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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

Bronchogenic Carcinoma - Pancoast Tumors Pathogenesis and clinical findings

Bronchogenic Carcinoma - Pancoast Tumors Pathogenesis and clinical findings Abbreviations: • NSCLC- Non Small Cell Lung Cancer • SCLC — Small Cell Lung Cancer • RLN — Recurrent Laryngeal Nerve • SVC — Superior Vena Cava • RA — Right Atrium • STM — Superior Tarsal Muscle Chest pain Pleural rubs Shoulder pain SCLC (less common) Endothoracic fascia 1— Parietal pleura • 1— Upper ribs Large Cell Carcinoma Adenocarcinoma Squamous Cell Carcinoma Primary Bronchogenic Carcinoma Pancoast tumor: Local/metastatic growth in ipsilateral lung apex Disruption of structures adjacent to superior pulmonary sulcus NSCLC (more common) Invasion of airways ► causing obstruction (later stages) Author: Bradley Stebner Daniel Meyers Midas (Kening) Kang Reviewers: Natalie Morgunov Sadie Kutz Usama Malik Kerri Johannson* *MD at time of publication Notes: • Pancoast Tumor: Malignant lesion occupying the superior pulmonary sulcus (lung apex) Bronchogenic carcinoma: primary malignant neoplasm arising from epithelium of bronchus or bronchiole Pancoast tumors can be caused by primary or metastatic pulmonary neoplasms (described here) as well as infectious foci Hemoptysis Compression of C8 and T1 nerves • Disruption of paravertebral sympathetic chain Shoulder • Weakness in intrinsic Horner's • 4, sympathetic to to iris muscle Syndrome 4, sympathetic radial to eccrine sweat gland Pain (ulnar hand muscles nerve) 4, sympathetic innervation STM Paresthesia in 4th /5th digits and arm/forearm medial Ptosis Mi o sis Anhidrosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Compression of SVC SVC Syndrome • 4, venous return to RA 4, Cardiac output to lungs Dyspnea Disruption of RLN 1 Hoarse voice 4, venous drainage from upper thoracic cavity Retention of fluid in upper limb •)r Facial and limb swelling

Hyperthyroidism

Primary Hyperthyroidism: Pathogenesis and clinical findings Abbreviation: TH — Thyroid hormones RAAS— Renin-angiotensin-aldosterone system TSH — Thyroid stimulating hormone '`Stimulating TSH receptor antibodies Graves Disease Toxic adenoma and/or multinodular goiter 1123 De Novo 4— synthesis of TH uptake Persistent 4, TSH Proptosis T3/T4 Lid retraction Conjunctivitis t osmotic pressure behind eyes Pretibial myxedema Tachycardia Palpitations Bruit over thyroid 4, exercise tolerance t cardiac output Legend: Pathophysiology Mechanism t local synthesis of glycosaminoglycan hyaluronic acid in dermis and subcutis TH production independent of TSH Acute thyroidits Damage to thyroid follicular cells Y Primary Hyperthyroidism 4 RAAS activation • erythropoietin synthesis Sign/Symptom/Lab Finding Release of stored TH t sympathetic stimulation T sweating thermogenesis Viral infection Authors: David Deng Reviewers: Amyna Fidai Hamna Tariq Joseph Tropiano Karin Winston* * MD at time of publication 4, 1123 uptake Transient 4, TSH T3/T4 Gut hypermotlity --* CNS overstimulation Diarrhea, t bowel movement t weight loss Heat intolerance t appetite Nervousness Hyperkinesia Hyperreflexia Tremor Poor attention Note: Although rare, gestational diseases can lead to thyrotoxicosis due to excess secretion of hCG, which is structurally similar to TSH. Secondary hyperthyroidism due to excess TSH production by the pituitary can also occur. Complications I Published MONTH, DAY, YEAR on www.thecalgaryguide.com 0 GS' I 4;

Orbital Cellulitis: Pathogenesis and clinical findings

Orbital Cellulitis: Pathogenesis and clinical findings Authors: Amanda Marchak Reviewers: Jaimie Bird Dr. Rupesh Chawla* * MD at time of publication Staphylococcus aureus, Streptococcus pyogenes Note: Orbital cellulitis is an extremely serious infection. If not caught and treated early, it can lead to death. CT should be performed if suspected. Involves the orbit Panopthalmitisb Endopthalmitisc Blindness Streptococcus pneumoniae, Moraxella catarrhalis, Haemophilus influenza Local infection or break in skin Eye surgery or trauma Direct inoculation Sinusitis (more common) Periorbital cellulitis1,2 Hematogenous spread Contiguous spread of infection Pathogens reach orbital tissue (posterior to the orbital septum) Spreads to periorbital tissue (anterior to the orbital septum) Localized inflammation Conjunctival chemosisa Eyelid and periorbital edema Pain on palpation Induration Warmth Orbital Cellulitis Inflammation of orbital tissue Proptosis Spreads to surrounding structures Subperiosteal abscess Brain abscess Cavernous sinus thrombosis Meningitis Subdural empyema Orbital abscess Notes: Impinges on ocular muscles Impaired extra- ocular movements Pain with eye movement or opthalmoplegia Definitions: Impinges on nerves Afferent pupillary defect Decreased visual acuity Exposes cornea Corneal drying and scarring a. Chemosis: Edema of the bulbar conjunctiva b. Panopthalmitis: inflammation of all coats of the eye including intraocular structures. c. Endopthalmitis: inflammation of the interior of the eye. 1. See slide on Periorbital Cellulitis for how sinusitis can lead to the development of periorbital cellulitis 2. The micro-organism responsible for periorbital cellulitis varies depending on how the pathogen was introduced to the system. Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 5, 2018 on www.thecalgaryguide.com

Primary Myelofibrosis pathogenesis and clinical findings

Primary Myelofibrosis: Pathogenesis and clinical findings Legend: Published March 30, 2019 on www.Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications thecalgaryguide.com Author: Tony Gu Reviewers: Naman Siddique Sonia Cerquozzi* Man-Chiu Poon* * MD at time of publication Definitions: Constitutive activation – Constant expression of gene Extramedullary hematopoeisis – red blood cell production outside of bone marrow Somatic mutations in genes that drive cancerous replication (e.g., JAK2, CALR, MPL) within hematopoietic stem cells Non-driver mutations in other myeloid genes (e.g., LNK, CBL, TET2, ASXL1, IDH) Constitutive activation of cellular proliferation pathways ↑ cell signaling ↑ gene transcription and expression Cellular proliferation and resistance to apoptosis Proliferation of abnormal megakaryocytes ↑ neutrophil engulfment by megakaryocytes ↑ growth factor release by megakaryocytes Stimulation of fibroblasts Stimulation of endothelial cells New blood vessel formation ↑ osteoprotegerin Unbalanced osteoblast proliferation Osteosclerosis Fibrosis of the bone marrow Anemia Bleeding and bruising Infections Fatigue and pallor Bone pain Increased cell turnover Tumor lysis syndrome Cachexia, night sweats, fever/chills, malaise Expanding marrow pushing against bone Extramedullary hematopoiesis Hepatomegaly Portal hypertension Splenomegaly ↑ LDH Thrombocytosis Leukocytosis Secretion of coagulation inducing cytokines Arterial and venous thromboembolism ↓ blood cell production & leukoerythroblastosis Thrombocytopenia Leukopenia ↑ K+, PO4 2-, uric acid ↓ Ca2+ Bone pain Periostitis Immature granulocyte and erythroid precursors with blasts ↑ cytokine production (+) ↑ sequestration of blood cells Disseminated intervascular coagulation (see MAHA slide) Definitions: Periostitis – Inflammation of the membrane surrounding bone Osteosclerosis – Abnormal hardening and increased in density of bone

Crohn's Disease

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

Ulcerative Colitis

Inflammatory Bowel Disease: Clinical Findings in Ulcerative Colitis Authors: Yan Yu Amy Maghera Reviewers: Jennifer Au Danny Guo Jason Baserman Crystal Liu Danielle Chang Kerri Novak* * MD at time of initial publication Inflammation is systemic, affecting: Environmental Factors Diet, bacteria/viruses, drugs Genetic Susceptibility Behavioral Factors: In UC, smoking and appendectomy are actually protective (unknown reason) Immune response against the GI tract. (Unclear mechanism, but thought to be mediated by cytokine release and neutrophil infiltration) Inflammation of the GI tract epithelial lining - Starting at the rectum and moves up the colon and is continuous (does not invade the small intestine) - Inflammation affects the mucosal and submucosal only Diarrhea, abdo pain and cramping causing avoidance of food Weight loss Apoptosis of GI tract mucosa Transporter proteins responsible for Na+ reabsorption gradually disappear from the epithelium Ulceration, into the anus, and more severe Prolonged Bleeding - GI and anus Anemia, often iron deficiency Inflammation ↑ permeability of the blood vessels supplying the GI tract wall Fluid leak out of capillaries into GI tract wall, causes edema and swelling Swelling narrows the GI tract lumen, causing bowel obstruction Inflammation, ulceration, or infection at the anus (all involve the RECTUM!) Anal irritation stimulates autonomic and somatic nerves leading up to the brain, causing the pt to want to defecate Tenesmus, urgency, frequency (feeling or urgency to defecate, but little stool is produced) Joints Skin Arthroplasty/ joint pain Erythema nodosum, pyoderma gangrenosum Mouth >5 canker sores More sodium (and thus water) is retained in the GI tract lumen Bloody Diarrhea, usually bloody due to anal bleeding and ulceration bleeding Abdominal Cramping and pain (see Bowel Obstruction page for full mechanism) Eyes (uvea, iris, sclera) Liver Blood Uveitis Iritis, scleritis Sclerosing Cholangitis Autoimmune hemolytic anemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published May 5, 2019 on www.thecalgaryguide.com

Ataxia Telangiectasia Pathogenesis and Clinical Findings

Ataxia-telangiectasia: Pathogenesis and clinical findings Genetics: Autosomal Recessive, with a defect on gene region 22 and 23 on Chromosome 11q Authors: Merna Adly Reviewers: Kara Hawker Crystal Liu Yan Yu* Laurie Parsons* * MD at time of publication Truncation and loss of the ATM protein, a serine/threonine protein Kinase Impaired ability to phosphorylate ATM, a key protein involved in the activation of the DNA damage checkpoint Impaired DNA damage and apoptosis signals Impaired ATM concentration ability at DNA damaged sites Failure to activate apoptosis in specific neural regions Genomically-damaged cells incorporated into the developing nervous system Progressive spinocerebellar granular neural cell damage and Purkinje Cell degeneration Cerebellar Ataxia (at 12-18 months); involuntary muscle contractions, hypotonia, IQ decline, and abnormal eye movement Loss of ATM leads to mitotic defects and arrest in gamete genetic recombination process Gonadal dysgenesis and delayed puberty DNA damage to tumor suppressors such as p53 and BRCA1 Impaired signaling of downstream cell cycle regulators Impaired genome stability and increased disposition to cancer ↑ Acute Lymphocytic Leukemia of T cell origin (in children) and Chronic Lymphoblastic Leukemia (in adults) Impaired recombination of DNA in immune cells Thymic hypoplasia; humoral & cellular immunodeficiency ↓ or absent functional immunoglobulins IgA, IgE, and IgG2 that function to prevent respiratory infections Respiratory infections with bronchiectasis and pneumonia Cells less able to undergo apoptosis in response to ionizing radiation Accumulation of DNA defects in the cells of sun exposed areas such as skin, hair, and conjunctiva Mucocutaneous telangiectasia on the bulbar conjunctiva and ears between 2-6 years of age May progress to involve periorbital skin, trunk, extremities, body folds, and other mucosal surfaces Sterility DNA damage and genomic instability Premature melanocyte stem cell differentiation Premature graying of skin and hair Abbreviations: • ATM – Ataxia-telangiectasia mutated protein • p53 – Tumor protein 53 • BRCA 1 – Breast cancer susceptibility protein. • IgA, IgE, IgG2 – Immunoglobulins Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 4, 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

