SEARCH RESULTS FOR: Hypothyroidism

Hyponatremia- Physiology

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

Hypoxemia- Pathogenesis and clinical findings

Hypoxemia- Pathogenesis and clinical findings interstitial lung disease pulmonary hypertension thickening of interstitium vasculature diffusion across alveolar membrane diffusion limitation exertional desaturation PE AVM pneumonia atelectasis cardiac defects airways disease inefficient blood flow ventilated areas blood bypasses aerated alveolar tissue V:Q mismatch R L shunt negligible significant improvement paO2 response 100% O2 Central drugs coma hypothyroidism peripheral damaged lung structure chest wall disorders minute ventilation alveolar gas exchange altitude barometric pressure driving pressure diffusion across membranes inspired a-a gradient hypoxemia tissue hypoxia cyanosis anaerobic metabolism organ brain anoxic angina

Pathogenesis-of-Female-Infertility

Pathogenesis of Female Infertility Author: Simonne Horwitz Reviewers: Claire Lothian, Hannah Yaphe, Yan Yu*, Nicole Paterson* * MD at time of publication Extreme stress, eating disorder, excessive exercise, intracranial tumor, or hyperprolactinemia* ↓ Gonadotropin releasing hormone (GnRN) from hypothalamus ↓ release of Luteinizing hormone (LH) & Follicle stimulating hormone (FSH) by pituitary ↓ release of estrogen by ovaries Anovulation (oocyte is not released) Fewer follicles available to ovulate * Causes of Hyperprolactinemia include: prolactinoma (prolactin-producing tumor), hypothalamic infiltrate or mass, chest wall irritation, hypothyroidism, renal or liver disease (↓ prolactin clearance), dopamine antagonists that ↑ prolactin secretion (antipsychotics, anti- depressants, anti-emetics) Polycystic ovary syndrome (see PCOS: Pathogenesis and Clinical findings) ↑ androgen production & ↑ estrogen earlier in the menstrual cycle ↓ FSHà↓ follicle growth ↑ rate of follicle depletion Oocyte not available every month for fertilization Premature ovarian insufficiency due to unexplained causes, chemotherapy, radiation, autoimmune ovarian destruction, Turner’s & Fragile X Syndromes Damage in germ cells that accumulates over a woman’s lifetime Age-related changes in quality of granulosa cells surrounding oocyte Genetic damage accumulates, such as ↑ rates of meiotic nondisjunction (failure of chromosomes to separate during gamete cell division) Tubal occlusion or ↓ transport of oocyte tubal cilia dysfunction through fallopian tube ↓ quality of oocytes Normal transport of oocyte & sperm through fallopian tube is impaired ↓ facilitation of sperm transportation Inhibits normal zygote implantation Chlamydial or gonorrhoeal pathogens Previous tubal surgery or ectopic pregnancy surgery tissue removal ↓ transport of oocyte through fallopian tube Female Infertility Previous abdominal infection or surgery Endometriosis Congenital malformations or trauma / surgery to cervix Uterine leiomyomata (benign smooth muscle monoclonal tumor) or polyp Intrauterine procedures Pelvic adhesions (scar-like tissue that tether together abdominal organs) may distort the shape and normal anatomy of the fallopian tube Ectopic endometrial cells implant & Local inflammatory response grow along pathway of egg/sperm further ↓ egg/sperm mobility Inability of cervix to produce normal mucus, and/or sperm physically unable to enter the cervix Submucosal or intracavitary component disrupts uterine lining Trauma to basalis layer of endometrium Intrauterine scarring or synechiae (adhesions) ↓ vascularization & endometrial regrowth Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published October 25, 2020 on www.thecalgaryguide.com

