ↓ H2CO3 production in PT cell ↓ HCO3- production in PT cell ↓ HCO3- reabsorption by PT cell into plasma Type II/Proximal Renal Tubular Acidosis (RTA) Defective HCO3- reabsorption in proximal tubule Normal anion gap metabolic acidosis (NAGMA) See NAGMA slide Accumulation of toxic metabolites systemically, including in the PT Disruption of endocytosis and intracellular transport systemically, including in the PT Accumulation of light chain/amyloid deposits in PT Interfere with PT’s ability to reabsorb ions/molecules • • • • Fanconi Syndrome: generalized PT dysfunction Defective tubular reabsorption of other ions/molecules to varying degrees, including phosphate, glucose, sodium and amino acids Tubular proteinuria Phosphaturia Glucosuria ↑ Na+ secretionàhypovolemia Mutation encoding NBCE1 transporter ↑ HCO3- delivery to distal nephron K+ in distal nephron lumen binds to HCO3- K+ is lost through osmotic diuresis Hypokalemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 24, 2022 on www.thecalgaryguide.com

Granulomatosis with Polyangiitis Pathogenesis

Granulomatosis with polyangiitis: Pathogenesis Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication Drugs Thiol- and hydrazine-containing medications (e.g., hydralazine, propylthiouracil, allopurinol) Environmental exposures Silica dust, cigarette smoke, infections (Staphylococcus aureus) Genetic factors Alpha-1 antitrypsin deficiency, proteinase 3 gene mutation ↑ Production of cytokines and antineutrophil cytoplasmic antibodies (ANCAs) (mechanism unknown) Cytokines bind to endothelial cells (that line blood vessels) and neutrophils, priming them Proteinase 3 (PR3), an enzyme that degrades extracellular matrix proteins, migrates from neutrophil granules to neutrophil cell surface Circulating ANCAs bind to PR3 on neutrophils PR3 stimulates maturation of dendritic cells in lungs Dendritic cells present antigen (PR3) to naïve CD4+ T cells in peripheral lymph nodes T cells differentiate into type 1 and type 17 helper T cells (Th1 and Th17 cells) Th1 and Th17 cells secrete cytokines (interferon γ (INF-γ) and tumor necrosis factor α (TNF-α)) in lungs Secreted cytokines trigger macrophage maturation Formation of granulomas (giant cells with central necrosis surrounded by plasma cells, lymphocytes, and dendritic cells) primarily in lungs and upper airways ANCA-activated neutrophils release proinflammatory cytokines, attracting more neutrophils to endothelium (blood vessel wall) ANCA-activated neutrophils undergo firm adhesion to endothelium ANCAs stimulate ↑ secretion of proteolytic enzymes and reactive oxygen species from neutrophils Endothelial damage and tissue injury Granulomatosis with polyangiitis (GPA) ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms with involvement of multiple organ systems (see slide on clinical findings) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com Granulomatosis with polyangiitis: Clinical findings Inflammation-mediated endothelial damage and granuloma formation (see slide on pathogenesis) Granulomatosis with polyangiitis (GPA) Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms Fever, unintentional weight loss, night sweats, arthralgias Skin involvement Inflammation of cutaneous vessels Systemic inflammation obstructing blood flow, with granulomatous lesions primarily in upper airways and lungs Ear, nose, and throat involvement ↑ C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (markers of inflammation) Necrotizing granulomas on biopsy of affected tissue Positive PR3-ANCA/c-ANCA blood test (antibodies present in ~90% of patients, described in GPA Pathogenesis slide) Renal involvement Inflammation of renal vessels Rupture of basement membrane (layer that filters blood from glomerular capillaries into Bowman’s capsule) Pauci-immune glomerulonephritis (see Nephritic Syndrome slide) Rapidly progressive glomerulonephritis Eye involvement Inflammation of ocular tissue Conjunctivitis Scleritis/ episcleritis (painful red eye) Lower respiratory tract involvement Inflammation of pulmonary vessels Vessel occlusion and ischemia Skin necrosis Vessels burst and blood pools under skin Round and retiform (net- like) palpable purpura of lower extremities Granulomatous destruction of nasal cartilage Collapse of nasal bridge Saddle nose deformity Inflammation of paranasal sinus and nasal cavity vessels ↓ Perfusion of lungs Dyspnea Damage to interstitial capillaries Hemoptysis Diffuse alveolar hemorrhage Rhinitis/ sinusitis Granulomatous obstruction of eustachian tube Otitis media (see Otitis Media slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

Granulomatosis with polyangiitis: Clinical findings

Granulomatosis with polyangiitis: Clinical findings Inflammation-mediated endothelial damage and granuloma formation (see slide on pathogenesis) Granulomatosis with polyangiitis (GPA) Author: Oswald Chen Reviewers: Ben Campbell *Liam Martin * MD at time of publication ANCA-associated vasculitis affecting medium and small-sized arteries, associated with necrotizing granulomas Constitutional symptoms Fever, unintentional weight loss, night sweats, arthralgias Skin involvement Inflammation of cutaneous vessels Systemic inflammation obstructing blood flow, with granulomatous lesions primarily in upper airways and lungs Ear, nose, and throat involvement ↑ C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) (markers of inflammation) Necrotizing granulomas on biopsy of affected tissue Positive PR3-ANCA/c-ANCA blood test (antibodies present in ~90% of patients, described in GPA Pathogenesis slide) Renal involvement Inflammation of renal vessels Rupture of basement membrane (layer that filters blood from glomerular capillaries into Bowman’s capsule) Pauci-immune glomerulonephritis (see Nephritic Syndrome slide) Rapidly progressive glomerulonephritis Eye involvement Inflammation of ocular tissue Conjunctivitis Scleritis/ episcleritis (painful red eye) Lower respiratory tract involvement Inflammation of pulmonary vessels Vessel occlusion and ischemia Skin necrosis Vessels burst and blood pools under skin Round and retiform (net- like) palpable purpura of lower extremities Granulomatous destruction of nasal cartilage Collapse of nasal bridge Saddle nose deformity Inflammation of paranasal sinus and nasal cavity vessels ↓ Perfusion of lungs Dyspnea Damage to interstitial capillaries Hemoptysis Diffuse alveolar hemorrhage Rhinitis/ sinusitis Granulomatous obstruction of eustachian tube Otitis media (see Otitis Media slide) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 4, 2022 on www.thecalgaryguide.com

hypovolemic-shock

Hypovolemic Shock: Pathogenesis, Complications, and Clinical Findings Authors: Dean Percy Miranda Schmidt Reviewers: Yan Yu Tristan Jones Frank Spence* Ben Campbell Ayaaz Sachedina* * MD at time of publication Progressive ↓ in level of consciousness Pulseless Electrical Activity Acute Kidney Injury ↑ Reabsorption of salt and water in the kidney Oliguria (↓ urine output) Inflammation (pancreatitis, cirrhosis, post-operative, etc.) Inflammatory mediators ­ vessel permeability and fluid leaks out Trauma Ruptured vessels leak fluid into potential spaces Hemorrhagic losses (GI bleed, postpartum hemorrhage, etc.) ↓ Intravascular volume ↓ Venous return to the heart ↓ Cardiac output (blood pumped from the heart) Hypovolemic Shock ↓ Oxygen delivery to tissues due to low blood volume Insufficient organ perfusion Non-Hemorrhagic losses (dehydration, GI losses, skin losses / burns, renal losses, etc.) ‘Third Spacing’ of fluid (fluid located outside the intravascular or intracellular space; large collections can occur in the pelvis, thorax, GI tract, long bones of children, intra-abdominally, retroperitoneally) P = Q x R; less ‘flow’ in the vessels (Q), with vessels not constricting enough to maintain resistance (R)à pressure (P) will drop ↓ Blood Pressure Caution: young, healthy individuals can maintain blood pressure during circulatory collapse with ­ cardiac output and ­ vasoconstriction; do not use blood pressure as an indicator of shock severity in children Carotid sinus baroreceptors sense low blood pressure ↓ Carotid sinus inhibition of sympathetic nervous system Release of sympathetic catecholamines (epinephrine and ↓ Pressure in venous circulation Brain Heart Kidneys ↓ Blood in the right internal jugular vein ↓ Oxygen delivery to the brain ↓ Myocardial contractility (from lactic acidosis) ↓ Blood flow to kidneys ↓ Jugular Venous Pressure Catecholamines bind to beta-1 receptors in the sinoatrial node of the heart Beta-1 receptor activation causes ↑ heart rate Tachycardia norepinephrine) Catecholamines bind to and stimulate alpha-1 receptors in peripheral vessels Vasoconstriction of peripheral vessels ↓ Blood flow to peripheral tissue Catecholamines bind to and stimulate beta receptors in sweat glands Diaphoresis (sweating) In all body tissues Inadequate oxygen delivery ↓ ATP production ↑ Anaerobic metabolism ↓ Body temperature Impaired neurological functioning Renal ischemia Activation of the renin-angiotensin aldosterone system ↓ Glomerular filtration rate ↓ Clearance of lactic acid by the kidney ↑ Lactic acid production ↓ Rate of activity of clotting enzymes Lactic Acidosis Unknown mechanism Coagulopathy Hypothermia Trauma Triad of Death ↑ Capillary Cold, mottled refill time extremities Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 24, 2013, updated December 4, 2022 on www.thecalgaryguide.com