Pathophysiology-Behind-the-Leukemias

Pathophysiology Behind the Leukemias Authors: Yan Yu, Katie Lin Reviewers: Jennifer Au Merna Adly Crystal Liu Lynn Savoie* * MD at time of publication Point Mutation (in DNA) Chromosomal Abnormality (duplication, loss, recombination error) Combinations of these genetic defects causes reduced tumor suppressor gene expression and/or increased oncogene expression Initiating Mutational Event ALL Any combination of mutations, chromosomal alterations, or other genetic abnormalities that creates a neoplastic cell (incapable of regulating cell growth/division). AML CLL CML Translocation between Chr 9 and Chr 22à Philadelphia chromosome ( abnormal Chr 22) àBCR-ABL1 oncogene (along with other genetic abnormalities) • In White Blood Cells and their precursors: Lack of cell growth inhibition and / or apoptosis. • Over stimulation of cell division/growth Neoplastic blood cell incapable of regulated cell division Neoplastic cells uncontrollably divide in a monoclonal way: one neoplastic cell originates all successive cells Genes regulating differentiation/maturation disrupted, affected neoplastic cells are incapable of further differentiation/maturation Genes regulating maturation remain intact (affected neoplastic cell is capable of further differentiation/maturation) Some neoplastic cells take time to mature furtheràless rapid disease progression (more indolent disease); cells don’t die CLL: Chronic Lymphoid Leukemia Note: Although it is tempting to group the leukemias together for study purposes, it is best to learn the 4 main types of leukemias independently of one another, as they have a uniquely different pathophysiology and clinical presentation Specific mutations cause slower disease progression CML: Chronic Myeloid Leukemia Degeneration during CML’s ”blast crisis” Specific mutations cause rapid division and buildup of existing neoplastic cells àAcute/rapid disease progression. ALL: Acute Lymphoblastic Leukemia AML: Acute Myeloid Leukemia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Re-Published January 19, 2020 on www.thecalgaryguide.com

Marfan-Syndrome

Marfan Syndrome: Pathogenesis and Clinical Findings Inherited or acquired mutation in TGFBR1/2 gene (TGF-β receptor) Dural ectasia (widening of the dural sac) Diminished and disorganized dural elastic fibres Abnormalities in connective tissues Tear in the aortic intima (innermost layer of aorta) Aortic dissection Type A (tear in ascending aorta) > Type B (tear in descending aorta) Back pain Sensory and motor deficits Ectopia lentis (lens dislocation) Development of lung bullae and blebs Rupture of bullae/blebs Pneumothorax ** Abnormal properties of lens + cornea ** Scoliosis ** Myopia Tall stature Chest wall (pectus) Inherited (autosomal dominant) or de novo mutation in FBN1 gene Distortion of neural roots Thinning of ciliary zonules of the eye Weakness and rupture of alveolar tissue Production of aberrant or reduced fibrillin-1 Formation of unstable microfibrils in extracellular matrix of connective tissues ** inactivate TGF-β1 ↑ production of matrix metalloproteinases ↑ cellular signaling cascades ↑ production of growth factors in the endocardium Cell proliferation and apoptosis suppression in mitral valve leaflets Change in valvular architecture Mitral prolapse Mitral regurgitation ↑ degradation of extracellular matrix Thinning of the aortic media Weakness of the aortic wall Inability of fibrillin- 1 to sequester and ↑ TGF-β1 signalling Abbreviations • TGF-β: Transforming growth factor beta (a cytokine) Notes **The underlying mechanisms are unclear Authors: Tony Gu Reviewers: Amanda Nguyen Davis Maclean Yan Yu* Michelle Keir* * MD at time of publication Aortic root dilation Aortic valve leaflets stretched outwards, unable to fully close Aortic regurgitation Aneurysmal dilation of the abdominal & thoracic aorta Aortic rupture Stroke Blood enters and pressurizes a ‘false lumen’ Obstruction of aortic branches End organ malperfusion ** deformities ** Joint hypermobility Thumb sign: Thumb tip extends from palm of hand when thumb is folded into closed wrist Wrist sign: thumb and fifth finger of the hand overlap when grasping opposite wrist Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published June 28, 2020 on www.thecalgaryguide.com

Avascular-necrosis-of-the-femoral-head

Avascular Necrosis (AVN) of the Femoral Head: Findings on X-Ray Blood supply to the subchondral bone is disrupted (for full pathogenesis, see Calgary Guide slide Avascular Necrosis: Pathogenesis and clinical findings) Hypoxia at boneàOsteocyte (primary bone cell) apoptosis Authors: Daniel Cusano, Evan Allarie, Reviewers: Yan Yu* Davis Maclean, Shelley Spaner* *MD at time of publication ↓ local osteoprotegerin (OPG) production OPG acts to 1) inhibit osteoclast formation, & 2) bind and sequester RANKL, a chemical that stimulates osteoclast activation & proliferation ↓ OPGà↑ osteoclast activation & proliferationà↑ bone resorption Areas that absorb ↑ X-ray radiation appear brighter on X-ray RANKL - Receptor activator of nuclear factor kappa-Β ligand Basic X-Ray Physiology Bone absorbs more X-ray radiation than other tissues in the body (e.g fat and muscle) Areas of ↓ bone density are darker: described as (radio)lucency on X-ray Areas of ↑ bone density are whiter: described as sclerotic on X-ray Image Credit: Alberta Health Services Repository ↓ Production of vascular endothelial growth factor (VEGF), which normally maintains & builds healthy bone & vasculature (via a multifactorial process) Osteopenia: generalized ↓ in bone density, visualized as ↑ radiolucency (darkness) of bone Bone demineralization and collagen matrix destruction Scattered Cysts: radiolucent areas of resorbed bone The femoral head’s trabecular bone is normally more porous (less dense) than the overlying cortical boneàosteopenia affects trabecular bone first, structurally weakening the femoral head Osteoclast activity, and a shift in the balance of multiple cell signaling factorsàcompensatory activation of osteoblasts (bone forming cells) Altered femur structure changes associated joint alignments (e.g. in hip, knee) Repetitive microtrauma and abnormal frictional forces in affected joints Degenerative arthritis: joint space narrowing, osteophytes, acetabular degeneration (late, chronic findings not pictured here) For examples, see Calgary Guide slide Osteoarthritis (OA): X-Ray Findings Fracturing of trabecular bone underneath the cortical bone of the femoral head Fracture creates a curved space between subchondral trabecular bone and overlying subchondral cortical bone Continued net resorption of bone & subcortical fracturingà overlying cortical bone collapses Flattening of femoral head (late, chronic finding; not pictured here) Deposition of collagen matrix and bone re-mineralization Patchy Sclerosis Dense (white) areas of bone deposition Crescent Sign Subcortical lucency indicative of fracture there (atypical outside of instances of avascular necrosis) • X-ray provides a fast and inexpensive imaging modality compared to MRI, however X-ray sensitivity varies from 41- 71% and is best suited to detect more advanced disease • MRI sensitivity is higher at 71-100% across different studies, with the added benefit of being able to detect internal bone changes earlier than X-ray Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 26, 2021 on www.thecalgaryguide.com

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

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

Corneal-Abrasion

Corneal Abrasion: Pathogenesis and clinical findings Mechanical Trauma / Foreign Body (fingernail scratch, dust, sand, debris in eyelid) Trichiasis (Misdirected eyelashes directly abrading the ocular surface) ↓ tear production (See Calgary Guide - Dry eye pathogenesis) ↓ quantity or quality of tear film Any condition causing incomplete or inadequate eyelid closureà↑ exposure of eye surface to atmosphere (Bell’s palsy, proptosis/ exophthalmos) ↑ Tear evaporation ↓ lubrication of eye surface Dryness and desiccative damage to ocular surface structures ↓ protective barriers against mechanical or foreign body damage Infection of epithelial defect by pathogens Damage deepens to inner layers of the cornea Immune response causes white blood cells to accumulate Pathogen and immune cells obstruct blood flow, causing tissue necrosis Infectious corneal ulcer Any condition affecting the trigeminal nerve and/or peripheral corneal nerves (e.g. Herpes zoster/simplex infection, diabetes, medications, surgery) Tight lens ↓ O2 reaching cornea Corneal epithelium hypoxiaà cellular damage Contact Lens use Extended use Lens dehydrates Corneal epithelium adheres to lens and is removed with the lens Neurotrophic keratopathy (corneal damage secondary to loss of innervation) ↓ stimulation of the cornea by neurotransmitters (complex and multifactorial) ↓ Blinking (if bilateral) Area of defect stained bright green under cobalt-blue filtered light Impaired sensory innervation of the corneaàImpaired Reflex Tearing ↓ adhesion between corneal epithelium and Bowman’s layer Trauma from insertion or removal of contact lens Previous traumatic abrasion with damage to Bowman’s layer or inadequate epithelial adherence (e.g. corneal dystrophy) Spontaneous erosion (occurs without antecedent injury or foreign body) ↓ structural integrity of corneal epithelium Fluorescein dyes the exposed Bowman’s layer (inner corneal layer between epithelium and stroma) Corneal Epithelial Damage (the transparent portion of the eye that covers the anterior portion of the eye and covers the pupil iris and anterior chamber) Corneal Abrasion: Focal area of epithelial loss - outermost layer of cornea (damage may extend to the bowman's layer below as well) Abrasions that overlay the pupil Epithelium (outermost portion on cornea) Bowman’s layer Stroma Descemet’s membrane Endothelium Cornea (cross section) Layers of the cornea Concurrent damage to other anterior segment structures in trauma Can induce traumatic uveitis Irritation and spasms of the iris/ciliary body muscle complex Light stimulus induces further movement of irritated/inflamed structures Damaged tissues & ensuing inflammatory responseà Inflammatory mediator release Conjunctival injection (vasodilation of vessels in the conjunctiva) Red eye Damage to corneal nerves stimulates corneal nociceptors Pain/ Foreign body sensation prevent light entry through the pupil Acute vision loss Hyperalgesia (lowered peripheral nerve threshold for firing while damaged tissues are healing, during which normally non- noxious stimuli like light, wind or temperature change - can induce pain) Nociceptors stimulate afferent neurons in trigeminal nerve, which then activates efferent neurons in the facial nerve Stimulation of the lacrimal gland Tearing Anterior chamber of the eye Photophobia (Light sensitivity or light-induced pain/ discomfort) – Pathophysiology is complex and multifactorial Authors: Yejun Hong, Davis Maclean Reviewers: Mehul Gupta, Adam Muzychuk*, Victor Penner*, Yan Yu* *MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 19, 2021 on www.thecalgaryguide.com

Dry-Eye-Syndrome-Pathogenesis

Dry Eye Syndrome (Keratoconjunctivitis sicca): Pathogenesis The Pathophysiology of Dry eye disease is complex and an area of active investigation – The mechanism and causes presented here represented the highest yield causes and mechanism for students Post laser eye surgery Disruption of corneal nerves ↓ corneal sensitivity Damage to trigeminal nerve, the sensory innervation of the eye (due to: Herpes Zoster, tumor, trauma, etc) Blepharitis (eyelid inflammation) Many medications can cause dry eye via multiple mechanisms presented here (e.g. ↓ corneal sensitivity, Meibomian gland dysfunction, lacrimal gland atrophy) Sex Hormones (e.g. androgens & estrogens) play a complex and poorly understood role in mediating dry eye disease (net effect is that women are more often affected by dry eye) Obstructed meibomian glands Eyelid damage Gland atrophy These items represent general causes of meibomian gland dysfunction – exact causes are numerous, their pathophysiology is beyond the scope of this slide Contact lens (long term use) Corneal nerve adaptation to chronic mechanical stimulation Autoimmune disease (e.g. Sjögren's syndrome) Chronic inflammatory infiltration of the lacrimal gland (and salivary gland) Autoimmune Lymphocytic infiltration Inflammatory cytokine release Autoantibody production Cell death and apoptosis Lacrimal gland degeneration Meibomian gland dysfunction (Located along the eyelid margins, these glands produce meibum, an oily substance that prevents evaporation of the tear film) ↓ meibum secretion Loss of lipid layer covering the eye, ↓ the barrier that blocks evaporation of tear film Tear Film instability Lifestyle Extended reading or TV or electronic device uses Exposure Keratopathy (any condition causing dryness due to incomplete or inadequate eyelid closure, e.g. Bell’s Palsy) ↓ activity of the afferent portion of corneal reflex arc (responsible for reflex tearing: tearing in response to irritation of the eye) Mechanical damage to goblet cells secrete mucins – a substance that lubricates the eye and preserves tear film ↓ blink rate ↑ time and area ↓ normal reflex tearing for evaporation Dry climate Wind exposure Infiltrative diseases (e.g. sarcoidosis) Lacrimal gland infiltration ↓ Lacrimal gland secretion of the the watery aqueous layer of the tear film (Aqueous deficient dry eye) Deficient or unstable tear film (Evaporative dry eye) ↑ tear evaporation Direct damage to lacrimal gland (e.g. infection or trauma of the eye) Authors: Davis Maclean, Yan Yu*, Michael Penny, O.D. Reviewers: Natalie Arnold, Saleel Jivraj, O.D., Adam Muzychuk*, Victor Penner* *MD at time of publication Hyperosmolar Tear Film (hyperosmolarity = ↑ solutes and ↓ solvent) (Further) Tear Film instability Corneal and conjunctival epithelial cells dry out, including goblet cells (which secrete mucins – a substance that lubricates the eye) Inflammatory immune response àRecruitment and activation of CD4+ (Helper) T-Cells, further produce cytokines Further irritation and damage to ocular surface structures (cornea, conjunctiva and Meibomian glands) and lacrimal glands See Calgary Guide: “Dry Eye Syndrome (Kerato- conjunctivitis sicca):Clinical Findings” for signs and symptoms Dry Eye Syndrome (Keratoconjunctivitis sicca): A multifactorial disease of the ocular surface and tears characterized by loss of tear film homeostasis, tear film hyperosmolality and inflammation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 7, 2021 on www.thecalgaryguide.com