abnormal-uterine-bleeding-aub-pathogenesis-and-clinical-findings

Abnormal Uterine Bleeding: Pathogenesis and clinical findings Authors: Joshua Yu, Karen Paik Reviewers: Ayaa Alkhaleefa, Parker Lieb, Hypothyroidism Hypothalamus senses ↓ serum thyroxine ↑Thyrotropin releasing hormone (TRH) release from hypothalamus ↑Prolactin (see Feedback Loop: Prolactin) Exogenous estrogen (e.g. estrogen-only birth control) ↑ Peripheral adipose tissue ↑ Aromatase (enzyme present in adipose tissue) ↑ Conversion of androgens to estrogens (aromatization) Excessive stress, exercise, low body mass (mechanism unclear) ↓ Hypothalamic gonadotropin releasing hormone secretion ↓Luteinizing hormone and follicle stimulating hormone release from pituitary ↑ Estrogen Heavier bleeding Angiogenesis in tumour tissue Polycystic ovarian syndrome (see slide) Pelvic inflammatory disease Immature hypothalamic- pituitary-ovarian axis (an immature axis is transient in most females) ↓ Positive feedback of estrogen in late follicular stage No LH surge Adenomyosis (endometrial tissue grows into uterus muscular wall) Endometrial polyps Retained products of contraception Infection Inflammation of endometrium Endometrium is more fragile Anovulatory Bleeding Leiomyoma (benign tumour in myometrium) Tara Shannon, Hannah Yaphe, Dr. Sarah Glaze* * MD at time of publication Ovarian Scarring Foreign bodies Intrauterine device perforation Physical trauma Impaired follicle maturation Anovulation Corpus luteum does not form No ovarian progesterone production ↑ Estrogen to progesterone ratio Proliferative effect of estrogen unopposed Endometrial proliferation No progesterone to organize growing endometrium Disorganized endometrium overgrows and sloughs off Irregular bleeding Menopause Premature ovarian insufficiency Intermittent congestion of polyp blood supply Transient ischemia and slight polyp necrosis Altered growth factor production Vascular dysregulation and leakier vessels Coagulopathies (e.g. von Willebrand disease) Impaired hemostasis Invasion of normal tissue ↓ Estrogen (hypoestrogenism) Atrophy of endometrium and vulvovaginal tissue Dry endometrial surfaces (↓ fluid to prevent friction) Endometrial carcinoma Micro- erosions of epithelium Inflammation Evidence unclear Heavier and more irregular bleeding Spotting Heavier and more irregular bleeding Light bleeding and spotting Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published May 2, 2022 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

Constipation in Children

Constipation in Children: Pathogenesis and clinical findings Neonate / Infant (≤1 years old) Older Child (>1 years old) Dietary (e.g., lack of fluids / fiber) Mechanical (e.g.,. intestinal Atresia, anal atresia) Congenital malformation (narrowing, absence, or malrotation) of structure of intestine / anus Interrupted flow of bowel contents Genetic (e.g., cystic Fibrosis) Mucous blocks pancreatic duct Inability of pancreatic enzymes to reach small intestine ↓ Digestion after a meal Large, thickened stool Neurologic (e.g., Hirschsprung's disease) Congenital disruption of the migration of neural crest cells to the distal colon Affected segment of the colon fails to relax Progressive secondary dilation of the healthy proximal colon Systemic (e.g., hypothyroidism) Thyroid hormone deficiency Reduction in the stimulation of gut tone & contractility by thyroid hormones ↓ Peristalsis (intestinal contractions) of the bowel Dietary (e.g., lack of fluids/ fiber) Mucosal (e.g., celiac disease) Inappropriate immune response against gluten Intestinal mucosal injury Malabsorpti on of water and other nutrients Functional (e.g., pain) Prolonged stool retention in bowel ↑ Time in bowel causing over- absorption of water from stool into the large intestine Mechanical (e.g., bowel obstruction) Mechanical obstruction in the intestines Interrupted flow of bowel contents Intestinal obstruction Neurologic (e.g., neglect, physical abuse) Disturbance in brain-intestine axis Mechanisms not fully understood Visceral hyper- sensitivity (increased pain sensation) Withholding behaviour Lack of soluble fiber ↓ Attractive forces between water & stool Prevention of secretion of water into stool Lack of insoluble fiber ↓ Stool bulk and laxation ↓ Secretion of water & mucous into stool Lack of soluble fiber ↓ Attractive forces between water & stool Prevention of secretion of water into stool Lack of insoluble fiber ↓ Stool bulk and laxation ↓ Secretion of water & mucous into stool Formation of dry & hard stool Formation of dry & hard stool Difficulty passing stool Difficulty passing stool Authors: Jennifer Wytsma Reviewers: Sophia Khan, Shahab Marzoughi, Sylvain Coderre* * MD at time of publication Intestinal obstruction Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Dec 15, 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