Approach to Arterial Blood Gases ABGs

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

Coronary Artery Bypass Graft CABG Indications

Coronary Artery Bypass Graft (CABG): Indications Author: Breanne Gordulic Reviewers: Miranda Schmidt Ben Campbell Sunawer Aujla Angela Kealey* * MD at time of publication Symptomatic multivessel (≥ 3 vessels) coronary artery disease (MVCAD) or complex MVCAD Acute coronary syndrome (ACS) Left main coronary artery disease Multivessel (≥ 3 vessels) CAD and diabetes Cardiac surgery required for other pathology Multivessel CAD, LV dysfunction and congestive heart failure (CHF) Complex CAD includes stenosed vein grafts, bifurcation lesions, calcified lesions, total occlusions, ostial lesions STEMI initial treatment is PCI/thrombolysis CABG outcomes compared to percutaneous coronary intervention (PCI) in MVCAD include ↑ survival in diabetes, ↑ survival with LV dysfunction, ↓ repeat revascularization, ↓ myocardial infarction, ↓ stroke ↑ Risk of failure in complex CAD with PCI Rapid reperfusion to myocardium most important in STEMI to decrease myocardial damage CABG can be considered for residual stenoses 6-8 weeks later NSTEMI or unstable angina (UA) with MVCAD involving at least three vessels including the proximal left anterior descending (LAD) Left main coronary artery divides into left anterior descending (LAD) and left circumflex (LCx) which supplies 2/3 of myocardium ↑ Survival Myocardial infarction from left main artery occlusion Death Left main stenosis Ventricular dysrhythmias Ongoing ischemia LV dysfunction Hemodynamic instability ↑ risk of PCI CABG has mortality benefit ↓ Number of operations ↑ Risk of cardiovascular disease in diabetes Revascularization indicated along with other cardiac surgery Multivessel CAD with >90% stenosis and CHF LV ejection fraction <35% ↑ Risk of atherosclerosis from hyperglycemia and dyslipidemia CABG bypasses several atherosclerotic plaques in coronary arteries ↑ Durability ↑ Complete perfusion Valve stenosis or regurgitation Septal defect Aortic root or arch pathology Combination procedure Evidence of ischemia at rest Evidence of impaired LV function at rest ↓ All-cause mortality in CABG vs medical management Chronic obstructive pulmonary disease Abbreviations: • ACS- acute coronary syndrome. Acute reduction in blood flow to heart muscle resulting in cell death. • CAD- coronary artery disease. Narrowing or blockage of the coronary arteries by plaque • NSTEMI- myocardial infarction (heart attack) with no ST elevation on electrocardiogram • PCI- percutaneous coronary intervention. A balloon tipped catheter is used to open blocked coronary arteries; a stent may be placed. • STEMI- myocardial infarction with ST segment elevation on electrocardiogram Consider revascularization (restore blood flow to blocked or narrowed blood vessels) of coronary arteries to increase perfusion to myocardium (heart muscle) Coronary artery bypass graft recommended Assess surgical risk and comorbidities with evaluation by heart team that includes both a cardiac surgeon and interventional cardiologist (SYNTAX Trial) Individual management plan for patients with comorbidities that increase mortality Frailty Chronic Renal Failure ↑ Inflammation and deregulated angiogenesis affects all organ systems ↓ Physiologic reserve and ↓ ability to recover from acute stress ↑ Pneumonia ↑ Respiratory and Renal Failure ↑ Stroke ↑ In hospital mortality ↓ Survival two years after surgery Use Society of Thoracic Surgeons Score, EuroSCORE, or SYNTAX II Score to predict patient outcome with anatomy, disease severity, and preoperative characteristics Coronary Artery Bypass Graft Surgery to take healthy blood vessels from the body and connect them proximally and distally to blocked coronary arteries Cardiopulmonary bypass, fluid overload, ↑ renal vasoconstriction and ↓ renal oxygenation from rewarming Kidney injury ↑ End stage kidney disease Blood flow restored to ischemic myocardium ↓ Angina ↑ Quality of life ↑ LV function ↑ Survival Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 12, 2023 on www.thecalgaryguide.com

normal neonatal changes pathogenesis and clinical findings

Normal Neonatal Changes: Physiology and Clinical Findings The neonatal period is between infants’ time of birth and 4 weeks gestational age. This slide focuses only on changes that are part of the normal growth and development of neonates born at full term (38-42 weeks). Authors: Erin Auld, Dasha Mori Reviewers: Kayla Feragen Mao Ding Danielle Nelson* *MD at time of publication Birth weight: Loss of birth weight up to 10%; should be re-gained within 10-14 days (30 g/day) Stool: transitions from meconium (first stool of neonate that is black, tarry and sticky) to normal (green/brown or yellow mustard) within 2-3 days Meconium passage: within 24 hours of birth Growth • Height: 2.5 cm/month • Head Circumference: Average 1 cm/month in the first year with greatest growth in the first month • Weight: 20-30 g/day for the first 3 months Urination: within the first 24 hours Mother receives intravenous fluids during delivery Colostrum (first milk secretion that contains antibodies) produced in first 2-3 days of lactation post-partum (Lactogenesis I) GI tract maturation Adequate dietary intake Maturation of urinary tract Adequate fluid intake ↑ maternal blood volume Fluid moves between fetus and mother through placenta Fetus’s fluid volume ↑ Infant’s urine output ↑ in first 24 hours post-partum Low breast milk intake in first 2-3 days ↓ progesterone, ↑ prolactin in mother at birth Infant ingests colostrum Mostly water loss, some fat loss ↑ Breast Milk Production (Lactogenesis II) Stomach stretches ↑ in gastrointestinal tract motility (gastrocolic reflex) Ingestion of milk post-partum further stimulates GI maturation 110-120 kilocalories/kg/day Gastrointestinal tract formation begins when the fetus is 4 weeks old. Maturation continues into infancy. Normal gestational age (38-42 weeks) Fetus ingests amniotic fluid in utero Stimulates structural changes, enzymatic activity, and metabolic activity of GI tract Mature detrusor sphincter complex, appropriate bladder capacity, proper renal perfusion, and regular arousal of the neonate Breast milk: Feeding when infant demands it, approximately every 2-3 hours Formula: Feeding when infant demands it, approximately every 4 hours Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 24, 2015, updated Sept 28, 2023 on www.thecalgaryguide.com