Pneumoconioses

Pneumoconioses: Pathogenesis and Clinical Findings Authors: Austin Laing Reviewers: Yan Yu* Tara Lohmann* * MD at time of publication Bronchogenic carcinoma and mesothelioma Inhalation of asbestos (Asbestosis) Inhalation of carbonaceous dust (Carboconiosis) Inhalation of metal dust (Metaloconiosis) Inhalation of silica dust (Silicosis) “-Coniosis”: disease which comes from inhaling dust particles Internalized asbestos fibers disrupt cellular processes through a complex series of theorized mechanisms Inhaled dust particles (1-5μm in size) are trapped and deposited in the alveolar airspaces Alveolar macrophages ingest dust particles, which activates the macrophages and sometimes causes apoptosis Activated macrophages create an inflammatory microenvironment by releasing pro-inflammatory cytokines, chemokines and reactive oxygen species Inflammatory products (e.g. reactive oxygen species) damage alveolar epithelial cells, causing activation and release of inflammatory cytokines into the alveolar space Inhaled dust particles, inflammatory products & other pro- tussive mediators activate airway vagal afferent receptors Activated receptors stimulate the cough center located in the medulla oblongata Cough Alveolar capillaries vasoconstrict in response to hypoxia à↑ Pulmonary vascular resistance Pulmonary Hypertension Right heart must pump blood into lungs against higher pressure àcardiomyocyte growth (via sarcomeres formed in parallel within myofibrils)àconcentric hypertrophy of right heart Cor Pulmonale (right heart failure due to pulmonary hypertension) Asbestos fibers accumulate in the airspace and translocate to the pleural surface Macrophage apoptosis: ↓ alveolar macrophages Fibroblasts are recruited to the alveolar wall and are activated Activated fibroblasts produce and deposit collagen in the extracellular space between alveoli Thickening of tissue between alveoli and capillaries ↑ the diffusion distance of atmospheric and blood gasses ↓ Diffusion of CO2 from blood to alveoli and ↓ diffusion of O2 from alveoli to blood ↑ Respiratory rate to maintain minute ventilation due to ↓ lung volumes and diffusion limitations Dyspnea and Exertional Hypoxemia ↓ Innate immune response in the lungs Chest X-Ray: Nodular and reticulonodular opacities are seen in varying lung regions depending on the underlying inhaled dust Excessive collagen deposition ↓ lung compliance and ↓ lung expansion ↓ Diffusing capacity for carbon monoxide (DLCO) on pulmonary function test ↓ Arterial oxygen contentà ↑ deoxyhemoglobin and ↓ oxyhemoglobin ↑ Deoxyhemoglobin within the vasculature causes the skin and mucous membranes to appear blue Cyanosis ↑ Risk of respiratory infections. Mycobacterial infections (e.g. tuberculosis) associated primarily with silicosis ↓ Inhalation volume ↓ Expiratory volume Hypoxemia ↓Total lung capacity (TLC) and ↓ residual volume (RV) on pulmonary function test ↓Forced vital capacity (FVC) and ↓ forced expiratory volume in 1 second (FEV1) on pulmonary function test Note: Forced Vital Capacity: the volume of air that can forcibly be blown out after full inspiration Forced Expiratory Volume in 1 second: the volume of air that can forcibly be blown out in first 1 second, after full inspiration Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published September 12, 2021 on www.thecalgaryguide.com

Langerhans Cell Histiocytosis

Langerhans Cell Histiocytosis: Pathogenesis and clinical findings Precursor cells differentiateàClonal expansion of abnormal (constitutive MAPK activation) CD1a+/CD207+ (Langerhans cell phenotype surface receptors) dendritic cells in tissue(s) Somatic BRAFV600E mutation: BRAF is a kinase in the MAPK pathway Other somatic (non- reproductive cell) mutations Idiopathic (unknown cause) Mutation(s) can occur in one of these precursor cell types* Hematopoietic stem cell (earliest cell of blood cell differentiation) in bone marrow Committed dendritic cell (type of myeloid antigen-presenting cell) precursor in bone marrow or blood Committed dendritic cell precursor in tissue Constitutive activation of the MAPK pathway (signalling pathway that regulates variety of cellular processes) in one of these precursor cell types *Note: Based on the “misguided myeloid differentiation” modelàthe earlier the mutation(s) occur in the myeloid cell differentiation pathway, the more severe the disease. Langerhans Cell Histiocytosis Accumulation of abnormal CD1a+/CD207+ dendritic cells (Langerhans Cell Histiocytosis cells or LCH cells) with an inflammatory background in one or more organs Authors: Ran (Marissa) Zhang Reviewers: Mehul Gupta Kiera Pajunen Yan Yu* Lynn Savoie* * MD at time of publication ↑ recruitment & activation of T cells, macrophages, eosinophils in tissue(s) around the body ↓ CCR7 & CXCR4 (chemokine receptors) expression on LCH cellsàinhibits migration of LCH cells to lymph nodes ↑ BCLXL (an apoptosis regulator protein) expression on LCH cellsà inhibits apoptosis of LCH cells Immune cell infiltration & ↑ pro-inflammatory chemokine/cytokine release à dysregulated local & systemic inflammation Accumulation of LCH cells in tissue(s) around the body Inflammatory lesion (an area of abnormal tissue) formation in one or more organs: In pituitary stalk Mass effectà obstruction of antidiuretic hormone (complex mechanisms) In liver Invasion & accumulation of cells foreign to liverà expands liver Chronic local inflammation Scarring of bile ducts ↓ bilirubin clearance from liveràbuildup into serum ↑ serum bilirubin Jaundice In cortical bone Cytokine production à↑ osteoclast (cells that break down bone) activity ↑ rate of bone loss Osteolytic bone lesions In bone marrow Unclear mechanism but likely due to macrophage activation ↑ phagocytosis (ingestion & destruction) of blood cells In spleen Invasion & accumulation of cells foreign to spleen Forms aggregates that expand the red pulp (functions as the blood filter in spleen) Splenomegaly In skin Unclear mechanisms Variable presentations: most commonly pinpoint erythematous (red) papules or erythematous plaques with crusting & scaling Hepatomegaly • BRAF- B-Raf proto-oncogene, serine/threonine kinase • CCR7- C-C motif chemokine receptor type 7 • CD1a- Cluster of differentiation 1A • CD207- C-type lectin domain family 4 member k • CXCR4- C-X-C chemokine receptor type 4 • LCH- Langerhans Cell Histiocytosis • MAPK- Mitogen-activated protein kinase Diabetes Insipidus Abbreviations: • BCLXL- B-cell lymphoma-extra large Anemia, thrombocytopenia &/or neutropenia Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 13, 2022 on www.thecalgaryguide.com

Vitiligo Pathogenesis and Clinical Findings

Vitiligo: Pathogenesis and clinical findings Authors: Wisoo Shin Reviewers: Lauren Lee Stephen Williams Ben Campbell Laurie Parsons* Yan Yu* * MD at time of publication Genetic predisposition Variants in over 30 susceptibility loci Environmental exposure UV light, monobenzone, phenol, catechol Production of IgG auto- antibodies to melanocyte-specific proteins Auto-antibodies bind to melanocytes and trigger antibody-dependent cellular cytotoxicity: marking melanocytes for destruction by Fc- receptor bearing immune cells such as neutrophils Impaired mitochondrial function in melanocytes ↑ Susceptibility of melanocytes to oxidative stress ↓ E-cadherin or ↑ anti- adhesion molecule expression in melanocytes ↓ Adhesion of melanocytes to keratinocytes ↑ Clearance of melanocytes from epidermis ↑ Reactive oxygen species production within melanocytes Activation of apoptosis and senescence signaling pathways Pressure or friction Melanocytes excrete exosomes (melanocyte- specific antigens, microRNA, heat shock proteins) that, through complex mechanisms, stimulate the immune system’s CD8+ T-cells to destroy melanocytes Melanocytes enter apoptotic or senescent state ↓ Functional melanocytes ↓ Melanin production Overall loss of functional melanocytes Vitiligo Normal Skin Pigmented Epidermis Dermal- Epidermal Junction Dermis Autoimmune destruction of melanocytes Depigmented Epidermis Melanocytes Immune-mediated destruction of melanocytes (by both neutrophils and CD8+ T cells) A depigmenting skin disorder characterized by selective loss of melanocytes Depigmentation in areas of ↑ pressure, friction and/or trauma Nonsegmental vitiligo Smooth unpigmented macules or patches in bilateral, often symmetric pattern Somatic mosaicism (mutation limited to a subset of cells) in zygote during development Segmental vitiligo Smooth unpigmented macules or patches in unilateral pattern not crossing midline Vitiligo Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published February 15, 2022 on www.thecalgaryguide.com

isotretinoin-systemic-retinoid-mechanisms-and-side-effects

Isotretinoin (Systemic Retinoid): Mechanisms and Side Effects Isotretinoin Authors: Ayaa Alkhaleefa Reviewers: Mehul Gupta, Ben Campbell Stephen Williams, Lauren Lee, Yan Yu*, Laurie Parsons* * MD at time of publication ↑ Apoptotic signaling in sebocytes Inhibits androgen nuclear receptors responsible for sebum secretion ↓ Sebaceous lipogenesis ↑ Apoptotic signaling in neural crest cells during embryonic development Alterations in hindbrain, neural crest, otic anlage, and reduced pharyngeal arch in embryo Craniofacial, cardiac, thymic, and central nervous system malformations in fetus Isotretinoin isomerizes to all-trans retinoic acid (ATRA) ATRA enters cell nucleus and binds retinoic acid receptors and retinoic X receptors ATRA induces tumour necrosis factor-related apoptosis-inducing ligand ↑ Apoptotic signaling in epidermal keratinocytes ↑ Expression of FoxO1 ↑ Expression of p53 (tumour suppressor) Release of caspases 3, 6, 7, and 9 ↑ Cell cycle inhibitors p21 and p27 ↓ Pro-survival proteins (Survivin) Sebaceous gland involution Sebum suppression C. acnes unable to break down sebum into pro- inflammatory lipids ↓ Colonization with C. acnes Teratogenicity ↑ Cornification (death) of epidermal keratinocytes ↓ Corneodesmosomes (main adhesive structures of the stratum corneum) ↓ Cohesion of corneocytes (dead keratinocytes) ↓ Corneocyte buildup in pilosebaceous follicles C. acnes unable to populate and release cytokines in corneocytes Epidermis Dermis Pilosebaceous follicle ↓ Stratum corneum thickness ↑ Trans-epidermal water loss Dryness, peeling & inflammation of lips (cheilitis), skin (dermatitis) & mucosa (mucositis) ↓ Comedogenesis Sebum Hair follicle Dermal- Epidermal Junction Sebaceous gland (sebocytes) Death of sebocytes in pilosebaceous follicles Reduction of number and size of acne lesions Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 20, 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