PROP1-Related Combined Pituitary Hormone Deficiency

↓ DNA-binding & transcriptional Impaired pituitary stem cell differentiation & anterior pituitary development ↓ Prolactin (PRL) from lactotrophs Impaired mammary gland stimulation prevents adequate milk production PROP1-Related Combined Pituitary Hormone Deficiency: Pathogenesis and clinical findings Consanguinity Inherited PROP1 mutation Family history of PROP1 mutation Sporadic PROP1 mutation Autosomal recessive or sporadic mutation of PROP1 on chromosome 5q35 (various mutations identified; ex. frameshift, insertion, deletion) activation ability of pituitary- specific transcription factor encoded by PROP1 gene PROP1-Related Combined Pituitary Hormone Deficiency Genetic disorder resulting in combined pituitary hormone deficiency (CPHD) characterized by a deficiency in growth hormone (GH) & ≥ 1 additional anterior pituitary hormone ↓ Follicle stimulating hormone (FSH) from somatotrophs ↓Luteinizing hormone (LH) from gonadotrophs ↓ GH from gonadotrophs ↓ Thyroid stimulating hormone (TSH) from thyrotrophs ↓ Adrenocorticotropic hormone (ACTH) from corticotrophs ↓ Gonad stimulation ↓ Sex hormone production Hypogonadotropic hypogonadism (hypogonadism due to problem at level of hypothalamus or pituitary) ↓ Secretion of insulin-like growth factor 1 (primarily ↓ Stimulation of growth at ↓ Thyroid stimulation ↓ Stimulation of adrenal glands epiphyseal plate of long bones ↓ Thyroid by liver) ↓ Serum hormone levels cortisol Absent secondary sexual characteristics Delayed or absent puberty Short stature Secondary/central hypothyroidism** Secondary/central adrenal insufficiency** Postpartum lactation failure Authors: Juliette Eshleman Taylor Krawec Reviewers: Annie Pham Emily J. Doucette Danielle Nelson* *MD at time of publication Impaired glucose regulation (↓ gluconeogenesis, ↓ glycogenolysis & ↓ lipolysis) Altered stress response to illness or injury ↓ Vascular tone & catecholamine response (fight-or-flight response) Impaired glucose metabolism Neonatal hypoglycemia** Adrenal crisis Hypotension Weakness Fatigue **See corresponding Calgary Guide slide Legend: Pathophysiology Published May 19, 2025 on www.thecalgaryguide.com Infertility Mechanism Sign/Symptom/Lab Finding Complications

Obesity Hypoventilation Syndrome

Obesity Hypoventilation Syndrome: Pathogenesis and clinical findings Obesity (BMI ≥ 30 kg/m2) risk factors: Poor eating patterns, sedentary lifestyle, genetic predisposition, hypothyroidism, Cushing’s syndrome, socio-economic factors, age Sleep-disordered breathing risk factors: Family history, tonsillar or adenoidal hypertrophy, ↑ neck circumference, type 2 diabetes, HTN Authors: Mohammad Omer Mujtaba Siddique Reviewers: Ali Babwani Luiza Radu Jonathan Liu* MD at time of publication* ↑ Adipose deposition in abdomen Abdominal fat pushes against diaphragm ↑ Diaphragmatic displacement ↑ Resistance to chest wall expansion ↑Leptin resistance High pressure Pharyngeal on upper airway dilations unable Secondary depression ↓ Chest wall ↓ Leptins ability to stimulate ↑ lung to compensate Narrowing of (compromised function) of Poor ventilation to expansion ventilation (mechanism unknown) collapsibility for weight upper airways respiratory system lower lobes of lungs ↓ Tidal volume (air that moves in/out of lungs in a respiratory cycle) ↑ Respiratory rate ↑ Chest wall thickness ↑ Leptin (a hormone released by adipose tissues that controls hunger by signaling fullness) ↑ Adipose deposition near upper airways ↑ Buildup of edema in lower extremities ↑ Respiratory workload ↓ Chest wall compliance (ability to stretch) ↓ Leptin receptor expression ↓ Leptin through blood-brain barrier ↓ Pharyngeal space Respiratory system is unable to compensate to ↑ Fluid shifts from demands legs to neck during sleep Hypoventilation in sleep ↓ Ventilation (air exchange in lungs) ↑ PaCO₂ (partial pressure of arterial carbon dioxide) ↑ Serum [H+] ↑ Serum [HCO3 -] by renal reabsorption buffers [H+] rise ↓ PaO₂ (partial pressure of arterial oxygen) Hypoxia (low O₂ in tissue) Higher PaCO₂ required to reduce pH ↓ O₂ levels in alveoli triggers pulmonary vessel vasoconstriction PaCO₂ > 45 mmHG Respiratory acidosis ↓ response to CO₂ in central chemoreceptors in brain Pulmonary hypertension (high pressure in pulmonary arteries) ↓ Neural drive ↓ Ventilatory responsiveness ) Right heart pumps against higher pulmonary pressure leading to cardiomyocyte hypertrophy Cor pulmonale (right-sided heart failure) Fatigue Chronic hypercapnia (↑ CO2 retention) Pathophysiology Legend: Mechanism Sign/Symptom/Lab Finding Complications Morning headaches Daytime lethargy Published Jun 16, 2025 on www.thecalgaryguide.com