Alcohol Withdrawal Syndrome

Alcohol Withdrawal Syndrome (AWS): Pathophysiology & clinical findings Authors: Rupali Manek Gurreet Bhandal Erika Russell Reviewers: Harjot Atwal Yvette Ysabel Yao Mao Ding Nureen Pirbhai* * MD at time of publication Chronic alcohol use ↓Autonomic adrenergic systems ↓ Dopamine in the nucleus accumbens ↑ EtOH depressant effects on brain ↓ Glutamate- induced excitation ↑ GABA-induced inhibition ↑ Glutamate receptors in attempt to maintain normal arousal state GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) Long-term physical dependence Abrupt alcohol cessation àabrupt ↓ in blood EtOH concentration Alcohol withdrawal Syndrome Symptoms that occur when patients stop drinking or significantly decrease their alcohol intake after long-term dependence ↓ GABA-induced inhibition &↑ glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities ↑ Autonomic adrenergic systems (rebound over-activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑ Heart rate (HR), ↑respiratory rate (RR) ↑blood pressure (BP), tremor & diaphoresis (↑sweating) Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (mostly visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑RR & ↓oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Phosphate (from malnutrition) Cardiac failure, rhabdomyolysis or muscle breakdown ↓ Phosphate available to make ATP ↓ ATP ↓ Magnesium (common in patients with DT) Impaired Na-K ATPase function Dysrhythmias ↑ Glutamate-activated depolarization in the brain ↑ Neuronal excitability Seizures Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Apr 15, 2017, updated Oct 18, 2023 on www.thecalgaryguide.com Alcohol Withdrawal Syndrome (AWS): Pathophysiology & clinical findings Authors: Rupali Manek Gurreet Bhandal Erika Russell Reviewers: Harjot Atwal Yvette Ysabel Yao Mao Ding Nureen Pirbhai* * MD at time of publication Chronic alcohol use ↓Autonomic adrenergic systems ↓ Dopamine in the nucleus accumbens ↑ EtOH depressant effects on brain ↓ Glutamate- induced excitation ↑ GABA-induced inhibition ↑ Glutamate receptors in attempt to maintain normal arousal state GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) Long-term physical dependence Abrupt alcohol cessation àabrupt ↓ in blood EtOH concentration Alcohol withdrawal Syndrome Symptoms that occur when patients stop drinking or significantly decrease their alcohol intake after long-term dependence ↓ GABA-induced inhibition &↑ glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities ↑ Autonomic adrenergic systems (rebound over-activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑ Heart rate (HR), ↑respiratory rate (RR) ↑blood pressure (BP), tremor & diaphoresis (↑sweating) Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (mostly visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑RR & ↓oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Magnesium (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) ↓ Phosphate available to make ATP ↓ ATP Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Alcohol Withdrawal: Pathophysiology & clinical findings Authors: Erika Russell Rupali Manek Gurreet Bhandal Reviewers: Yvette Ysabel Yao Harjot Atwal Nureen Pirbhai* * MD at time of publication ↓Autonomic adrenergic systems ↓ Glutamate-induced excitation Chronic alcohol use ↑ EtOH depressant effects on brain ↓ Dopamine in the nucleus accumbens ↑ GABA-induced inhibition ↑ Glutamate receptors in attempt to maintain normal arousal state GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) ↑ Autonomic adrenergic systems (rebound over- activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑ Heart rate (HR), ↑respiratory rate (RR) ↑blood pressure (BP), tremor & diaphoresis (↑sweating) Physical dependence due to chronic alcohol use Abrupt alcohol cessation Abrupt ↓ in blood EtOH concentration Alcohol withdrawal ↓ GABA-induced inhibition &↑ glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (mostly visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑RR & ↓oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Magnesium (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) ↓ Phosphate available to make ATP ↓ ATP Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Authors: Erika Russell Rupali Manek Gurreet Bhandal Reviewers: ↓Autonomic adrenergic systems ↓ Dopamine in the nucleus accumbens Yvette Ysabel Yao Harjot Atwal Nureen Pirbhai* * MD at time of publication Alcohol Withdrawal: Pathophysiology & clinical findings Chronic alcohol use ↑ EtOH depressant effects on brain ↓ Glutamate-induced excitation ↑ GABA-induced inhibition ↑ Glutamate receptors in attempt to maintain normal arousal state GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) ↑ Autonomic adrenergic systems (rebound over- activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑ Heart rate (HR), ↑respiratory rate (RR) ↑blood pressure (BP), tremor & diaphoresis (↑sweating) Physical dependence due to chronic alcohol use Abrupt alcohol cessation Abrupt ↓ in blood EtOH concentration Alcohol withdrawal ↓ GABA-induced inhibition &↑ Glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (mostly visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑RR & ↓oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Magnesium (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Alcohol Withdrawal: Pathophysiology & clinical findings Chronic alcohol use ↓ Dopamine in the nucleus accumbens ↓Autonomic adrenergic systems Authors: Erika Russell Rupali Manek Gurreet Bhandal Reviewers: Yvette Ysabel Yao Harjot Atwal ↑ GABA-induced inhibition Nureen Pirbhai* * MD at time of publication ↑ EtOH depressant effects on brain ↓ Glutamate-induced excitation ↑ Glutamate receptors in attempt to maintain normal arousal state GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) ↑ Autonomic adrenergic systems (rebound over- activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑Heart rate (HR), ↑respiratory rate (RR) ↑blood pressure (BP), tremor & diaphoresis (↑sweating) Physical dependence due to chronic alcohol use Abrupt alcohol cessation Abrupt ↓ in blood EtOH concentration Alcohol withdrawal ↓ GABA-induced inhibition &↑ Glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (mostly visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑RR & ↓oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Magnesium (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Alcohol Withdrawal: Pathophysiology & clinical findings Authors: Erika Russell Rupali Manek Gurreet Bhandal Reviewers: Yvette Ysabel Yao Harjot Atwal Nureen Pirbhai* * MD at time of publication ↑ EtOH depressant effects on brain ↓ Glutamate-induced excitation ↑ Glutamate receptors in attempt to maintain normal arousal state Chronic alcohol use ↑ GABA-induced inhibition GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) ↓ Dopamine in the nucleus accumbens ↓Autonomic adrenergic systems Abrupt alcohol cessation Physical dependence due to chronic alcohol use Alcohol withdrawal ↓ GABA-induced inhibition &↑ Glutamate-induced excitation relative to chronic alcohol use Central nervous system overactivity Withdrawal seizures: Generalized tonic-clonic convulsions 24-48 hours after alcohol cessation ↑ Autonomic adrenergic systems (rebound over-activity of the brain and noradrenergic systems) ↑ Sympathetic activity: ↑HR, ↑RR ↑BP, tremor & diaphoresis (↑sweating) Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation ↑ Dopamine in nucleus accumbens Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (predominately visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Fluid and electrolyte abnormalities Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑ RR & ↓ oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ Potassium (K) (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Magnesium (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Alcohol Withdrawal: Pathophysiology & clinical findings Authors: Erika Russell Rupali Manek Gurreet Bhandal Reviewers: Yvette Ysabel Yao Harjot Atwal Nureen Pirbhai* * MD at time of publication ↓ GABA-induced inhibition &↑ Glutamate-induced excitation relative to chronic alcohol use CNS overactivity Alcohol withdrawal delirium (delirium tremens or DT): Hallucinations (predominately visual), disorientation, tachycardia, hypertension, hyperthermia, agitation, and diaphoresis 48-96 hours after alcohol cessation and lasts 1-5 days Alcohol cessation ↓ Dopamine Alcohol withdrawal Chronic alcohol use ↑ EtOH depressant effects on brain in the NAc ↓Autonomic adrenergic systems ↑ Dopamine in nucleus accumbens (NAc) relative to chronic alcohol use Alcoholic hallucinosis: Usually visual (but can be auditory or tactile), normal vitals 12-24 hours after alcohol cessation, typically resolve within 24-48 hours ↑ Autonomic adrenergic systems relative to chronic alcohol use ↑ Sympathetic activity: ↑HR, ↑RR ↑BP, tremor & diaphoresis (↑sweating) ↓ Glutamate- induced excitation ↑ Glutamate receptors in attempt to maintain normal arousal state ↑ GABA-induced inhibition GABA insensitivity (↑ GABA needed to maintain a constant inhibitory tone) Early symptoms: Insomnia, tremulousness, anxiety, digestive upset, anorexia, headache, sweating, palpitations 6-12 hours after alcohol cessation Withdrawal seizures: Generalized tonic- clonic convulsions 24-48 hours after alcohol cessation Fluid and electrolyte abnormalities Abbreviations: CNS – Central nervous system K – Potassium DT – Delirium tremens Mg – Magnesium NAc – Nucleus accumbens NMDA – N-methyl-D-aspartate EtOH – Alcohol NT – Neurotransmitter Hypovolemia (from diaphoresis, hyperthermia, vomiting, ↑ RR & ↓ oral intake) Metabolic acidosis (from hypoperfusion, infection, alcoholic ketoacidosis, or ↓ thiamine & other B vitamins) ↓ K (renal & extrarenal K losses, alterations in aldosterone concentrations, and changes in K distribution across the cell membrane) ↓ Mg (common in patients with DT) Dysrhythmias, seizures ↓ Phosphate (from malnutrition) Cardiac failure, rhabdomyolysis or muscle breakdown Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published April 28th, 2014 on www.thecalgaryguide.com Alcohol Withdrawal: Clinical Findings and Complications Authors: Erika Russell Reviewers: Harjot Atwal Nureen Pirbhai* * MD at time of publication Note: *The onset of alcohol withdrawal generally begins 6-24 hours after the last drink with symptoms peaking between 24-36 hours after and gradually lessening. Symptoms typically progress from early symptoms and increased sympathetic activityà hallucinationsàseizures àpotentially Delirium Tremens. Alcohol withdrawal is mild-moderate in severity for 90% of patients. Those who progressively worsen however can enter Delirium Tremens (DT) which has a mortality rate of up to 20%. More likely to have DT if had DT before, age >30 years, concurrent illness, >2 days after EtOH cessation before seeking help, and history of sustained drinking. Long term, heavy alcohol use that leads to physical dependence Abrupt ↓ in blood EtOH concentration Negative physiological reactions to ↓ alcohol intake Adaptive suppression of GABA activity from chronic alcohol enhancement Alcohol Withdrawal* Withdrawal symptoms alleviated by ingesting alcohol Alcohol taken to relieve withdrawal AND/OR Social and internal relapse cues trigger urge to use alcohol Blood EtOH levels >600 mg% can lead to lethal respiratory depression by suppressing the respiratory centers in the brainstem Upregulated autonomic adrenergic systems from chronic alcohol inhibition Discontinuation of alcohol leads to rebound over- activity of the brain and noradrenergic systems Increased Sympathetic Activity Tachycardia, hypertension, tremor and diaphoresis Generalized Tonic-Clonic Seizures Usually begin within 8-24 hours of alcohol cessation and peak after 24 hours. Risk of having seizures ↑ with repeated withdrawals. 1/3 of people can progress to DT if seizures left untreated. Discontinuation of alcohol causes a sudden relative deficiency in inhibitory GABA activity Reduction in dopamine in the nucleus accumbens (NAc) from chronic alcohol exposure Discontinuation of alcohol causes a increase in dopamine levels in NAc Hallucinations Commonly visual (but can be auditory or tactile), develop 12-24 hours after alcohol cessation. Early Symptoms Anxiety, insomnia, vivid dreams, anorexia, nausea, headache and psychomotor agitation Delirium Tremens (DT) Life-threatening state of greatly exaggerated withdrawal symptoms (severe tachycardia, diaphoresis etc.) with confusion/disorientation and hallucinations that generally appears 72-96 hours after the last drink and lasts 2-3 days. Legend: Published MONTH, DAY, YEAR on www.thecalgaryguide.com Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications

Pharmacotherapy for Dyslipidemia Overview

Pharmacotherapy for Dyslipidemia: General overview Dyslipidemia Authors: Rupali Manek Reviewers: Gurreet Bhandal, Raafi Ali, Yan Yu*, Samuel Fineblit* *MD at time of publication Hypolipidemia (↓ HDL or ↓ apoB containing lipoproteins like LDL) Bile-acid sequestrants Bind bile acids in intestinal lumen to prevent reabsorption by enterohepatic (gut-liver) circulation ↑ Excretion of bile acids and cholesterol in stool ↓ LDL in blood Side effects: GI disturbances, commonly interact with other drugs by interfering with absorption See Calgary guide slide on “Bile-acid sequestrants: Mechanisms of action & side effects” for complete description of mechanism and side effects (clinical imbalance of lipids) Hypertriglyceridemia (if VLDL mediated & in need of treatment for pancreatitis prevention) Hypercholesteremia (↑ LDL in blood) Ezetimibe Inhibits cholesterol absorption via NPC1L1 transporter ↑ Hepatic (liver) LDL receptor expression ↑ LDL clearance from blood ↓ LDL in blood Avoid in pregnancy See Calgary guide slide on “Ezetimibe: Mechanisms of action & side effects” for complete description of mechanism and side effects Combined hyperlipidemia (↑ Triglycerides and ↑ cholesterol) Statins (ex. rosuvastatin, atorvastatin, simvastatin, pravastatin) Competitive inhibitors of HMG-CoA reductase (rate-limiting enzyme in cholesterol synthesis) Fibrates (ex. fenofibrate, gemfibrozil) Activate PPAR! (nuclear receptor) ↑ Lipolysis (breakdown of lipids) and free fatty acid oxidation ↓ Triglycerides in blood Side effects: GI discomfort, rash, pruritis Contraindicated in pregnancy, renal failure, liver & gallbladder disease See Calgary guide slide on “Fibrates: Mechanisms of action & side effects” for complete description of mechanism and side effects PCSK9 inhibitors (ex. evolocumab and alirocumab which are monoclonal antibodies) Inhibit PCSK9 (holds the LDL:LDL receptor complex together as it is internalized into the cell for destruction of LDL) LDL receptor returns to surface without being destroyed ↑ LDL receptor expression ↑ LDL clearance from blood ↓ LDL in blood See Calgary guide slide on “PCSK9 Inhibitors: Mechanisms of action & side effects” for complete description of mechanism and side effects ↓ Cholesterol synthesis in liver ↑ LDL receptor expression in liver LDL receptor recognizes apoB100 (structural protein on LDL) and apoE (structural protein found on chylomicron, VLDL, IDL) ↑ Clearance of LDL cholesterol from bloodstream ↓ LDL cholesterol in blood ↑ HDL in blood ↓ Triglycerides in blood ↓ Atherosclerosis (plaque along walls of blood vessels) Abbreviations: HDL – High density lipoprotein; HMG-CoA – Hydroxymethylglutaryl- CoA; LDL – Low-density lipoprotein; PCSK9 – Proprotein convertase subtilisin/kexin type 9; PPAR! – Peroxisome proliferator-activated receptor alpha; NPC1L1 – Niemann-Pick C1-Like 1; VLDL – Very low-density lipoprotein Side effects: Myalgias (muscular aches), rhabdomyolysis (muscle breakdown), transaminitis (liver inflammation), liver failure, ↑ risk of diabetes mellitus Contraindicated in pregnancy See Calgary guide slide on “Statins: Mechanisms of action & side effects” for complete description of mechanism and side effects Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 6, 2023 on www.thecalgaryguide.com

Death Cardiovascular Respiratory and Neurologic Mechanisms

Death: Cardiovascular, Respiratory and Neurologic Mechanisms Mitochondria in tissues unable to utilize O2 Reduced hemoglobin in blood to carry O2 Low oxygen content in blood (CaO2) Hypoxemia (Type I Respiratory Failure): low dissolved oxygen in blood (PaO2) Lungs can’t oxygenate blood fast enough Lungs can’t rid blood of CO2 fast enough Hypercapnia / hypercarbia (Type II Respiratory Failure): elevated dissolved CO2 in blood (PaCO2) Cerebral vasodilation Toxins: e.g. cyanide, pesticides, arsenic Severe anemia Distributive problems: Systemic inflammation (sepsis, anaphylaxis, pancreatitis), adrenal insufficiency, vasodilatory drugs Obstructive problems: Cardiac tamponade*, tension pneumothorax* or massive pulmonary embolism* Hypovolemic* problems (low blood volume): Hemorrhage, dehydration, widespread skin disruption or burns Cardiac valve dysfunction Myocardial infarction* or cardiomyopathy Cardiac arrhythmia or heart block Disturbed electrical activity in cardiomyocytes Peripheral metabolic disturbances Hypokalemia*, Hyperkalemia* Acidosis* (including renal failure) Hypothermia* Toxins* (e.g. cocaine, beta blockers, tricyclics) Severe thyroid derangement Inappropriate systemic vasodilation Adjacent forces impair heart filling Low cardiac preload Low stroke volume (SV; depends on valves, contractility, preload) Decreased systemic vascular resistance (SVR) Low blood pressure (BP = CO x SVR) Decreased cardiac output (CO = SV x HR) Disseminated intravascular coagulationàwidespread thrombi that occlude blood flow (also causes hemorrhage, see relevant box at left) Methemoglobinemia: some hemoglobin gets stuck in a state that can’t carry O2 Hemoglobin has reduced capacity to carry or release O2 Drugs: e.g. dapsone, nitrates Carbon monoxide poisoning Circulatory collapse / shock: inadequate perfusion of tissue with blood Respiratory collapse: blood has insufficient useable O2 content Ventricular fibrillation (VF) or pulseless ventricular tachycardia (VT) Hypoxia*: inadequate O2 delivery or utilization in tissues Hypoxia creates metabolic disturbances that impair cardiac cells. Alternatively, any of the preceding conditions marked with (*) can directly trigger cardiac arrest first Pulseless Electrical Activity (PEA): organized activity on ECG with no cardiac output (can be preceded or mimicked by pseudo-PEA, in which there is still some output on ultrasound) Low atmospheric pressure or oxygen content Severe lung disease Asthma, COPD, interstitial lung disease, congestive heart failure, pulmonary hypertension, pulmonary embolism, lung collapse / atelectasis Acute respiratory distress syndrome Pneumonia, aspiration pneumonitis, inhalational injury, systemic inflammation, drowning Severe hypoventilation Respiratory fatigue, advanced COPD, chest wall disorders, neuromuscular disorders, upper airway obstruction, toxins (e.g. opioids, botulism) Can degenerate at any time Asystole: no cardiac electrical activity or output Death Respiratory arrest: cessation of breathing Inability to protect airway Decreased level of consciousness Note This is a broad overview of the many scenarios that can result in death. For detailed explanations of the various disease mechanisms, refer to the corresponding slides. * = reversible causes of cardiac arrest (Hs and Ts) Author: Ben Campbell Reviewers: Yan Yu* Huma Ali* * MD at time of publication Bradycardia (low heart rate, HR) Unopposed parasympathetic stimulation of heart (can also cause vasodilation, see Distributive problems) Disruption of spinal cord sympathetic control Injury to cervical or upper thoracic spinal cord Irreversible cessation of cardiac, respiratory, and brain function Prolonged seizure initially causes increased cardiovascular activity, until the system fatigues Disruption of respiratory control center in medulla Expanding skull contents squeeze brainstem (herniation) Increased intracranial pressure Edema from intracranial hemorrhage, trauma, brain mass Edema, inflammation, hypoxia and/or metabolic derangements cause diffuse neuron dysfunction Central nervous system infection Dementia, particularly with delirium Massive ischemic stroke Seizure activity prevents or alters breathing Metabolic disturbances that affect the central nervous system Hypoglycemia Hypocalcemia, hypercalcemia Hyponatremia, hypernatremia Uremia Acute liver failure (hyperNH4) Many drugs / toxins Withdrawal (e.g. EtOH) Status epilepticus Brainstem lesion (e.g. stroke, neoplasm, inflammatory) Nervous System Insult Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 11, 2023 on www.thecalgaryguide.com Respiratory System Insult Cardiovascular System Insult Cardiogenic problems

Turner Syndrome Pathogenesis and Clinical Findings

Turner Syndrome: Pathogenesis and clinical findings Author: Simran Pherwani Ashar Memon, Christy Chong Reviewers: Tara Shannon Simran Sandhu, Mao Ding Danielle Nelson* * MD at time of publication Non-disjunction in phenotypically female gametes (i.e. homologous X-chromosomes or sister chromatids fail to separate) Partial or complete absence of second sex chromosome, leaving only one normal X-chromosome Possible Chromosomal Profiles Other meiotic error → deletion or misdivision of X-chromosomal material Complete loss of one X- chromosome in all cells (45,X) (45%) Skeletal Abnormalities ↓ Expression of SHOX gene (present on X- and Y-chromosomes) ↓ Cellular proliferation in growth plates of bones in extremities during embryonic development Short stature High-arched palate Genu valgum (knock knees) Micrognathia (smaller lower jaw) Broad chest Cubitus valgus (forearm angled outward) Mosaicism (complete loss of one X-chromosome in some cells (e.g., 45,X/46,XXX, etc)) (50%) Congenital Heart Defects (most serious) Single copy of TIMP1 gene and presence of risk TIMP3 allele, and differential expression of KDM6A gene Bicuspid aortic valve Aortic coarctation Aortic dilation (worsened by hypertension) One X-chromosome and presence of Y-chromosomal material in some or all cells (e.g., 45,X/46,XY) Presence of an X- isochromosome (most commonly i(Xq)) Other structural abnormalities of X-chromsome (e.g., Ring Chromosome X, partial deletion of X, X or Y marker chromosome) Endocrine Disorders Turner Syndrome The most common sex chromosomal abnormality in females (affects 1/2000-3000) Results in deletion or non- functioning of one X chromosome Clinical presentations vary depending on chromosome profile Aortic dissection Renal disease Neurocognitive Deficits Mechanism unknown Deficit in social skills Specific (non-verbal) learning disorder (otherwise normal intelligence) ↓ Executive function skills ↓ Visuospatial skills ↓ Attention Accelerated follicular apoptosis (i.e., loss of oocytes from ovaries) → streak gonads Ovaries are unable to respond to high gonadotropins (FSH, LH) Hypergonadotropic hypogonadism Premature ovarian insufficiency ↓ Expression of immune- associated genes on X- chromosome ↑ Autoimmunity Autoimmune diseases (celiac, thyroiditis, IBD, metabolic abnormalities) ↓ Estrogen levels Lack of breast development ↑ Liver enzymes (Additional mechanisms likely) ↓ Bone mineral density Other Dysmorphic Features Lymphedema Webbed (buildup of lymph neck fluidàswelling) Primary amenorrhea Infertility Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 25, 2023 on www.thecalgaryguide.com