chronic-pancreatitis-complications

Chronic pancreatitis: Complications Hypothesis: Cytokines stimulate hypersecretion of secretory proteins (lithostathine, GP2) from acinar cells in exocrine pancreas (early in disease course) Proteins precipitate and form aggregates within pancreatic ducts Accumulation of protein aggregates and localized fibrosis block pancreatic ducts Rupture of acinar cells near blocked ducts → release of intracellular enzymes and fluid Accumulation of enzyme- rich fluid within pancreas Intra-pancreatic pseudocysts (differ from pseudocysts in acute pancreatitis, which are primarily extra-pancreatic) Chronic Pancreatitis Recurrent episodes of acute pancreatitis leading to irreversible fibroinflammatory pancreatic damage Inflammatory cytokines are continuously released from damaged pancreas over years Cytokines damage endothelium of intra- and peri-pancreatic blood vessels (including splenic vein, which runs posteriorly behind pancreas and allows for its venous drainage) Thin and weakened vessel walls balloon outwards from pressure of blood flow Pseudoaneurysms Venous stasis (low blood flow) → ↑ concentration of clotting factors Obstruction of peripancreatic ducts Author: Ashar Memon Reviewers: Yan Yu*, Kiana Hampton, Sylvain Coderre* * MD at time of publication Exocrine insufficiency (↓ secretion of digestive enzymes, e.g., Lipase, into gastro-intestinal tract) ↓ digestion of foods and absorption of nutrients (including fats) ↓ absorption of fat-soluble vitamin D Metabolic bone disease (a group of disorders of decreased bone mineralization) Blood vessels dilate and swell from increased blood flow Gastric varices Cytokines perpetually activate pancreatic stellate cells (stellate cells produce proteins that remodel extra- cellular matrix) Pancreatic stellate cells increase amounts of collagen and other extra- cellular matrix molecules in pancreas → Fibrosis Pancreatic proteolytic enzymes (e.g., trypsin) in fluid-filled pseudocysts digest walls of adjacent blood vessels Fibrotic tissue and pseudocysts compress peripancreatic structures (including splenic vein) Cytokines stimulate apoptosis of hormone- producing pancreatic Islet cells (e.g., beta cells) Endocrine insufficiency (↓ production and secretion of pancreatic hormones) Damaged endothelial cells of splenic vein trigger coagulation cascade (See Calgary Guide slide on Coagulation Cascade) Splenic vein thrombosis ↑ resistance to blood flow through splenic vein Cytokines stimulate apoptosis of acinar cells in exocrine pancreas Malnutrition ↓ secretion of insulin ↓ cellular uptake and metabolism of glucose → hyperglycemia Diabetes mellitus Collateral blood vessels develop around stomach so blood can circumvent splenic vein and relieve splenic vein hypertension Duodenal obstruction Biliary obstruction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2022 on www.thecalgaryguide.com

felty-syndrome

Felty Syndrome: Pathogenesis and clinical findings Authors: Anjali Arora Reviewers: Ben Campbell, Liam Martin*, Yan Yu* * MD at time of publication Longstanding chronic Rheumatoid Arthritis Rheumatoid Arthritis (RA): a disease of systemic autoimmunity – refer to Rheumatoid Arthritis slides for detailed pathogenesis Genetic susceptibility Presence of a specific type of Human Leukocyte Antigen (HLA-DR4), a surface protein on immune cells that is known to be associated with or worsen autoimmune activity Idiopathic autoimmunity Neutrophil activation, apoptosis and adherence to endothelial cells in the spleen Felty Syndrome An uncommon extraarticular manifestation of seropositive Rheumatoid Arthritis characterized by the triad of splenomegaly, neutropenia and arthritis Immunologic stress leads to proliferation of white pulp in spleen (responsible for initiating immune responses to foreign antigens) Splenomegaly ↑ RBC and platelet sequestration within the spleen leading to a quantitative shortage of these cells in circulation Enlarged spleen compresses stomach Loss of appetite Complex autoimmune phenomena lead to ↓ neutrophil production and ↑ removal from the circulating pool Neutropenia For a detailed mechanism, refer to Neutropenia slides ↓ Circulating neutrophils leads to ↑ susceptibility to infections Severe, untreated Rheumatoid Arthritis will lead to systemic inflammation See Rheumatoid Arthritis slides for detailed mechanism Chronic erosion of synovial membranes in joints commonly affecting the hands, wrists and knees Arthralgia (symmetric polyarthritis, usually with small joint distribution) Thrombocytopenia Refer to Thrombocytopenia slides for signs and symptoms Normocytic Anemia Refer to Normocytic Anemia slide for signs and symptoms Host becomes infected Fever Recurrent infections Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 18, 2022 on www.thecalgaryguide.com

Erythema multiforme (EM): Pathophysiology and clinical findings

Erythema multiforme (EM): Pathophysiology and clinical findings Infectious agents (cause >90% of EM) Herpes simplex virus types 1 and 2 Mononuclear cells transport herpes simplex virus DNA fragments to keratinocytes in epidermis Herpes simplex virus-specific CD4 T-cells of the immune system are recruited to the epidermis CD4 T-cells release interferon-gamma (a pro-inflammatory cytokine) in response to viral antigens in keratinocytes in the epidermis Lymphocytes infiltrate along the dermal-epidermal junction of the skin Lymphocytes create an inflammatory and edematous environment Keratinocytes irreversibly degenerate and undergo apoptosis and necrosis Formation of inflammatory epidermal lesions Authors: Ayaa Alkhaleefa Reviewers: Ben Campbell Damilola Omotajo Jori Hardin* *MD at time of publication Drugs (a rare cause of EM) Non-steroidal anti- inflammatory drugs i.e. diclofenac sodium Antibiotics i.e. TMP- SMX Topical 5% Imiquimod, used to treat actinic keratoses Activate tumour-necrosis-factor- alpha, an inflammatory cytokine Skin Epidermal layer Dermal-Epidermal Junction Dermal layer Triggering agent (infection, drugs) Immune-mediated inflammation and epidermal tissue damage Erythema multiforme Inflammation ↑ capillary blood flow in dermis Red colouring of skin in the area Centre of lesions contain a necrotic core Inflammatory edema causes margins around necrosis to form a raised and pale ring Inflammation stimulates cutaneous itch receptors Erythematous, papular, target-shaped, pruritic lesions on mucosal and acral (palms of hands, soles of feet) sites and face Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 29, 2022 on www.thecalgaryguide.com

rheumatoid-pneumoconiosis-caplans-syndrome-pathogenesis-and-clinical-findings

Rheumatoid Pneumoconiosis (Caplan’s Syndrome): Pathogenesis and clinical findings Authors: Christopher Li Keerthana Pasumarthi Reviewers: Daniela Urrego, Ben Campbell, Liam Martin* * MD at time of publication Dust-exposed occupation (e.g. coal, asbestos, silica) ↑ Accumulation of dust particles in lungs Dust (e.g. silica) mobilizes from the lungs to other organs such as the kidneys, lymph nodes, and spleen Accumulation of silica in other organs which activate the immune system to secrete cytokines, chemokines, and lysosomal enzymes Activation of antigen- presenting and antibody- producing cells Increased risk to produce autoantibodies Increased risk for autoimmune conditions such as rheumatoid arthritis See slide: Rheumatoid Arthritis (RA): Extra- articular manifestations for mechanism of systemic inflammation See slide Pneumoconioses: Pathogenesis and clinical findings for mechanism Note: Rheumatoid arthritis may precede lung nodules or develop later in the course Rheumatoid arthritis Systemic autoimmune inflammatory disease that mainly involves synovial joints (+) Alveolar macrophages and neutrophils ingest dust particles ↑ Inflammation and cytokine production in pulmonary parenchyma (e.g. interleukin-1, tumor necrosis factor-α) Rheumatoid pneumoconiosis Interstitial lung disease, with characteristic nodules, resulting from the interaction between dust inhalation and rheumatoid arthritis inflammation Cytokines recruit histiocytes, neutrophils, lymphocytes, and fibroblasts to the area to produce a zone of inflammation around the dust-containing cell Necrosis and apoptosis of dust-containing cells, macrophages, and surrounding collagen Necrotic cells are digested by new macrophages to restart the process Production of nodules that contain a central necrotic area surrounded by alternate layers of dust and necrotic tissue (Caplan nodules) Hyperactive immune response to foreign materials in lungs Multiple concentric rings of dust seen histologically on light microscopy 0.5-5 cm rounded opacities on chest X-ray in periphery of lungs See slide on Pneumoconioses for symptoms and pulmonary function test results Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 17, 2022 on www.thecalgaryguide.com

Acute Liver Failure: Pathogenesis and clinical findings

Acute Liver Failure: Pathogenesis and clinical findings Authors: Juliette Hall Reviewers: Vina Fan, Ben Campbell, Mayur Brahmania* * MD at time of publication Acetaminophen Overdose Accumulation of toxic NAPQI (a metabolite of acetaminophen) NAPQI binds hepatocellular proteins (see Acetaminophen Overdose: pathogenesis and clinical findings slide) Drug-induced liver injury Metabolism of drugs by the liver can produce reactive drug metabolites Intracellular stress, mitochondrial injury, or immune response Viral Hepatitis (i.e. HAV, HBV, HEV, HSV) Acute infection or infection flare provokes an immune response against infected hepatocytes Autoimmune Hepatitis Autoimmune antibodies attack hepatocytes (see Auto-immune Hepatitis (AIH) slide) Ischemia (i.e. from shock) ↓ O2 delivery to the liver Hepatocellular hypoxia Wilson’s Disease Heritable mutation in the ATP7B gene ↓ Biliary excretion of copper Hepatic copper accumulation injures hepatocytes (see Wilson’s Disease slide) Accelerated rate of hepatocellular necrosis or apoptosis Hepatocyte death exceeds regeneration such that liver function is compromised within a short amount of time Acute Liver Failure An illness of <26 weeks duration in the absence of pre-existing cirrhosis, characterized by INR ≥1.5 and evidence of altered mentation (hepatic encephalopathy) Injured hepatocytes leak hepatic enzymes (AST, ALT, GGT) into circulation ↑ Liver enzymes Hepatocellular inflammation Stimulation of foregut autonomic nerves Right upper quadrant pain ↓ Toxin metabolism Toxins build up and activate microglial cells (brain macrophage) Oxidative stress and cerebral edema Hepatic encephalopathy Characteristic set of neuropsychiatric symptoms (see Hepatic Encephalopathy slide) ↓ Hepatocellular function and number ↓ Complement protein synthesis ↓ Ability to clear immune complexes and activate B cells Accumulation of pigmented bilirubin ↓ Synthesis of coagulation factors ↑ INR ↓ Conjugation of bilirubin by the liver and ↓ transport into bile for excretion ↑ Serum bilirubin Jaundice Infection Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 15, 2022 on www.thecalgaryguide.com

Hemorrhagic Stroke

Hemorrhagic Stroke: Pathogenesis and clinical findings Authors: Andrea Kuczynski Oswald Chen Reviewers: Sina Marzoughi Usama Malik Anjali Arora Ran (Marissa) Zhang Mao Ding Michael D Hill* Gary Klein* * MD at time of publication Primary Intracerebral Hemorrhage (~75%) Secondary Intracerebral Hemorrhage (~25%) Amyloid Angiopathy Amyloid deposits in blood vessels and weakens vessel walls Hypertension Lipohyalinosis (lipid and protein aggregation in arterial walls) weakens blood vessels Unknown Aneurysm Dilation of a weakened blood vessel Drugs (e.g., cocaine, crystal meth, decongestants, anticoagulants) Vascular Malformations Note: the pathophysiology and exact mechanism is not well known Release of toxic blood plasma components (coagulation factors, immunoglobins) Red blood cell lysis Cytotoxic hemoglobin (heme, iron) release Fenton-type free radical generation (Fe(II) + H2O2 → Fe(III) + OH− + OH•) Oxidative damage to carbohydrates, lipids, nucleic acids, and proteins in brain Necrosis of hypoxic brain tissue Neurological signs: focal motor weakness, aphasia, vision loss, sensory loss, imbalance/incoordination, altered LOC Rupture of blood vessel(s) Accumulation of blood → hematoma formation ↓ Cerebral tissue perfusion (↓ O2 availability) ↓ Mitochondrial oxidative phosphorylation (final step in aerobic glucose metabolism) ↓ Adenosine triphosphate (ATP) production ↑ Anaerobic glucose metabolism → ↑ Cerebral lactate production Cerebral lactic acidosis Impaired cellular metabolism Death of neurons and glia Microglia clear debris and release inflammatory markers (TNFα, IFγ, IL-1β) ↑ Endothelial cell apoptosis and ↑ blood-brain barrier permeability Cerebral edema Increased intracranial pressure: papilledema, sudden headache, non-reactive pupils, ↓ level of consciousness (LOC), nausea/vomiting Astrocytes release glutamate (main excitatory neurotransmitter) Activation of neuronal metabotropic glutamate receptors ↑ Ca2+ influx into neurons Excitotoxicity (excess stimulation of glutamate receptors leading to neuronal death) Dysfunction of Na+/K+ ATPase pump (moves 3 Na+ out of cell and 2 K+ into cell) on neurons ↓ Na+ efflux and ↓ K+ influx Neuronal membrane potential becomes less negative (closer to threshold potential) Neurons depolarize → ↑ Glutamate release General findings: Seizures, lethargy Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications First published June 6, 2018, updated February 28, 2023 on www.thecalgaryguide.com