Sugammadex

Sugammadex: Mechanism of action and adverse side effects A direct reversal agent with a high affinity for rocuronium and lesser affinity for vecuronium, capable of reversing even deep neuromuscular blockade. Binds rocuronium and vecuronium (non-depolarizing neuromuscular blocking drugs (nNMBs)) in plasma when administered IV ↓ Concentration of functional nNMBs in plasma Creates a concentration gradient from muscle tissue (high) to plasma (low) nNMBs move from muscle compartment to plasma Sugammadex in plasma encapsulates nNMBs that moved to the plasma ↓ Concentration of functional nNMBs in the plasma ↓ Concentration of nNMBs at the nicotinic acetylcholine receptor within the skeletal neuromuscular junction Reverses neuromuscular blockade created by nNMBs Sugammadex Progesterone is similar in structure to nNMBs Sugammadex binds progesterone ↓ Progesterone activity in the body Progesterone is critical for maintenance of early pregnancy Unknown significance, avoid use in early pregnancy Sugammadex-nNMB complex is cleared by the kidneys Higher concentrations of sugammadex facilitate faster nNMB clearance Unknown mechanisms Post operative nausea and vomiting Headache Bradycardia Cardiovascular Collapse ↓ Effectiveness of progesterone-based contraception for 7 days ↓ Clearance in patients with severe renal impairment Reversal of profoundly deep neuromuscular blockade at higher doses Binds to IgG or IgE receptors on sensitized basophils/mast cells in allergic reactions Activation of basophils/mast cells Degranulation of basophils/mast cells Release of granulation products Anaphylaxis Bronchospasm Hypotension Authors: Arzina Jaffer, Kayleigh Yang Reviewers: Jasleen Brar, Mao Ding Joseph Ahn* * MD at time of publication Movement of limbs or body during anesthesia Coughing during anesthesia Grimacing or suckling on the endotracheal tube Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2024 on www.thecalgaryguide.com

Bacterial Infections from Transfusion

Bacterial Infections from Transfusion: Signs and Symptoms Caused by bacterial contamination of any blood product, most commonly platelets due to room-temperature storage Bacteria enters bloodstream directly through transfusion Immune cells (ex. macrophages, dendritic cells, monocytes, neutrophils) recognize bacteria Immune cells release pyrogens (either bacterial components or signalling molecules) upon recognition Pyrogens bind to receptors on the hypothalamus Hypothalamus ↑ body temperature set point Body generates and conserves heat to reach set point Immune cells release pro- inflammatory cytokines (messenger protein) Cytokines activate sympathetic nervous system via hypothalamus Adrenal glands release stress hormones (epinephrine and norepinephrine) into bloodstream Stress hormones bind to receptors on cardiomyocytes (heart muscle cells) ↑ Heart contractility ↑ Heart rate Cytokines circulate throughout the body Cytokines interact with endothelial cells of the blood vessels ↑ Nitric oxide production Relaxes smooth muscle cells of blood vessel walls Vasodilation (↑ blood vessel diameter) Hypotension Systemic inflammation Stimulate nerve endings in muscles Stimulate nerve endings in gastrointestinal tract’s lining Blood brain barrier’s integrity is compromised Nitric oxide reacts with oxygen to form reactive nitrogen species Tissue damage Fatigue Weakness Muscle aches Nausea and vomiting Immune and inflammatory cells enter the brain Authors: Arzina Jaffer Kayleigh Yang Reviewers: Nimaya De Silva Raafi Ali Michelle J. Chen Yan Yu* Kareem Jamani* * MD at time of publication Inflammation in the brain Activates pain processing centers in the brain Headache Damages neurons and disrupts cell communication Confusion and altered mental state Shivering Fever Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 30, 2024 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

Stable Angina

Angina Pectoris/Stable Angina: Pathogenesis and clinical findings Authors: Ryan Iwasiw Alexander Arnold Julia Gospodinov Reviewers: Mandy Ang Sarah Weeks* Frank Spence* Shahab Marzoughi * MD at time of publication Atherosclerosis (Fatty plaque accumulates inside the intimal walls of arteries) ↓ Blood vessel lumen diameter ↓ Volume of blood is supplied to the heart Predictable period of physical activity or emotional stress ↑ Heart rate ↓ Time for coronary arteries to fill heart with blood (diastole) ↑ Heart contractility ↑ Oxygen demand of heart muscle tissue (myocardium) ↓ Myocardial blood supply Imbalance between blood supply & oxygen demand causes myocardial ischemia Angina Pectoris/Stable Angina Myocardial ischemia causes cardiac muscle cells (cardiomyocytes) to switch from oxygen-dependent (aerobic) to oxygen-absent (anaerobic) metabolism Anaerobic metabolism produces metabolites that stimulate cardiac spinal afferent nerves Myocardial visceral afferent & somatic sensory nerve fibers mix & enter the spinal cord via T1-T4 nerve roots Brain interprets ↑ nerve signaling as nerve pain coming from the skin of T1-T4 dermatomes (referred pain) ↑ lactic acid production & ↓ cellular pH impairs cardiomyocytes’ function Damaged cardiomyocytes impair myocardial relaxation & cause ↓ left ventricular contractility & cardiac output Blood backs up into left ventricle, atrium, & pulmonary vasculature ↑ Pulmonary capillary pressures pushes fluid out & into the lung’s alveoli ↓ Gas exchange & oxygenation ↑ Respiratory rate & Dyspnea (shortness of breath) Blood flow begins at the epicardium (outer heart layer) & ends at endocardium (inner layer) Subendocardium (innermost heart layer) receives the least blood flow causing non-transmural (partial thickness) heart wall ischemia Anterior/septal & lateral wall ischemia triggers ↑ sympathetic nervous system (SNS) activity given the proximity of cardiac SNS innervation Inferior wall ischemia triggers involuntary ↑ in Vagus nerve activity given the nerve’s proximity Bradycardia (↓ heart rate) Nausea Adrenal medulla releases Norepinephrine hormone Activation of sweat glands via SNS acetylcholine neurotransmitter release Hypotension (↓ blood pressure) Pain radiation to left arm, jaw, abdomen & upper back Chest pain, pressure, or discomfort Unstable Angina (unpredictable & worsening chest pain) See relevant Calgary Guide slide on Unstable Angina Binds arterial smooth muscle α1 receptors ↑ Coronary arteries’ vascular tone (vasoconstriction) Hypertension (↑ blood pressure) Activates β1 receptors in the heart Tachycardia (↑ heart rate) Diaphoresis (↑ sweating) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 8, 2013; updated Feb 5, 2024 on www.thecalgaryguide.com

Gestational Diabetes Risk factors and pathogenesis

Gestational Diabetes: Risk factors and pathogenesis Normal metabolic changes occurring in pregnancy (e.g., increased lipid storage, increase renal filtration, increased glucose production etc.) Authors: Amyna Fidai Maharshi Gandhi Reviewers: Laura Byford-Richardson Shahab Marzoughi Yan Yu* Hanan Bassyouni* * MD at time of publication High risk population (Aboriginal, Hispanic, South Asian, Asian, African) Previous or current macrosomia (>4000g) or polyhydramnios Other conditions associated with Diabetes Mellitus such as polycystic ovarian syndrome, hypertension, metabolic syndrome Placental counter regulatory hormones (particularly Human Placental Growth Hormone) oppose the action of insulin ↑ Insulin resistance (liver, muscle, adipose tissues become less responsive to insulin) ↑ Fetal demands after 18 weeks gestation (fetus requires 80% of its energy from maternal glucose) ↑ Carbohydrate intake to keep up with the demands Previous history of gestational diabetes or glucose intolerance Family history of diabetes Advanced maternal age Obesity Previous unexplained stillbirth Multiples (larger placental mass and activity) Corticosteroid use ↑ Risk for pregnancy induced glucose intolerance (mechanism unclear and/or complex) ↑ Insulin requirements Initially pancreatic beta cells work overtime to keep up with the ↑ insulin demands Eventually insulin demands are not met due to the exhaustion of pancreatic beta cells Plasma glucose rises (Fasting plasma glucose ≥5.3 mmol/L) Gestational Diabetes (or exacerbation of pre-existing DM) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jan 28, 2017, updated Feb 24, 2024 on www.thecalgaryguide.com

Infectious Small Bowel Diarrhea

Infectious small bowel diarrhea: Pathogenesis and Signs/Symptoms Undercooked poultry, beef, pork, other foods Food, or travel to underdeveloped countries E. coli (ETEC) May produce Shiga toxins (a specific family of toxins that can lead to complications) Authors: Noriyah Al Awadhi Yan Yu Sara Cho Reviewers: Paul Ratti Jason Baserman Shahab Marzoughi Kerri Novak* * Indicates MD at time of publication Y. enterocolitica (also milk, cheese) Shellfish, undercooked seafood V. parahaemolyticus V. cholerae Enterohemorrhagic E. coli (EHEC) Daycare centers/nurseries Drinking/swimming in bad water — mountains/wells S. aureus B. cereus Noroviruses Rotavirus G. lamblia C. parvum May produce emetic toxins (toxins that cause vomiting) Adequate amount of organism and/or toxin is ingested Organism adheres to the intestinal liningàorganism colonizes the small intestine Organism releases enterotoxin (a toxin that affects the intestines) Binds to and disrupts intestinal transporters used in secretion and absorption of water and electrolytes Toxin enters systemic vasculature Shiga toxins inhibit ADAMTS13 (cleaving enzyme) Failure to cleave von Willebrand Factor (vWF) multimers Accumulation of vWF multimers Platelets and thrombi accumulate in microvasculature Hemolytic uremic syndrome (hemolytic anemia, thrombocytopenia, and acute renal damage) ↑ Water and electrolyte secretion ↓ Fluid absorption Chemoreceptor trigger zone in medulla detects circulating emetic toxins Nausea & vomiting Triggers release of inflammatory mediators and cytokines that travel to the central nervous system Prostaglandin is synthesized and released Neurotransmitter cyclic AMP (cAMP) is released cAMP ↑ hypothalamic thermoregulation set point Fever Large volume profuse diarrhea Loss of water Distention (swelling) of intestines stimulates visceral sensory pain fibers Visceral pain fibers crosstalk with somatic nerves from the same spinal cord level Occasional referred pain/cramping (typically diffuse pain around the abdomen) Loss of bicarbonate, sodium, potassium, magnesium, and chloride Dehydration Electrolyte deficiency Metabolic acidosis (pH < 7.4 & serum bicarbonate < 24) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Mar 25, 2024 on www.thecalgaryguide.com

Post-Renal Acute Kidney Injury AKI

Post-Renal Acute Kidney Injury (AKI): Pathogenesis and clinical findings Blood clot or cellular debris Foreign body Neurogenic bladder Obstruction intrinsic to urine excretion system Nephrolithiasis (kidney stones) Anatomical defect(s) Intra- abdominal adhesions Retroperitoneal fibrosis (scar-like tissue) Benign or malignant masses Prostate cancer Benign prostatic hyperplasia ↓ Urine flow across point of obstruction Obstruction extrinsic to urine excretion system Urine buildup distends urine collecting system (hydronephrosis) Compression of renal vasculature due to mass effect ↑ Volume/pressure proximal to obstruction ↑ Intratubular pressure ↓ Pressure gradient between glomerular afferent arteriole and Bowman’s space Casts occlude tubules ↓ Filtration of plasma into nephrons ↓ Glomerular Filtration Rate (GFR) Obstruction is relieved ↓ Intratubular pressure Rapid GFR ↑ Rapid diuresis of fluid and electrolytes Dilated pelvicalyceal system on ultrasound ↓ Urine output ↓ Venous drainage and arterial supply Local ischemia and inflammation of kidney Impaired resorption, excretion, and fine tuning by tubules Acute Tubular Necrosis (ATN) with granular casts ↓ Urine output ↓ Clearance of free water and solutes ↑ Intravascular volume ↑ Serum creatinine ↓ Medullary solute concentration, ischemia, ↓ response of collecting ducts to antidiuretic hormone Lasts > 24hrs Post-obstructive diuresis causes hypovolemia and electrolyte derangements Authors: David Campbell, Matthew Hobart Reviewers: Raafi Ali, Luiza Radu Huneza Nadeem, Marissa Zhang, Julian Midgley* * MD at time of publication Resolves < 24hrs in euvolemia Physiologic post- obstructive diuresis ↑ Na+ and Cl- delivery to distal convoluted tubule is sensed by macula densa Secretion of adenosine by macula densa Adenosine constricts afferent arterioles ↓ GFR ↓ Renal clearance of drugs and waste products ↑ Venous hydrostatic pressure ↑ Volume in arterial system overwhelms pressure regulation mechanisms Hypertension Fluid extravasation from veins and capillaries Generalized Edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Mar 25, 2024 on www.thecalgaryguide.com

Operative Vaginal Delivery Indications

Operative Vaginal Delivery (forceps/vacuum): Indications Authors: Taylor Pigott Akaya Blair Reviewers: Michelle J. Chen Sylvie Bowden* Stephanie Cooper* Sarah Glaze* * MD at time of publication Abnormal fetal heart rate/fetal distress ↓ Risk of maternal and fetal morbidity/ morality Rupture of membranes without fetal head adequately applied to maternal pelvis Small pelvic outlet Narrow vaginal canal Cardiovascular disease Diabetes Hypertension Abdominal trauma Short umbilical cord Large for gestational age (LGA) fetus Neurological/ muscular disease ↑ Pain during labor Maternal contraindication to Valsalva maneuver (e.g., cardiac disease, cystic lung) Rush of fluid past the fetal head out through cervix Umbilical cord prolapse Umbilical vasoconstriction Umbilical cord compression ↓ Blood flow through umbilical cord Fetal presenting part applies pressure on umbilical cord Impaired vascular function and narrowed vessels ↓ blood flow around the body ↓ Oxygen transfer across the placenta Fetal oxygen deprivation and hypoxia Operative vaginal delivery with forceps or vacuum expedites delivery Placenta partially or completely separates from uterine wall (abruption) Increased tension of umbilical cord on placenta Fetal shoulder is lodged behind maternal pubic symphysis Delivery of the body is delayed Inability to adequately bear down to push Myometrium runs out of energy from repeated contractions and becomes less able to contract (↓ uterine tone) Uterine spiral arteries dependent on contractions for vasoconstriction remain dilated, allowing blood flow Postpartum hemorrhage Uterine rupture ↑ Risk of future pelvic organ prolapse ↑ Risk of future incontinence Prolonged labour Repeated contraction/ relaxation of the uterus without progress tears and damages uterine muscles ↓ Maternal endurance Inadequate fluid and food intake prior to/ during labor Multiples ↑ Sympathetic nervous system activation during labor Maternal exhaustion Uterine muscles stretch to accommodate multiple growing fetuses ↑ Pushing against pelvic floor and perineum Pushing force damages pelvic floor muscles and nerves ↓ Myometrial contractility ↑ Need for vaginal exams to check on labour progress Bacterial overgrowth in vagina and/or uterus Maternal infection Fetal infection ↓ Strength of contractions Epidural anesthetic Inability to ambulate to urinate ↑ Urinary catheterizations ↑ Epinephrine secretion from adrenal cortex Blood is shunted away from uterus/internal organs and towards heart and skeletal muscle Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published 03, ##, 2023 on www.thecalgaryguide.com

Sickle Cell Disease Pathogenesis Clinical Findings and Complications

Sickle Cell Disease: Pathogenesis, Clinical Findings, and Complications DNA point mutation in chromosome 11 causes a substitution of glutamate to valine for the sixth amino acid of the β-globin chain Authors: Yang (Steven) Liu Priyanka Grewal Reviewers: Alexander Arnold Luiza Radu JoyAnne Krupa Yan Yu* Lynn Savoie* * MD at time of publication Hemoglobin S (HbS) variant formed instead of normal Hemoglobin A (HbA) Hb electrophoresis shows approximately 45% HbS, 52% HbA (ααββ), 2% HbA Hb electrophoresis shows approximately 90% HbS, 8% HbF, & 2% HbA . No HbA present (ααδδ), & 1% HbF (ααγγ;2 fetal hemoglobin) Heterozygous: point mutation in one of the two chromosomes (Hb AS) Sickle cell trait (asymptomatic unless severely hypoxic) Homozygous: point mutation in both chromosomes (Hb SS) Sickle cell disease An inherited blood disorder characterized by defective hemoglobin that leads to red blood cells sickling 2 Dehydration Hypoxemia Acidosis ↓ Volume of RBC cytoplasm ↓ O2 Saturation of Hb O morereadily 2 released from Hb in low pH environment ↑ Concentration of deoxygenated HbSinred blood cells (RBCs) Hydrophilic glutamate→ hydrophobic valine substitution makes HbS less soluble in the cytoplasm & more prone to polymerization & precipitation in its deoxygenated state ↑ Concentration of deoxygenated Hb in RBC leads to ↑ polymerization rate Polymerized & precipitated HbS forms long needle-like fibers RBC shape becomes sickled Sickle cells on peripheral blood smear Vaso-occlusion (sickled RBCs lodge in small vessels, blocking bloodflow to organs & tissues) Blockage of venous outflow Occlusion of vessels in lungs ↑ pulmonary blood pressure Fluid extravasates into interstitial tissue leading to pulmonary edema Acute chest syndrome (chest pain, hypoxemia (↓blood oxygen), etc.)** to the penis: to the spleen: Priapism (persistent, painful erection) Splenic Sequestration (blood pools in spleenà splenomegaly & hypotension) Extravascular hemolysis (macrophages in the spleen phagocytose sickled RBCs) Normocytic anemia ↑Marrow erythropoiesis (RBC production) to compensate for hemolysis Infarction of bone Pain crises If occurring in hands Dactylitis (inflammation of digits) Blockage of arteries ↓ oxygenation of organs & tissues Vaso-occlusion of the splenic artery Splenic infarction (↓ blood supply leads to tissue death) RBC inclusions (structures found in RBCs) not removed by spleen Howell-Jolly bodies (RBC DNA remnants) on blood smear Vaso-occlusion of other arteries (cranial, renal, etc) Stroke, renal failure ↑ RBC breakdown ↑ Unconjugated bilirubin released from RBC breakdown RBC precursors (reticulocytes) are released into the blood stream Reticulocytosis (increased number of immature red blood cells) on peripheral blood smear Patient’s RBC level becomes dependent on increased marrow activity Bone marrow infarction or viral infections (i.e. Parvovirus B19) suppresses bone marrow activity Aplastic crises (profound anemia) ** See corresponding Calgary Guide slide(s) ↑ Serum level of unconjugated bilirubin Some of the circulating unconjugated bilirubin deposits in the skin Jaundice (yellowing of skin) ↑ Conjugation of bilirubin in liver ↑Amounts of conjugated bilirubin released into bile Gallstone formation Cholelithiasis (presence of gallstones in the gallbladder) Spleen releases invasive encapsulated bacteria (eg. Haemophilus influenzae, Streptococcus pneumoniae, Neisseria meningitidis) into circulation, which causes infections Meningitis Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 16, 2013, updated Apr 29, 2024 on www.thecalgaryguide.com