Myelodysplastic Syndrome Pathogenesis and clinical findings

Myelodysplastic Syndrome (MDS): Pathogenesis and clinical findings Authors: Mao Ding Reviewers: Ashar Memon Man-Chiu Poon Yan Yu* * MD at time of publication Stem cells differentiateà accumulation of bone marrow cells with aberrant morphology & maturation Idiopathic (unknown cause) Treatment related: exposure to ionizing radiation, chemotherapeutic agents (e.g., alkylating agents, anti- metabolite, topoisomerase II inhibitors) Environmental toxins (e.g., tobacco, benzene & other organic solvents) Familial predisposition to MDS Acquired somatic (non- reproductive) gene mutations (DNA alterations) Inherited germline (reproductive cells) gene mutations Recurrent mutations cause alteration(s) in one or more protein functions with/without chromosomal abnormalities in hematopoietic stem cell (earliest cell of blood cell differentiation): Mutation in the transcription factor gene RUNX1 impairs regulation of normal hematopoietic (blood cell) development Mutation(s) in epigenetic regulator genes (DNMT3A, TET2) impairs regulation of DNA methylation Mutation in splicing regulator genes (SF3B1) causes mistakes in splicing mRNA moleculesàaberrant translation (production) of proteins Chromosomal abnormalities: deletions (chromosome 5, 7, and/or 20), duplications (chromosome 8), structural abnormalities (inversion of a gene segment) Myelodysplastic Syndrome Mutation-associated clonal disorders of hematopoietic stem cells, causing dysplasia (abnormal development) of one or more myeloid cell lineages (granulocytes, monocytes, red blood cells & platelets) in the bone marrow Genetic mutations or chromosomal abnormalities occur in hematopoietic stem cellsàclonal expansion of abnormal cells in bone marrow Apoptosis (programed cell death) of clonal cells, inhibiting development of granulocytes, monocytes, red blood cells & platelets in the bone marrow Neoplastic myeloid precursor cells (blasts) accumulate in the bone marrow Acute Myeloid Leukemia (AML) > 20% Blasts in the bone marrow Excessive blasts displace other precursor cells & inhibit differentiation Pancytopenia (↓ number of cells of ALL 3 cell lines: platelets, white blood cells & red blood cells) (see Acute Myeloid Leukemia for signs/symptoms/complications) ↓ Number of mature functional blood cells leave the bone marrow to go to peripheral bloodà↓ number of cells of one or more cell lines Bone marrow’s inability to make sufficient blood cells cause extramedullary hematopoiesis (formation/activation of blood cells outside the medulla of bone) at sites such as liver and/or spleen Hematopoietic stem cells migrate to the spleen/liver & differentiate into blood cells Expanding bone marrow physically pushes on bone’s cortex from within, activating nociceptors Multifactorial causes mostly with unclear mechanisms Intracellular granules precipitate inside blasts & the precipitate spills into the blood ↑Division & death of cancerous cells → ↑ cell lysis & release of intracellular contents into plasma Bone pain B symptoms: Weight loss, fever, night sweats Auer Rods (needle- like crystals) seen on blood smear ↑ Serum levels of uric acid, K+, LDH ↓ Red blood cells Anemia fatigue, pallor ↓ White blood cells Leukopenia Recurrent infections ↓ Platelets Thrombo- cytopenia Bruising, bleeding Accumulation of cells within the spleen/liver increase the size of the organ Splenomegaly Hepatomegaly Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published March 4, 2023 on www.thecalgaryguide.com

Telogen Effluvium

Authors: Ayaa Alkhaleefa Telogen effluvium (TE): Causes, pathophysiology, and clinical findings Reviewers: Elise Hansen, Sunawer Aujla, Dr. Jori Hardin* *MD at time of publication Telogen effluvium: non-scarring alopecia characterized by diffuse shedding of telogen-phase hair due to a reactive process Hypothyroidism ↓ Thyroid hormones (T3,T4) ↓ Binding of thyroid hormone to receptors in the skin and hair Cell division ceases in keratinocytes The catagen phase of the hair cycle is triggered (involuting phase where hair enters apoptosis) Delayed re-entry of telogen (resting) hair into the anagen (growing) phase Post-partum hair loss (telogen gravidarum) ↑ Circulating placental estrogen Prolonged anagen phase ↑ Hair growth during pregnancy Baby is delivered ↓ Estrogen and other trophic hormones postpartum The increased amount of anagen hairs from pregnancy all enter catagen phase simultaneously Nutritional deficiencies i.e. iron deficiency Critical illness Fever triggers various pro- inflammatory cytokines (tumor necrosis factor, interleukin 1b, interleukin 6, and interferon types 1 and 2) Premature entry into catagen phase (the body induces cell-cycle arrest in all non-essential structures) Hair follicle keratinocytes undergo apoptosis in response to inflammation Ribonucleotide reductase (an enzyme involved in DNA synthesis) cannot utilize iron as a co-factor ↓Iron stores ↓ Expression of iron- dependent genes (CDC2, NDRG1, ALAD, and RRM2) ↓ Expression of matrix genes of a healthy hair follicle (Decorin and DCT) ↓ Production of matrix keratinocytes (cells that form the hair shaft of growing hair) Arrest of matrix proliferation Hair shedding commonly occurs in the bitemporal areas 2-3 months after triggering event Hair shaft Hair follicle Telogen phase Skin Epidermis Dermal- Anagen phase Epidermal Junction Dermis Catagen phase Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 10, 2023 on www.thecalgaryguide.com

Menopause

Menopause: Pathogenesis and Clinical Findings Perimenopause/Menopausal Transition: Phase preceding last menstrual period in which the first symptoms may occur. Many clinical findings of menopause can occur in perimenopause. 1-2 million primordial follicles first appear in fetal ovaries in the end of the first trimester of the mother’s pregnancy Typically beginning in adolescence, puberty triggers physiological and anatomical changes Menarche (commencement of menstrual cycles) See relevant slide: Menstrual Cycle Physiology: Ovarian Cycle – Brief Overview Each cycle involves ovulation, during which an oocyte is released from the ovary’s dominant follicle into the Fallopian tube Some non-dominant follicles degenerate in a process known as atresia Menstrual cycle stops Menopause marks 1 year since last menstrual cycle ↓ Fluid transudatio n from blood vessels of vaginal wall ↓ Vaginal lubrication Vaginal tissue becomes thinner and more easily irritated Over time, fewer follicles remain in the ovary Some cycles become anovulatory (no oocyte is released from ovary) ↓ Ovulation causes prevents thickening of the endometrial lining ↓ regularity and frequency of periods Ovaries eventually stop releasing oocytes ↑ Oxidative stress- induced apoptosis of dermal fibroblasts Remaining non-dominant follicles become less sensitive to LH and FSH Since follicular cells are responsible for estrogen production, less follicles result in reduced estrogen production ↓ Expression of serotonin receptors in the CNS ↓ LDL receptor expression and ↑HMG- CoA reductase activity ↓ Regulation of the production and clearance of LDL ↑ LDL Cholesterol levels Author: Sunawer Aujla Reviewers: Ashar Memon Yan Yu* * MD at time of publication ↓ Serotonin activity ↓ Density of ↓ Healthy vaginal flora ↑ pH of vaginal fluid ↑ Spread of bacteria otherwise unable to survive in low pH environment Recurrent urinary tract infections ↓ Calcitonin ↑ Sensitivity of bone mass to Parathyroid Hormone ↑ Activation of osteoclasts Mechanism is likely multifactorial and the subjective symptoms of menopause may contribute Depression 5HT receptors in thermoregulatory region of hypothalamus ↑ Inhibition of sexual responses initiated in prefrontal cortex ↓ Libido 2A ↓ Collagen, elastin, and hyaluronic acid ↓ Proliferation of smooth muscle fibers ↓ Inhibition of osteoclasts Narrower thermoregulatory zone Injury to epithelial tissue in multiple areas of the body Atrophy of bladder and urethra epithelium Urinary incontinence More bone resorption than formation Osteoporosis See relevant slide: Osteoporosis: Pathogenesis and risk factors Sometimes, for unknown reasons, core body temperature increases above upper threshold of narrowed thermoregulatory zone Hot Flashes Sudden, temporary onset of body warmth, flushing, and sweating Sometimes, for unknown reasons, core body temperature decreases below lower threshold of narrowed thermoregulatory zone Chills Sudden, temporary onset of shivering, tingling, cold feeling Atrophy of vaginal epithelium Dyspareunia Pain during sexual intercourse ↓ Integrity of of blood vessels Atherosclerosis ↑ Risk for cardiovascular disease Genitourinary Syndrome of Menopause Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published June 7, 2023 on www.thecalgaryguide.com

Rotator Cuff Disease

Rotator Cuff Disease: Pathogenesis and clinical findings Authors: Jared Topham Reviewers: Raafi Ali, Yan Yu*, Kelley DeSouza* * MD at time of publication Aging Collagen fiber disorientation and myxoid degeneration Tendons, ligaments, and connective tissue are replaced by gelatinous and/or mucoid substance Obesity ↑ Loading on shoulder structures ↓ Static stability (from glenoid labrum and ligamentous components) of glenohumeral joint Tensile forces Repeated eccentric tension from overhead activities Trauma, sports, and occupation ↑ Torque, compression, and translational stresses Metabolic syndromes Reactive oxygen species interact with ↑ glucose forming advanced glycation end-products (AGEs) which accumulate in soft tissues Smoking Impingement syndromes Vessel damage, ischemia, tenocyte apoptosis Macro-trauma causing an acute, complete tear in the rotator cuff muscle(s) ↓Dynamic stability (from rotator cuff and periscapular muscles) and range of motion of the shoulder at the glenohumeral joint ↑ Bone on bone contact of proximal humeral head and boney structures of the scapula Subacromial bursa degeneration ↓ Protection of underlying supraspinatus muscle from attrition between humeral head and acromion Rotator Cuff Syndrome (Inflammation, impingement, or tearing of one or more of the four muscles/tendons of the rotator cuff: supraspinatus, subscapularis, infraspinatus, teres minor) Repetitive loading and micro-tearing of tendon/muscle fibers ↑ Oxidative stressors and inflammatory cascades ↓ Vascularity of rotator cuff structures Radiographic changes: See Rotator Cuff Disease: X-ray and ultrasound features slide, in addition to: calcific tendonitis, calcification of in the coracohumeral ligament, and hooked acromion (calcification from tendon pulling) In some cases, soft tissues enclose/surround shoulder joint capsule thicken (fibrose) and tighten Degenerative joint disease and rotator cuff arthropathy Proximal humeral head migration and ↓ subacromial space Inflammation and insufficient healing of rotator cuff structures, which may lead to: Supraspinatus (shoulder abduction) degeneration Pain, shoulder stiffness, ↓ active AND passive range of motion Adhesive Capsulitis (frozen shoulder) Infraspinatus and teres minor (external rotation) degeneration Rotator cuff tendons become inflamed and irritated as they rub against acromion Subacromial impingement Subscapularis (internal rotation) degeneration +Lift-off test: Inability to hold dorsum of the hand off lumbar spine while internally rotating shoulder ↓ Shoulder strength and muscular atrophy Pain with passive shoulder flexion beyond 90° Winging of the scapula during arm adduction +Empty-can test: Weakness and/or arm depression with resisted abduction with arm internally rotated in 90° +Drop-arm test: Inability to maintain shoulder in abducted position at 90° and/or adduct the arm in a controlled manner (resulting in ”dropping”) Weakness to resisted external rotation with elbow in 90° flexion, inability to keep arm externally rotated (infraspinatus) +Hornblower’s sign: decreased external rotation strength in arm abduction (suggests additional teres minor tear) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published July 30, 2023 on www.thecalgaryguide.com

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

Non-Alcoholic Fatty Liver Disease

Non-Alcoholic Fatty Liver Disease: Pathogenesis and clinical findings Diagnosis of Metabolic Syndrome when ≥ 3 out of the 5 preceding risk factors are present Authors: Stephanie Happ Reviewers: Obesity Hypertension Diabetes Hypertriglyceridemia Hypercholesterolemia Iffat Naeem Sunawer Aujla Edwin Cheng* * MD at time of publication Insulin resistance develops in adipose tissue and hepatocytes ↓ Ability of insulin to suppress lipolysis of adipose tissue ↑ Delivery of free fatty acids from adipocytes to the liver ↑ De-novo lipogenesis in the liver Hepatic Steatosis: accumulation of fat in the liver (in the absence of alcohol consumption, termed Non-Alcoholic Fatty Liver (NAFL)) Steatohepatitis: chronic inflammatory and apoptotic climate in the hepatocytes (in the absence of alcohol consumption, termed Non-Alcoholic Steatohepatitis (NASH)) Fibrosis of the Liver: excessive scarring of liver tissue resulting from chronic inflammation, although liver architecture is largely intact Fat droplets form and grow in the hepatocytes Hepatic mitochondria increase their workload in attempt to break down the excess free fatty acids through beta-oxidation ↑ in cellular workload creates more reactive oxygen speciesà Inflammation and apoptosis of hepatocytes On-going inflammation damages hepatic stellate cells (the primary extracellular matrix–producing cells of the liver) causing the release of fibrinogenic cytokines Cirrhosis of the liver: normal lobular structure distorts and is replaced by regenerating nodules and bridging septa, disrupting normal liver blood flow Deposition of fibrotic material and collagen within the perisinusoidal spaces of the liver Decompensated Cirrhosis Hepatocellular carcinoma Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 25, 2023 on www.thecalgaryguide.com