Gynecomastia

Gynecomastia: Pathogenesis Authors: Sara Cho Reviewers: Michelle J. Chen Samuel Fineblit* *MD at time of publication Physiologic causes Puberty Placenta transfers maternal estrogens to newborn male babies Older age (>60 years) Hyperthyroidism Klinefelter Syndrome (males with > 1 X chromosome) Liver cirrhosis Certain tumors (e.g., germ cell, adrenal, Leydig cell, Sertoli cell) Anabolic steroid usage (containing testosterone) Finasteride (treatment for benign prostate hyperplasia and male pattern baldness) Cimetidine - inhibits stomach acid production Spironolactone (diuretic used to treat high blood pressure and heart failure) Ketoconazole (antifungal) Cytotoxic agents (e.g. alkylating agents, vincristine, methotrexate) Imbalance between estrogens and androgens Estrogen stimulates breast tissue growth in newborn Changes in metabolic rate ↑ fat production Unclear mechanism ↑ Proinflammatory mediators and cytokines (e.g. prostaglandin E2, TNF⍺, IL-1, IL-6, cyclooxygenase-2) Prostaglandin E2 and IL- 6 upregulate aromatase enzyme expression Available estrogen is higher than available testosterone ↑ Aromatase enzyme activity, converting androgens to estrogen ↓ Testosterone release from the testes ↓ Testosterone ↑ Serum sex hormone binding globulin (SHBG) SHBG binds estrogen with less affinity to testosterone Thyroid hormone stimulates liver to express more sex hormone binding globulin Thyroid hormone stimulates aromatase activity Overexpression of aromatase enzyme Seminiferous tubules in the testes hyalinize and fibrose Suppression of the hypothalamic pituitary thyroid axis through an unclear mechanism Tumor may produce estradiol Tumor produces β- human chorionic gonadotropin (β-HCG) ↑ serum testosterone Inhibits 5-α reductase Blocks binding of 5-DHT to androgen receptors ↓ 2-hydroxylation of estradiol Mimics structures of testosterone Inhibits 17,20 desmolase and 17α-hydroxylase Damage to Leydig cells in testes ↑ Estrogen to androgen ratio Pathological causes Impaired spermatogenesis and testosterone production ↓ GnRH secretion from hypothalamus ↓ Testosterone ↓ Luteinizing hormone (LH) release from anterior pituitary ↓ 5-DHT and/or testosterone binding to androgen receptors in chest tissue ↓ inhibition of breast development Normal or increased estrogen acts on estrogen receptor on chest tissue Estrogen receptors stimulate breast development Estradiol negatively feedbacks on luteinizing hormone β-HCG stimulates LH receptors on Leydig cells in the testes Aromatase enzyme converts excess testosterone into estrogen and estradiol ↓ conversion of testosterone to 5- dihydrotestosterone (5-DHT), a more potent form of testosterone Glandular proliferation in male breasts Gynecomastia (development of breast tissue in males) Drug side- effects ↓ Metabolism of estradiol Competitively binds to androgen receptors ↑ Serum estradiol levels Exhibits physical attributes that do not align with gender identity Psychological distress In some cases, hormones stabilize Involution and atrophy of ducts Gynecomastia resolves ↓ Steroid synthesis ↓ Androstenedione produced (testosterone precursors) ↓ Serum testosterone levels ↓ Testosterone production Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Jun 9, 2024 on www.thecalgaryguide.com

Anesthetic Considerations in Pregnancy

Anesthetic Considerations in Pregnancy: Pathophysiology driving anesthetic management Authors: Calah Myhre Reviewers: Jasleen Brar Luiza Radu Leyla Baghirzada* Yan Yu* * MD at time of publication Airway ↑ Estrogen serum levels Mucosal capillary engorgement ↑Airway tissue friability & edema ↑ Laryngoscopy difficulty & intubation time Secure airway & avoid hypoxemia Consider video laryngoscopy Preoxygenate with ↑100% oxygen Optimize intubation positioning (e.g. “Sniffing position”) ↑ Progesterone serum levels ↓ Esophageal tone & sphincter pressure ↑ Aspiration risk >20 weeks gestation & during labor Aspiration prophylaxis Rapid sequence induction Nonparticulate antacid prophylaxis (e.g., sodium citrate, famotidine) Pre-operative fasting & gastric ultrasound to assess volume Breathing ↑ Minute ventilation ↓ PaCO2 at baseline Uterine artery vasoconstriction with maternal PCO2 levels exceeding 32 mmHg Impaired uteroplacental perfusion Maintain physiologic alkalosis, avoid maternal hypercapnia Maintain maternal arterial PCO2 28–32 mmHg Avoid permissive hypercapnia ↑ Progesterone serum levels Disproportionate ↑ in plasma volume ↓ Serum colloid osmotic pressure Drug-specific alterations in absorption, distribution, metabolism & excretion (e.g. ↑ distribution of acidic drugs due to ↓ albumin; ↑ clearance of renally- metabolized drugs) Optimize anesthetic dosing for altered pharmacokinetics Adjust dosages based on drug recommendations Circulation ↑ Maternal blood volume Peripheral vasodilation ↓In systemic vascular resistance by 25–30% ↓ Blood pressure ↑Abdominal pressure Compression of the aorta & inferior vena cava Supine hypotension Impaired uteroplacental perfusion Fetal ischemia Optimize placental blood flow Position patient on left side to maintain uterine displacement Diaphragmatic elevation & lung compression ↓ Functional residual capacity ↑ Risk of rapid desaturation Fetal hypoxemia Maintain maternal & fetal oxygenation Optimize positioning (e.g., patient on left side to maintain uterine displacement) & supplement oxygen as needed Heart rate ↑ 15-25% ↑ Cardiac output Manifestations of significant blood loss are delayed Avoid hypotension ↑ Stroke volume Avoid fluid overload Treat abnormal variation in blood pressure at lower values Fetus Requirement to assess & treat two patients Achieve optimal anesthetic dosing for mother while maintaining fetus safety Maintain oxygenation of both mother & fetus & ensure adequate uteroplacental perfusion Consider fetal-drug transfer & adjust agent & dose accordingly Monitor maternal vital sign & fetal heart rate Utilize a multidisciplinary team (e.g., pharmacy, nursing, physical & occupational therapy) Legend: Pathophysiology Mechanism Goal Management Published July 5, 2024 on www.thecalgaryguide.com

Diabetes Mellitus Pathophysiology Behind Lab Findings

Diabetes Mellitus: Pathophysiology behind laboratory findings Author: Nathan Archibald Reviewers: Gurreet Bhandal, Julia Gospodinov, Luiza Radu Samuel Fineblit* * MD at time of publication ↓ Transit of glucose transporter GLUT4 to cell surface (mainly adipose & muscle cells) ↓ Glucose uptake into cells Autoimmune destruction of pancreatic beta cells (type 1 diabetes mellitus) Insulin resistance (type 2 diabetes mellitus) Other causes of diabetes mellitus (genetic, drug- induced, pregnancy, etc.) ↑ Lipolysis (fat breakdown) in adipose tissue ↑ Free fatty acids & glycerol in bloodstream ↑ Oxidation of fatty acids in liver to form acetyl CoA ↑ Conversion of acetyl CoA to ketone bodies (ketogenesis) to be used as fuel for the brain Relative or absolute insulin deficiency ↓ Activation of adipose (fat tissue) & muscle cell transmembrane insulin receptors ↓ Activation of intracellular insulin signaling pathways (PI3K & MAP kinase) Cells cannot use glucose as a source of energy; thus body reacts as if it is starving ↑ Protein breakdown in muscle tissue ↑ Amino acids & lactate in bloodstream ↑ Substrates (glycerol, amino acids & lactate) available to produce glucose in the liver ↑ Glycogenolysis (breakdown of stored glucose - glycogen) & gluconeogenesis (production of glucose) in liver Glucose in bloodstream glycates (coats) hemoglobin in red blood cells; thus ↑ blood glucose leads to ↑ glycated hemoglobin ↑ Hemoglobin A1C ↑ Fasting blood glucose level ↑ Random blood glucose level ↑ Blood glucose following oral glucose tolerance test Diabetic ketoacidosis (DKA) in absolute insulin deficiency *See DKA slide Filtered ketone bodies exceed the reabsorption capacity of renal tubules Ketonuria (↑ ketones in urine) ↑ Glucose in bloodstream Build-up of glycation end products causes damage to glomerular tissue Transient glomerular hyperfiltration followed by long-term ↓ in glomerular filtration rate Albuminuria (↑ albumin in urine) Diabetic nephropathy *See slide Filtered glucose exceeds reabsorption capacity of renal tubules in the kidney Glucosuria (↑ glucose in urine) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 8, 2024 on www.thecalgaryguide.com