Cranial Nerve IV Palsy

Cranial Nerve IV Palsy: Pathogenesis and clinical findings Congenital (e.g. Möbius Syndrome) Dysgenesis (defective development) of CN IV Microvascular Disease (e.g. Stroke) Damage or occlusion (complete or partial blockage) to the blood vessels supplying CN IV Trauma Temporary or permanent damage to the nerve fibers Neoplasm Metastasis (e.g. Leptomeningeal) Compression of the nerve fibers along the nerve tract Primary (e.g. Schwannoma) Tumor develops new blood vessels that redirect blood flow to the malignancy, away from the nerve Ischemia of CN IV Infection (a rare cause) (e.g. Ehrlichia chaffeensis, Tuberculosis meningitis) Infectious process in the subarachnoid space Damage to axons of CN IV Cranial Nerve (CN) IV Palsy Superior oblique musculature weakness due to CN IV dysfunction Lesion to the fascicle of CN IV (extending from midbrain to cavernous sinus) Impaired ability to conduct motor commands from nucleus to superior oblique muscle in the eye Weak superior oblique innervation Difficult abduction and intorsion of the eye Contralateral superior oblique weakness Lesion to the nucleus of CN IV (located in the midbrain) Disturbed signal production occurring prior to demarcation of fibers to contralateral side The pathophysiology above can cause damage to structures surrounding CN IV in the midbrain Impacting ipsilateral sympathetic chain descending from the hypothalamus prior to reaching the superior cervical ganglion Authors: Shahab Marzoughi Reviewers: Sunawer Aujla Yvette Ysabel Yao Yan Yu* Gary Michael Klein* * MD at time of publication Vertical/oblique Diplopia (double vision) Hypertropia (one eye is deviated upward compared to the other) Perinaud’s Syndrome (upgaze palsy, convergence retraction nystagmus, and pupillary hyporeflexia) See relevant Calgary Guide slide on Parinaud’s Syndrome Loss of eye muscle movement coordination and function of other structures relating to gait Ataxia Ipsilateral Primary Horner’s Syndrome (miosis, anhidrosis, ptosis) See relevant Calgary Guide slide on Horner Syndrome Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published January 16, 2024 on www.thecalgaryguide.com

Neonatal Necrotising Enterocolitis in Premature Neonates

Neonatal Necrotising Enterocolitis (NEC) in Premature Neonates: Pathogenesis and clinical findings Prematurity risk factors ↓ Intestinal motility ↑ Intestinal stasis allows bacteria more time to proliferate Bacterial overgrowth in gut ↓ Goblet cells in intestinal epithelium ↓ Intestinal mucus layer production leads to impaired mechanical defense against pathogenic bacteria Immature tight junctions in intestinal epithelium ↑ Permeability of intestinal epithelial barrier ↑ Toll-like receptor 4 (TLR4) expression on intestinal epithelial cells Aberrant bacterial colonization of gut Impaired gut barrier allows for ↑ bacterial translocation across intestinal epithelium TLR4 on intestinal mesentery endothelial cells bind lipopolysaccharides (LPS) on Gram-negative gut bacteria Immune cells release proinflammatory mediators (TNF, IL-12, IL-18) Cytokines mediate ↑ enterocyte apoptosis (including enteric stem cells) and ↓ enterocyte proliferation Intestinal mucosa healing is impaired, leading to local inflammation & injury TLR4 on intestinal epithelial cells binds LPS from Gram-negative gut bacteria Authors: Rachel Bethune Naima Riaz Reviewers: Nicola Adderley Michelle J. Chen Kamran Yusuf* Jean Mah* * MD at time of publication Endothelial nitric oxide synthase expression is reduced Vasoconstriction from ↓ NO reduces blood flow to intestines Prolonged ↓ in O2 perfusion results in irreversible intestinal mucosal cell death (necrosis) Gas escapes into abdominal cavity Leakage of intestinal contents irritates parietal peritoneum Bacteria enter bloodstream Pneumo- peritoneum Abdominal distention Peritonitis Sepsis Blood from tissue damage mixes with intestinal contents Bloody stool Intestinal sensory neurons detect damage and send signals to medullary vomiting centre Bilious vomiting Damaged intestinal cells are unable to absorb nutrients Short gut syndrome Persistent intestinal mucosal injury creates penetrating lesions through intestinal wall Intestinal perforation Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 6, 2019; updated Mar 21, 2024 on www.thecalgaryguide.com

Irritant Contact Dermatitis Pathogenesis and Clinical Findings

Irritant Contact Dermatitis: Pathogenesis and clinical findings Authors: Zaini Sarwar, Mina Youakim Reviewers: Shahab Marzoughi, Ryan T. Lewinson, Yan Yu*, Laurie M. Parsons* * MD at time of publication Repeated/chronic exposure causes damage to cell membranes Skin barrier disruption Chronic non-specific inflammatory response Repetitive keratinocyte cytokine-mediated injury Keratinocytes exhibit ↑ proliferation as a compensatory response Rapid turnover of stratum corneum (outermost layer of the epidermis) Hyperkeratotic skin is less amenable to skin stretching and pressure Skin fissures (cracks in the skin) Irritant agents (abrasives, cleaning solution, oxidative & reducing agents, dust, soils, water) Acute exposure triggers inflammatory response Keratinocytes undergo cytotoxic damage with ↑ neutrophil & cytokine release Common occupational exposures (housekeeping, cleaning, catering, medical/dental, construction) Risk factors (atopy, fair skin, low temperature, low humidity) Stimulation of local nociceptors (free nerve endings extend into the mid epidermis) Perivascular (around the blood vessel) inflammation causes histamine release from mast cells Damaged keratinocytes are destroyed via apoptosis (programmed cell death) Epidermal Necrosis (death of epidermal tissue) Shedding of necrotic tissue Ulceration (deep open wound on skin) Burning pain (uncomfortable stinging sensation) Pruritus (itching) Histamine causes local blood vessel dilation and ↑ blood flow to the area of skin affected Erythema (area appears red from ↑ blood flow) Burning & Itching Spongiosis Neutrophils Neutrophils Histamine causes local blood vessel walls to have ↑ permeability, thereby ↑ leakage of fluid Spongiosis (↑ fluid between keratinocytes in the epidermis) Fluid continues to build up from ongoing inflammation Vesiculation (fluid collections in the epidermis) Long-term skin scratching causes chronic irritation which eventually hardens the skin Lichenification (thick, hardened patches of skin) ↑ Overall keratin production Hyperkeratosis (thickening of the outermost skin layer) Further fluid buildup bursts vesicles leaving behind erosions and dried crust on the epidermis Crust (scaling over the skin) Lichenification Erosions (open sore on skin) Ulcer Epidermis Perivascular Inflammation Hyperkeratosis Dermis Dermal-epidermal junction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 19, 2016; updated Mar 30, 2024 on www.thecalgaryguide.com

Febrile Neutropenia Pathogenesis and clinical findings

Febrile Neutropenia (Neutropenic Fever): Pathogenesis and clinical findings Administration of cytotoxic chemotherapy for cancer treatment Acquired aplastic anemia Autoreactive T cells destroy bone marrow stem cells Congenital mutations in ELA2 gene (encodes neutrophil elastase) ↑ Neutrophil apoptosis Chemotherapy eliminates beneficial bacterial species from gut microbiota New microbiota composition allows for growth of colonizing bacteria Indwelling catheters inserted to deliver chemotherapy Skin-colonizing bacteria access tissues through catheters Bacteria penetrate tissue barriers Chemotherapy injures gastrointestinal mucosa Broken mucosal barrier increases susceptibility to infections Chemotherapy destroys circulating neutrophils Chemotherapy impairs bone marrow stem cells ↓ Production of neutrophils Neutropenia (Absolute Neutrophil Count (ANC) < 0.5x109 cells/L ↓ Immune cell ↓ Production of engulfment of microbes inflammatory mediators Fewer circulating neutrophils blunts the innate immune response Pathogens enter bloodstream from tissues Systemic infection Authors: Max Lazar Braxton Phillips Reviewers: Naman Siddique Michelle J. Chen Lynn Savoie* * MD at time of publication Dormant viral infections reactivate (e.g. cytomegalovirus, herpes simplex virus) ↑ Susceptibility to common bacterial infections Positive blood bacterial cultures Fever (T ≥ 38.3 oC or sustained T ≥ 38 oC for 1 hour) Immune system mounts an excessive inflammatory response that damages tissues and organs Sepsis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 5, 2018; updated Mar 30, 2024 on www.thecalgaryguide.com

Spontaneous Rupture of Membranes

Pre-Labour Rupture of Membranes: Pathogenesis and clinical findings Gestational age approaching term (>37 weeks) Authors: Wendy Xu Reviewers: Riya Prajapati Michelle J. Chen Dr. Jadine Paw* * MD at time of publication Intrauterine inflammation Fetal maturation Fetal growth Uterine contractions ↑ Pro-inflammatory cytokine & chemokine release in fetal membranes & amniotic fluid ↑ Stretch forces on fetal membranes ↑ Pro-apoptotic factors induces cellular apoptosis of fetal membranes Changes in collagen and protein composition drive extracellular matrix remodeling in fetal membranes ↓ Tensile strength Structural weakening of fetal membranes Occurs primarily in the focal area of fetal membranes overlying the cervix ↑ Matrix metalloproteinases triggers extracellular matrix degradation in fetal membranes Amnion and choriodecidua separation Amniotic fluid flows from vagina Amniotic fluid pools in posterior fornix on speculum exam Pre-labour rupture of membranes Membranes rupture before onset of uterine contractions Chorioamnionitis (infection of the fetal membranes and amniotic fluid) Neonatal infection Endometritis (infection of the endometrium) Amniotic fluid leaks through the cervix Prolonged rupture of membranes (>18hrs) before delivery Microbes ascend through vaginal canal Low amniotic fluid volume on ultrasound Amniotic fluid (pH 7.0-7.5) mixes with normal vaginal fluid (pH 4.5-6.0) which increases vaginal fluid pH to > 6.5 Positive nitrazine (pH indicator) test Ion- and estrogen-containing amniotic fluid enters vaginal canal Ferning (branching pattern) of vaginal fluid under microscope Accompanies uterine contractions, cervical effacement & cervical dilation Delivery/birth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 4, 2024 on www.thecalgaryguide.com

Vaccine-Mediated Immunity General Physiology

Vaccine-Mediated Immunity: General Physiology Pathogen-derived antigen Adjuvants boost the immune response Preservatives inhibit microbial growth Stabilizers prevent vaccine degradation Vaccine components are formulated and administered to patient Antigen Presenting Cells (APCs) phagocytose and process antigen Adjuvants in vaccines activate local immune response ↑ Production of pro-inflammatory signals (chemokines & cytokines) Chemokines & cytokines act as signaling molecules that attract APCs to draining lymph nodes APCs present antigen on MHC I molecules to CD8+ T cells APCs present antigen on major histocompatibility complex II (MHC-II) molecules to naïve CD4+ T helper cells Recognition of antigenic material activates naïve CD4+ T helper cells A subset of naïve B cells differentiate into short-lived plasma cells Plasma cells produce antibodies Antibodies cover the pathogen’s surface (neutralization) Antibody-coated pathogens are phagocytosed by macrophages/neutrophils (opsonization) ↑ Pathogen-specific antibody titers CD8+ T cells multiply to form an antigen- specific cytotoxic T cell population (clonal expansion) ↑ Lymphocyte counts Authors: Tanis Orsetti Reviewers: Allesha Eman Michelle J. Chen Dr. Russell Sterrett* Prevention of specific pathogen from causing severe disease upon subsequent exposure * MD at time of publication Some activated CD4+ T helper cells stimulate naïve B cells A subset of activated CD4+ T helper cells differentiate into memory CD4+ T cells A subset of CD8+ T cells differentiate into memory CD8+ T cells A subset of naïve B cells differentiate into memory B cells Memory B cells circulate the body and monitor for secondary exposure to the pathogen Memory T cells circulate the body and monitor for secondary exposure Memory T cells are activated upon secondary exposure to the pathogen Activated memory T cells differentiate into effector T cells Memory B cells differentiate into plasma cells when there is a secondary exposure to the pathogen Effector CD4+ T helper cells stimulate B lymphocytes CD8+ cytotoxic T cells induce apoptosis of infected cells Vaccine-Mediated Immunity Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Nov 23, 2024 on www.thecalgaryguide.com