Neonatal Hypoglycemia Pathogenesis

Neonatal Hypoglycemia: Pathogenesis Normal physiology Placenta supplies fetal circulation with glucose Clamping of the umbilical cord stops the source of glucose Blood glucose level declines rapidly in the first 2-3 hours of life Low glucose causes an ↓ in insulin and an ↑ in epinephrine, cortisol and glucagon Glucagon and epinephrine act on receptors in the liver and skeletal muscle to promote gluconeogenesis (glucose production from non- carbohydrate sources), glycogenolysis (breakdown of glycogen into glucose), and fatty acid oxidation (conversation of fatty acids to ATP) Low glucose levels stimulate the neonate’s appetite, allowing them to adapt to intermittent feeds Infant feeding regularly on a diet with sufficient carbohydrates creates a consistent plasma glucose concentration Pregnant Parent Causes Impaired Glucose Production Inadequate Glucose Supply Pregnant parent using β-blockers β-blockers prevent epinephrine from binding to adrenergic receptors in skeletal muscle and liver Blocked sympathetic signaling in these organs prevents glycogenolysis ↓ Breakdown of glycogen into glucose Infant of a parent with diabetes Parent has a high level of glucose in their blood The fetus receives a glucose-rich blood supply Fetal pancreatic β cells ↑ insulin production Post-birth, glucose levels in the infant’s circulation ↓ but insulin levels remain high Excessive glucose uptake into cells Fetus born with a metabolism disorder (e.g. organic amino acid disorder, disorder of glycogen metabolism, disorder of gluconeogenesis) Genes that make proteins or hormones responsible for production, breakdown and regulation of glycogen are mutated Fetus born with an endocrine disorder (e.g. congenital adrenal hyperplasia, hypopituitarism, Turner Syndrome) Pituitary and/or adrenal gland dysfunction ↓ release of hormones that regulate glucose balance Fetal growth is restricted, fetus is small for gestational age, or is premature (<37 weeks gestation) Glycogen is deposited during the 3rd trimester of pregnancy. Infants born early have fewer stores; smaller infants born at term have ↓ stores, ↑ insulin sensitivity, & poorly coordinated counter- regulatory hormones ↑ Glucose demand for the transition to life out of the womb Glycogen stores used up quickly Perinatal stress (e.g. sepsis, asphyxia) Stress stimulates fetal adrenal glands to ↑ epinephrine secretion Fetal pancreatic ⍺- cells ↑ glucagon secretion ↑ Breakdown of muscles and fat for glucose- building blocks Glycogen stores used up quickly ↑ Glucose usage as fetal metabolic demands ↑ to manage stress Fetal β-cells secrete inappropriately high levels of insulin despite hypoglycemic state; this hyperinsulinism state can last for months & resolve spontaneously ↓ Serum glucose Neonatal hypoglycemia Authors: Dasha Mori Reviewers: Michelle J. Chen *Dr. Danielle Nelson *MD at time of publication Blood glucose < 2.6 mmol/L in term & preterm infants within 72 hours of birth or < 3.3 mmol/L after 72 hours of birth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2024 on www.thecalgaryguide.com

Generalized Anxiety Disorder GAD

Generalized Anxiety Disorder (GAD): Pathogenesis and clinical findings Authors: Keira Britto Reviewers: Sara Cho, Luiza Radu, *Margaret Oakander *MD at time of publication Altered cognition Scan environment for perceived threats Genetic predisposition & family history: polygenic, >30% heritability Adverse childhood & life experiences: e.g., abuse, neglect, divorce, bereavement Morbidity & stressors from chronic medical conditions Hypersensitivity & reactivity to stimuli áHPA axis activity Neurobiological differences Trait neuroticism (emotional instability & nervousness) Reacts to unfamiliarity with withdrawal & fear áLevel of uninhibited excitatory signaling Psychomotor agitation Frequent sympathetic nervous system (fight or flight) activation to perceived threats Cycles of epinephrine surges Inadequate recovery State of hyperarousal Disturbed sleep Ongoing sleep deprivation Easily fatigable áACTH released from hypothalamus áCortisol released from adrenal glands áSerotonin uptake âSerotonin Impaired neuroplasticity &âcomplexity of synaptic connections in amygdala & hippocampus âAbility to deal with emotional stressors Impaired engagement of prefrontal cortex âRegulation of emotional reactions áAnticipatory emotional responses âInhibition from GABA áAmygdala volume & activity áFear & anxiety circuits Attentional focus directed towards worries & perceived threats Divert blood to muscles Skeletal muscle activation Muscle tension Psychomotor agitation (excessive motor activity associated with a feeling of inner tension) áEmotional intensity Chronic state of high physiological stress âHippocampal BDNF (brain derived neurotrophic factor) Hippocampal atrophy &â hippocampal neurogenesis â Inhibitory control of the hippocampus over the HPA axis áAlertness & wakefulness Disturbed sleep Strengthening of memories rooted in fear, to prevent encounters with future threats Behavioural & cognitive changes to facilitate coping with threats Irritability **Excessive, persistent Bottom up, stimulus driven attention áDistractibility Difficulty concentrating anxiety & worry that is distressing &/or impairs functioning Irritability Generalized Anxiety Disorder: **occurring more days than not for ≥ 6 months; **difficult to control; presence of ≥ 3 remaining symptoms Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 21, 2024 on www.thecalgaryguide.com

Underfill Edema Pathogenesis

Underfill Edema: Pathogenesis Acute respiratory Sepsis, burns, distress syndrome, trauma anaphylaxis ↑ Inflammatory mediators Gaps form between epithelial cells lining blood vessels ↑ Capillary permeability Fluid extravasation into interstitial space Blood backing up in vena cava ↑ capillary hydrostatic pressure in venous system Pressure creates net fluid movement from vascular space into interstitial space Authors: Matthew Hobart Richard Chan Nojan Mannani Michelle J. Chen Reviewers: Raafi Ali Varun Suresh Saif Zahir Andrew Wade* Adam Bass* * MD at time of publication Nephrotic syndrome ↑ Renal albumin loss Scarring of liver tissue (cirrhosis) Vasodilatory medications Various mechanisms Right-sided heart failure Compromised right heart function ↓ forward flow ↓ Hepatic albumin synthesis Blood is unable to pass through hepatic vessels disrupted by cirrhosis and backs up in portal vein ↑ Blood pressure in portal vein (portal hypertension) Less blood volume in hepatic veins and vena cava (underfilling) Pregnancy ↑ Estrogen, progesterone and relaxin Vasodilation Gravity causes fluid accumulation in peripheral veins ↑ Capillary hydrostatic pressure ↑ Net fluid movement into interstitial space ↓ Serum albumin ↓ Capillary oncotic pressure Fluid extravasation into interstitial space More blood in portal vein ↑ capillary hydrostatic pressure in venous system Pressure creates net fluid movement from vascular space into interstitial space Less blood volume in arteries (underfilling) ↓ Effective arterial blood volume (EABV) ↓ Renal blood flow activates the renin-angiotensin-aldosterone system (RAAS) Angiotensin and aldosterone ↑ Anti-diuretic hormone released by tubular Na+ and H2O resorption posterior pituitary ↑ H2O resorption ↑ Fluid in circulation, worsening existing venous congestion ↑ Hydrostatic capillary pressure and fluid extravasation into interstitial space Underfill edema (edema worsened by activation of RAAS) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 19, 2015; updated Aug 5, 2024 on www.thecalgaryguide.com

IgA Nephropathy

IgA Nephropathy: Pathogenesis & clinical findings Authors: David Campbell Matthew Hobart Reviewers: Huneza Nadeem Raafi Ali Ran Zhang Luiza Radu Julian Midgley* * MD at time of publication Galactose-deficient IgA1 (GD- IgA1) created by mucosa- bound IgA1 plasma cells is secreted into plasma instead of onto mucosal surface IgA1 plasma cells hyper- responsive to triggers (eg. URTIs, gastroenteritis) ↑ synthesis of GD-IgA1 → spill-over into plasma Immunoglobulin A1 (IgA1) plasma cells destined to reside in mucosa (eg. gut or respiratory tract) travel to and reside in inappropriate site(s) (eg. bone marrow) releasing GD-IgA1 into plasma GD-IgA1 is not cleared from plasma as quickly as IgA1 → ↑ plasma GD-IgA1 levels Hit 3: GD-IgA1-IgG complexes deposit in mesangium C3 predominant complement activation amplifies inflammatory response Renal biopsy: IgA deposits in mesangium (100% sensitive) Renal biopsy: Complement in mesangium (C3 predominant) (90-95% sensitive) A cascade of multiple immunologic hits is initiated Hit 1: ↑ Serum levels of GD-IgA1 multiple immunologic hits GD-IgA1 hinge region is structurally distinct from IgA1 that would normally circulate in plasma (lack of galactosyl groups) GD-IgA1 hinge region may mimic pathogens (ex. bacteria and viruses) or other antigens Cross reactivity of IgG against GD-IgA1, or synthesis of anti-GD-IgA1 IgG antibodies Immunoglobulin G (IgG) binds GD-IgA1 hinge region Hit 2: GD-IgA1-IgG immune complex formation Circulating GD-IgA1-IgG complexes have high affinity for glomerular endothelial cells where they damage the glycocalyx → ↑ permeability of immunoglobulins into the mesangium ↑ Production of chemokines, cytokines and complement → ↑ mesangial cell proliferation and matrix expansion Leukocyte recruitment and activation damages glomerulus and mesangium Hit 4: Inflammatory response to GD-IgA1 complexes in mesangium induce glomerular structure disruption (endothelium, basement membrane, podocytes, mesangium) and impaired glomerular function Loss of barrier functions of glomerulus allows for extravasation of blood & proteins into Bowman’s space and subsequently through tubules Renal biopsy: Glomerulosclerosis, tubulointerstitial fibrosis, glomerular vasculitis, podocyte damage Eventual end-Stage Renal Disease (ESRD) Progressive ↓ of filtration surface area within glomeruli and ↓ number of functional glomeruli Proteinuria Synpharyngitic hematuria (hematuria with dysmorphic red cells co-occurring with pharyngitis) ↓ Glomerular Filtration Rate (GFR) Nephrotic Syndrome ↑ Serum creatinine Chronic kidney disease and eventually ESRD IgAN is an autoimmune disease where IgA deposition in the glomerulus leads to an inflammatory cascade, endothelial dysfunction and mesangial expansion that damages glomeruli causing kidneys to leak blood and protein into urine and decreased kidney function. IgA nephropathy is a multifactorial disease requiring multiple immunologic hits IgA Nephropathy (IgAN) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Sept 5, 2024 on www.thecalgaryguide.com