Barretts Esophagus

Barrett’s Esophagus: Pathogenesis, clinical findings and complications Gastroesophageal Reflux Disease (GERD) Authors: Sophia Khan Reviewers: Claire Song Shahab Marzoughi Sylvain Coderre* * MD at time of publication Reflux of stomach acid, bile salts + digestive enzymes through lower esophageal sphincter (located at junction between esophagus and stomach) Chronic reflux exposure to squamous epithelium (cells lining distal esophagus) Squamous epithelial cells release inflammatory cytokines: interleukin-8 and interleukin-1beta Inflammation of squamous epithelium Adaptive changes of squamous epithelium to prevent damage by acidic reflux Migration of stem cells in gastric cardia (proximal region of the stomach) into distal esophagus Replacement of esophageal squamous epithelium by gastric columnar epithelium Conversion (metaplasia) of normal esophageal squamous epithelium into abnormal gastric columnar epithelium with interspersed goblet cells Z line (the squamocolumnar junction between the esophagus and stomach) is irregular and displaced proximally on esophagus on endoscopy Heartburn (retrosternal burning sensation from stomach reflux) Regurgitation (involuntary expulsion of stomach content back into esophagus) Development of goblet cells (intestinal mucus-producing cells) within esophageal epithelium Abnormal presence of goblet cells on histology of distal esophagus Abnormal presence of columnar epithelial cells on histology of distal esophagus ↑ Atypical proliferation & ↓ apoptosis of Barrett’s epithelial cells Dysplasia (disordered growth of cells with the potential to develop into cancer) of Barrett’s epithelium Esophageal adenocarcinoma Improper division of nuclear chromatin (packaged DNA) Cellular nuclei increase in size due to retained chromatin from improper division Excess chromatin absorbs more stain during histology Double- stranded DNA breaks Nuclear enlargement on histology Continued acidic reflux causes oxidative DNA damage Hyperchromatic (darkly stained) nuclei on histology Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 2024 on www.thecalgaryguide.com

Ptosis

Ptosis: Pathogenesis and Clinical Findings Neurogenic causes of low Mechanical causes of low eyelid position Mass lesion of the upper eyelid (Chalazion, hemangioma, malignancy, etc.) Gravitational effect from excess eyelid weight Traumatic causes of low eyelid position Direct injury limits function of LPS or conduction of generated force to the tarsal plate Laceration of the LPS limiting its function or transection of the levator aponeurosis Congenital causes of eyelid drooping Fibrofatty replacement of the LPS muscle at birth Reduced levator function eyelid position Insult to the oculomotor nerve (CNIII) (e.g., compressive, microvascular, demyelinating) CNIII innervates levator palpebrae superioris, the main muscle responsible for upper eyelid elevation Insult to the sympathetic innervation (e.g., Horner’s syndrome) Ocular sympathetic innervate the Muller muscle, which provides approximately 2mm of the upper eyelid’s height Neuromuscular or myogenic causes of low eyelid position (e.g., myasthenia gravis) LPS muscle myopathy or defect at its neuromuscular junction that limits the elevation of the eyelid Aponeurotic causes of low eyelid position Involutional change (disinsertion) of the levator aponeurosis which connects the LPS to the tarsal plate Ptosis (also called blepharoptosis) Abnormally low position of the upper eyelid ↓ distance between the central corneal light reflex (as produced by an examiner’s penlight) and the level of the center of the upper-eyelid margin ↓ Margin-Reflex Distance (Normal: 4-6mm) Obstruction of the pupil/visual axis Decreased or occluded superior visual field ↓ distance between the upper eyelid margin and the lower eyelid margin ↓ Palpebral Fissure Height (Normal: 10-12mm) Flattening of the peripheral cornea by eyelid pressure Induced with-the-rule astigmatism Authors: Mina Mina Reviewers: Aicha Djaoutkhanova Shahab Marzoughi Lucy Yang Mao Ding William Trask* * MD at time of publication Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published December 29, 2024 on www.thecalgaryguide.com

Ankle Fracture

Ankle fracture: Pathogenesis and clinical findings High mechanical force to ankle Risk factors Age Post-menopause ↓ Osteoblast activity Twisting force (e.g. sports injury) Crushing force (e.g. limb Loading force entrapment beneath heavy object) (e.g. fall) Force exceeds mechanical strength of bone Ankle eversion or inversion Osteoporosis Compromised bone scaffolding & repair impairs the structural integrity of bone. Force required for fracture is lowered Ankle Fracture (Fracture of the talus and/or the distal 6 cm of the tibia and/or fibula) Fractured bone is displaced through the dermal layers Open Fracture Compromised dermal layers create an opportunity for pathogens to enter the wound site Infection Multiple malleoli are fractured within the ring of the ankle Lack of ligamentous & bone support makes ankle joint unstable Displacement of bone from fracture site Misalignment of bone segments prevents regeneration & union Malunion of unreduced fracture Ligamentous injury occurs concurrently from excessive tensile force Fractured bone disrupts surrounding vasculature Hyaline cartilage of the articulating surface is damaged Trauma induces synovitis, chondrocyte apoptosis, & necrosis Fractured bone disrupts surrounding peripheral nerves Numbness Localized Pain Pain is induced when the patient attempts to weight bear Inability to weight bear Authors: Ethan Smith Reviewers: Nojan Mannani Michelle J. Chen Dr. Gerhard Kiefer* * MD at time of publication Platelets are exposed to the extravascular environment, thereby releasing platelet derived factors & complement factors Plasma coagulation cascade is activated Chondrocyte dysfunction in proliferation Reduced synovial functioning ↑Vascular permeability from inflammatory cytokines Protective hematoma forms in the joint space Hyaline cartilage loss Lost cartilage over time degrades proper articulation & causes joint narrowing, osteophytes, subchondral sclerosis Post traumatic osteoarthritis Edema Fluid in the joint space changes position of bony articulations Bruising Restricted range of movement Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 30, 2024 on www.thecalgaryguide.com

Pituitary Tumour Classification and Clinical Outcomes

Pituitary Tumour: Classification and clinical outcomes Functional tumour: Secretes excess Non-functional tumour (30%) (lack of hormone-producing cells or due to gene mutations) Authors: Chris Oleynick Caroline Kokorudz Reviewers: Amyna Fidai Laura Byford- Richardson Joseph Tropiano Julia Gospodinov Luiza Radu Hanan Bassyouni* * MD at time of publication hormones (70%) Relative abundance & predisposition for lactotroph (prolactin-producing), somatotroph (growth hormone – producing), thyrotroph (TSH producing) & corticotroph (adrenocorticotropic hormone – producing) cells to form adenomas (epithelial cell tumours) ↑ Lactotroph cells ↑ Prolactin (PRL) (most common) Hyper- prolactinemia (high prolactin blood levels) ↑ Somatotroph cells ↑ Growth hormone (GH) Acromegaly* (excess tissue growth & metabolic dysfunction) ↑ Corticotroph cells ↑ Adrenocortico- tropic hormone (ACTH) Cushing disease* (prolonged exposure to excess cortisol) ↑ Thyrotroph cells ↑ Thyroid stimulating hormone (TSH) Central hyper- thyroidism (↑ T4 & T3) Large size (macro) (>10mm on MRI) may cause mass effect (tissue compression from mass) Small size (micro) (<10mm on MRI) unlikely to cause mass effect (compression to surrounding structures) Asymptomatic Headache Nausea & vomiting Compresses pituitary gland & impairs blood supply & function of pituitary cells Impinges pituitary stalk & disrupts hormone transport from hypothalamus to the anterior and posterior pituitary Compresses surrounding structures ↑ Pressure & stretching of dural mater Stretching of the meninges activates mechanoreceptors (stretch receptors) in GI tract Pituitary hormone deficiency (typically in left-right order with mass effect): Dopamine release obstruction ↓ Inhibition of prolactin secretion Antidiuretic hormone (ADH) obstruction Inferior tumour growth Growth into sphenoid sinus Lateral growth of the tumor compresses surrounding cranial nerves Superior tumour growth ↓ GH ↓ Protein production & muscle cell proliferation ↓ Luteinizing hormone (LH) (triggers ovulation & sex hormone synthesis) & follicle stimulating hormone (FSH) (stimulates ovarian follicles & sperm growth) ↓ (TSH) ↓ ACTH (stimulates cortisol & androgen release) Cranial nerve (CN) II (optic) ↓ Visual acuity Diplopia (double vision) CN III, (oculomotor) IV (trochlear), or VI (abducens) Ptosis* (drooping upper eyelid) CN V (trigeminal) branches V1 & V2 Facial numbness Ophthalmoplegia (eye muscle paralysis) Compresses optic chiasma Bitemporal hemianopsia (decreased lateral peripheral vision) Tumour extends into hypothalamus Hypothalamic dysfunction due to damage to hypothalamic cells Disruption of multiple regulatory systems (i.e. sleep-wake cycles, appetite, temperature) Tumour occludes ventricles Tumour obstructs CSF flow ↑ Intracranial pressure Hydrocephalus* (abnormal buildup of CSF in ventricles of the brain) and papilledema Bacteria migrates from sinus flora into sphenoid sinus Cerebrospinal fluid (CSF) leaks into throat Post-nasal drip and nasopharyngeal mass Stunted growth and short stature in children ↓ Muscle mass & fatigue Diabetes insipidus* (excessive urination & extreme thirst) Central hypothyroidism* (↓ T4 & T3) Hyperprolactinemia Meningitis* (inflammation of the meningeal layers of central nervous system) *See relevant Calgary Guide slide Hypogonadotropic hypogonadism (↓ Sex hormones) Adrenal insufficiency* (↓ 8 AM cortisol) Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Oct 1, 2027; updated Jan 5, 2025 on www.thecalgaryguide.com

Varicella Zoster Virus

Varicella Zoster Virus (VZV) - Chicken Pox: Pathogenesis and clinical findings Exposure to individual with VZV infection VZV enters respiratory tract & conjunctiva VZV enters dendritic cells (DC) DCs travel to regional lymph nodes Primary viremia Authors: Morgan Garland, Sean Spence VZV replicates VZV proteins ↑ major ↓ MHCI Reviewers: in nasopharynx histocompatibility expression Yan Yu, Danny Guo, & CD4+ T cells complex class I on CD4+ T Emily J. Doucette, (MHCI) degradation cell surface Laurie Parsons*, James D. Kellner* *MD at time of publication Acute phase VZV evades the immune system VZV travels through the blood in CD4+ T cells Immune cells release cytokines to fight the virus (stronger in adults) Fluid & cellular debris accumulate between epidermal layers Generalized pruritic (itchy) vesicular rash at different stages of development (macule, papule, vesicle) Immune system activates & releases inflammatory compounds VZV replicates in liver, spleen & lymph nodes Erythema (redness) & pain Scratching lesions introduces bacteria Fibroblasts lay down collagen to heal skin lesions Resets thermostat in hypothalamus Systemic response Tissue damage in oropharynx Direct inflammation in neural tissues Cerebellar ataxia (more common in children) Bacterial superinfection from S. aureus & Streptococcus pyogenes (more common in children) Scarring Fever (prodromal) Malaise (prodromal) Sore throat (prodromal) Encephalitis (more common in adults) Abscess Cellulitis Toxic shock syndrome (TSS) Secondary viremia Immune cells release cytokines to fight infection (stronger in adults) Inflammation & fluid build up in lungs VZV travels through the blood in CD4+ T cells expressing skin homing receptors Fluid & cellular debris accumulate in damaged alveoli Lungs more susceptible to secondary bacterial infection Pneumonia** (more common in adults) VZV colonizes keratinocytes over several days VZV colonizes neurons & glial cells in the brain VZV colonizes alveolar epithelial cells Resolution & latency VZV tracks along neurons from sites of infection to dorsal root ganglia & cranial nerves ↓ MHCI expression in sensory ganglia Adaptive immune system controls viremia ↓ Viral gene expression Resolution of VZV infection & development of lifelong immunity Direct viral toxicity (DNA damage, mitochondrial dysfunction, & protein misfolds in infected cells) Apoptosis & dysfunction of infected cells Latent infection Stress or immune suppression may precipitate reactivation of VZV later in life Shingles** **See corresponding Calgary Guide slide Pathophysiology Mechanism Published Nov 12, 2012; updated Jun 22, 2025 on www.thecalgaryguide.com Legend: Sign/Symptom/Lab Finding Complications

Apert Syndrome

Apert Syndrome: Pathogenesis and clinical findings Gain of function mutation in fibroblast growth factor 2 receptor (FGFR2) on chromosome 10q Mutated FGFR2 protein has ↑ ligand binding & signalling activity Osteoblasts undergo early differentiation & maturation in response to ↑ FGFR2 ↑ Bone deposition & ossification Osteoblast progenitors proliferate at ↑ rate Abnormal mesenchymal differentiation in response to ↑ FGFR2 Authors: Merry Faye Graff, Taylor Krawec Reviewers: Emily J. Doucette, Ryan Frank* * Indicates MD at time of publication Apert Syndrome (Acrocephalosyndactyly Type I) A rare genetic disorder characterized by multisuture craniosynostosis, midface retrusion, & syndactyly of the hands & feet Craniofacial Abnormalities Premature differentiation of neural crest-derived mesenchyme in face Underdevelopment of midfacial bones (e.g. maxilla, zygoma) Orbit growth is rotated outward Extraocular muscles insert anomalously ↓ Control of eye movement Mesenchymal cells at palatal shelf undergo abnormal differentiation Palatal midline epithelial seam fails to undergo apoptosis Premature osteoblast maturation in suture mesenchyme Midface hypoplasia Hypertelorism (widely separated orbits) V-pattern exotropia (“V” shaped eye movement) ↓ Palatal shelf outgrowth & misalignment Bicoronal synostosis (premature fusion of coronal sutures) Shallow orbits displace globes forward Depressed nasal bridge ↓ Length of hard palate Abnormal eustachian tube development ↓ Anteroposterior growth of nasal cavity Cleft palate** Fusion of coronal sutures restricts anteroposterior skull growth Exorbitism (protruding eyes) Beaked nose ↓ Drainage of middle ear Choanal stenosis (narrowed nasal passages) Skull grows vertically as brain develops Cerebral spinal fluid accumulates in ventricles Incomplete eyelid closure ↑ corneal exposure & damage Class III malocclusion (underbite) V shaped dental arch High arched palate Recurrent ear effusions ↑ Nasal canal obstruction Breathing difficulty Turribrachycephaly (tower shaped skull) Ventriculomegaly (↑ ventricular size) Corneal scarring Exposure keratopathy Impaired ossicle function Conductive hearing loss Brain growth is restricted Developmental delay Limb & Skeletal Abnormalities Phalanges of fingers &/or toes undergo premature ossification ↑ Proliferation in apical ectodermal ridge at distal limb bud during embryonic development ↓ Regression of interdigital mesenchyme allow persistence of interdigital soft tissue bridges Other Abnormalities FGFR2 mutation leads to sebaceous gland hyperplasia & follicular keratinization Excess sebum production & follicular blockage Osseus syndactyly Legend: ↑ FGFR2 alters BMP & SHH signaling balance Pathophysiology Mechanism Sign/Symptom/Lab Finding Cutaneous syndactyly (may include nailbed) Severe acne Published Sept 16, 2025 on www.thecalgaryguide.com Complications

GLP-1 Receptor Agonists

Glucagon-like Peptide-1 (GLP-1) Receptor Agonists: Mechanism of action and side effects Management of Type 2 Diabetes Mellitus** Weight management Authors: Saania Tariq, Trevor Low Reviewers: Rafael Sanguinetti Luiza Radu, Emily J. Doucette Activated GLP-1 receptors in Activated GLP-1 Hanan Bassyouni* * MD at time of publication the myenteric plexus inhibit receptors stimulate gastric motor neurons pancreatic islet cells GLP-1 Receptor Agonists Synthetic analogs (e.g., Semaglutide) of GLP-1 peptide hormone endogenously produced by intestinal enteroendocrine L cells directly activate GLP-1 receptors to modulate food intake & glucose metabolism ↓ Gastric motility ↑ Pyloric sphincter tone via disinhibition ↓ Glucagon release from α-cells ↑ Regeneration, ↑ growth & ↓ apoptosis of β-cells Slowed gastric emptying Subcutaneous injection or oral ingestion prolongs GLP-1 receptor activation ↑ β-cell function & glucose- dependent insulin production GLP-1 receptor activation on neurons in the arcuate nucleus of the hypothalamus modulates appetite & satiety Activation of GLP-1 receptors in the gastrointestinal system regulates metabolism Prolonged gastric distension & stasis activates chemoreceptors & mechanoreceptors Delayed digestion of gastric contents ↓ glucose spikes after meals ↑ Glycogen synthesis & glucose uptake in liver & skeletal muscles Neuropeptide Y & agouti-related protein expressing neurons are hyperpolarized Pro-opiomelanocortin expressing neurons become ↑ excitable Activated GLP-1 receptors signal to hypothalamus via vagus nerve afferents ↑ Vagal afferent signaling to area postrema (vomiting centre) Nausea & vomiting ↓ Release of neuropeptide Y & agouti-related protein ↑ Anorexigenic signalling ↑ Parasympathetic output via dorsal motor nucleus of vagus nerve GLP-1 agonists directly activate receptors in area postrema ↑ Satiety (feeling of fullness) ↓ Adiposity (weight loss) ↓ Orexigenic drive ↓ Inflammatory stress in pancreatic β-cells ↑ β-cell function improves insulin secretion ↓ Appetite ↓ Caloric intake ↓ Inflammatory cytokines & lipotoxicity ↓ Systemic inflammation ↑ Insulin sensitivity in skeletal muscle & liver **See corresponding Calgary Guide slide Legend: Sign/Symptom/Lab Finding Pathophysiology Mechanism Complications ↓ Hepatic glucose production (glycogenolysis) ↓ Fasting & postprandial blood glucose ↓ Red blood cell (RBC) glycation (glucose irreversibly binds to hemoglobin in RBCs) ↓ Production of glycated proteins and lipids ↓ % of glycated RBCs over time ↓ Vascular endothelial damage and atherosclerosis ↓ Endothelial damage to glomeruli ↓ Hemoglobin A1c ↓ Risk of cardiovascular complications ↓ Risk of renal complications Published Jun 22, 2025 on www.thecalgaryguide.com

Lithium

Lithium: Mechanism of action and side effects Bipolar (I & II) Treatment-resistant depression Accumulated Li inhibits adenylyl cyclase Suicidality Schizoaffective Disorder Li passively enters cells in kidney, thyroid, & area postrema via sodium channels Li’s small size prevents active transport out of cells ↓ cAMP ↓ PKA phosphorylation Lithium (Li) Magnesium (Mg²⁺) analog which inhibits Mg²⁺-dependent enzymes such as glycogen synthase kinase-3β (GSK-3β) & inositol monophosphatase (IMPase). This activity modulates neuroplasticity, inflammation, & mood regulation. ↓ T3/T4 synthesis & release from thyroid Authors: Rida Mahmood, Hadi Hassan Reviewers: Taryn Stokowski, Emily J. Doucette, Rohit Ghate* * MD at time of publication ↓ T3/T4 ↑ TSH ↓ Aquaporin insertion in principal cells of collecting ducts of kidneys ↓ Water reabsorption Nephrogenic diabetes insipidus** Li carbonate (an inorganic salt) irritates gastric mucosa Li stimulates chemoreceptor trigger zone Subclinical or overt hypothyroidism Li competes with Mg2+ at cofactor site of IMPase & GSK-3β Enterochromaffin cells ↑ serotonin release ↑ Gut motility & vagal afferent nerve activation Activation of vomiting center in area postrema Nausea & vomiting** ↓ GSK-3β activity throughout brain IMPase & inositol polyphosphate phosphatase (IPP) inhibition prevents hydrolysis of inositol monophosphate to free inositol within neurons Inhibited IRS & ↓ Phosphorylation of transcription factors, PI3K/Akt signaling signaling proteins, & metabolic enzymes ↓ GLUT4 translocation & ↓ glucose uptake in muscle & adipose tissue ↓ Systemic insulin sensitivity Weight gain ↓ Downstream dopamine release in mesolimbic, mesocortical, & nigrostriatal pathways ↓ Conversion of inositol into phosphatidylinositol 4,5-bisphosphate (PIP2) ↓ Pro-apoptotic signaling (Bax, p53, & caspases) ↓ neural apoptosis ↑ Neurotrophic signaling (Akt & MAPK/ERK) ↓ D2 receptor stimulation in nucleus accumbens, prefrontal cortex, & striatum Sustained cAMP Response Element- Binding Protein activity promotes gene transcription ↑ Circadian clock proteins & transcription factor (CLOCK, BMAL1, CRY1, & PER2) stabilization in suprachiasmatic nucleus ↓ PIP2 available for cleavage into second messengers inositol triphosphate (IP3) & diacylglycerol (DAG) during G Protein activation ↓ Dopaminergic inhibition of GABAergic interneurons ↓ Availability of IP3 & DAG ↓ Reward drive in nucleus accumbens ↓ Drive & arousal in prefrontal cortex Dopamine & acetylcholine imbalance in striatum ↑ Circadian rhythm stabilization Thalamocortical motor circuit instability ↑ Brain-Derived Neurotrophic Factor expression in hippocampus & prefrontal cortex Improved sleep timing & stability ↓ Impulsivity Glutamatergic signalling stabilizes (↓ release, ↑ reuptake, ↓ NMDA activity) ↓ Aggression ↑ Involuntary rhythmic muscle activity ↑ Neuronal survival, synaptogenesis, & dendritic growth ↓ Tau hyper- phosphorylation ↑ GABAergic inhibition Excitatory–inhibitory balance in cortical & limbic regions normalizes ↓ Psychomotor agitation Upper extremity postural tremor ↑ Gray matter volume & prefrontal cortex– hippocampus connectivity Neuroprotection & ↓ dementia risk Prefrontal cortex exerts better top-down control ↓ Amygdala hyper-responsivity ↑ Hippocampal regulation of thought loops Improved ↓ Irritability ↓ Mood lability decision-making ↑ Working memory ↓ Distractibility ↓ Racing thoughts Mood stabilization (↓ frequency & severity of manic & depressive episodes) ** See Corresponding Calgary Guide slides Legend: Pathophysiology Mechanism Pharmacologic Effect Side Effects Published Nov 2, 2025 on www.thecalgaryguide.com

Acute Tubular Necrosis

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

Infectious Large Bowel Diarrhea

Infectious large bowel diarrhea: Pathogenesis and clinical findings Bodily fluids, organ transplantation (active in immuno- compromised hosts) Contaminated food, water, poor sanitation Eggs, contaminated Undercooked poultry Undercooked pork Contaminated food, water produce, undercooked poultry Unpasteurized milk Undercooked beef, contaminated vegetables Antibiotic use, healthcare associated infection Cytomegalovirus S. enteritidis, S. Enteroinvasive Enterohemorrhagic typhimurium E. histolytica Y. enterocolitica E. coli (EIEC) Shigella E. coli (EHEC) C. jejuni C. difficile Individual ingests an adequate amount of organism Bacteria employ protective mechanisms to survive gastric acid Organism adheres to colonic wall & colonizes the large bowel Organism releases a toxin that disrupts the colon (enterotoxin) Invading organisms activate local immune surveillance Toxins A & B (from C. diff) disrupt tight junctions between colonocytes Toxin enters bloodstream Release of pro-inflammatory cytokines triggers colonic inflammation Cytokines Inflammation &/or toxins stimulates act on nerve endings hypothalamus in rectal wall to trigger temperature change (pyrogens) Inflammation dysregulates enteric nervous system Inflammation spreads to visceral peritoneum Inflammation & invading bacteria breaks down colonic mucosa Triggers apoptosis of colonocytes Massive neutrophilic infiltration Toxin reaches the chemoreceptor trigger zone in medulla Shiga toxins (from Shigella or EHEC) bind to Gb3 receptors on endothelial cells Pseudomembranous colitis on endoscopy Abnormal peristalsis & spasms Diffuse abdominal pain & cramping Nausea & vomiting Toxin enters cells via endocytosis Fever Colonic epithelium loses Na⁺ resorptive channels Colonic epithelial cells secrete ↑ Cl⁻ into lumen ↑ Sense of urgency & incomplete evacuation (Tenesmus) Inflammation & organisms disrupts blood vessels & mucosa develops ulcers Intestine absorbs ↓ fluid from lumen Intestine secretes ↑ fluid into lumen Shiga toxin activates platelets (mechanism unclear) Toxin inhibits protein synthesis & induces apoptosis Authors: Merry Faye Graff, Noriyah Al Awadhi, Yan Yu Reviewers: Paul Ratti, Jason Baserman, Sergio F. Sharif Kerri Novak*, Sylvain Coderre* *Indicates MD at time of publication **See corresponding Calgary Guide slide Small volume diarrhea Ulcers bleed into colonic lumen Volume depletion Platelet activation & endothelial cell damage promote microthrombi formation within systemic vasculature Dehydration Hypotension Bloody stool (can be nocturnal) Hemolytic uremic syndrome** Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Aug 7, 2012; updated Nov 23, 2025 on www.thecalgaryguide.com