Sturge-Weber Syndrome

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

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

Hypothyroidism

Hypothyroidism: Pathogenesis & Clinical Findings Hashimoto’s thyroiditis Transient congenital hypothyroidism Congenital deficiency of thyroid hormone (TH) Iodine deficiency Infiltrative disease affecting thyroid gland cells Iatrogenic or medication- related thyroid dysfunction Hypothyroid phase of thyroiditis (inflammation of the thyroid) Pituitary gland dysfunction (central hypothyroidism) Progressive autoimmune destruction of thyroid gland cells ↓ T3/T4 levels activate the hypothalamus- pituitary-thyroid axis & ↑ TSH release by the pituitary gland Primary hypothyroidism (↑ TSH and ↓ T3/T4) ↓ T3/T4 levels cause ↓ expression of TH-dependent myocardial enzymes essential for cardiac contractility Cardiac myocytes (cardiac muscle cells) experience ↓ contractility ↓ Heart rate ↑ Bleeding Impaired function of the thyroid gland & ↓ thyroid hormone (TH) secretion Pituitary gland secretes ↓ levels of thyroid stimulating hormone (TSH) Hypothyroidism Low or significantly ↓ secretion of triiodothyronine (T3) & thyroxine (T4) from the thyroid gland ↓ T3/T4 levels ↓ production of nitric oxide (vasodilator) & cause systemic vasoconstriction of blood vessels Systemic vaso- constriction ↑ systemic vascular resistance ↑ Systemic vascular resistance à ↑ intrarenal vascular resistance & contributes to ↓ renal perfusion ↓ T3/T4 levels reduce the rate of metabolic reactions in the body including ↓ rates of carbohydrate, fat, & protein metabolism ↓ T3 levels allow fibroblasts (connective tissue cells) to synthesize ↑ glycosaminoglycans (GAGs – structural cell molecules capable of attracting large amounts of water) ↓ Basal metabolic rate (base energy required to sustain bodily functions) ↑ Diastolic blood pressure (diastolic hypertension) ↓ Renal blood flow à ↓ glomerular filtration rate (GFR) ↓ GFR impairs renal clearance of excess GAGs ↑ GAG deposits & water retention in body tissues ↓ Energy to support physiological function Narrowed pulse pressure (↓ difference between systolic & diastolic blood pressure) Compensatory mechanisms to manage blood volume & circulation during ↓ T3/T4 levels are overwhelmed in the presence of an infection or systemic trauma (e.g., heart attack, stroke) ↓ GFR impairs removal of excess free water from the blood volume by the kidneys ↑ GAG deposits & swelling in skin tissue ↑ GAG deposits in the larynx swell & stiffen vocal cords ↓ Skin gland activity & ↓ sebum (oil) & sweat production ↑ Fatigue ↓ Motility of the gastrointestinal (GI) tract causes ↓ movement of digested food & ↓ rate of waste excretion ↓ TH levels & ↓ metabolic rate impair neurologic function (e.g., neurotransmitter signaling & neuron functioning) Thickened skin Hoarse speech Dry skin ↑ Sodium (Na+) & water retention in blood volume ↓ Perspiration (sweating) Constipation Neurologic symptoms (e.g. depression, somnolence) Abnormally heavy menses Excessive water retention dilutes serum Na+ levels in severe hypothyroidism ↓ Caloric expenditure at rest & with activity ↑ Risk of infertility Myxedema coma** (extreme manifestation of hypothyroidism) Hyponatremia (↓ Na+) ↑ Fluid retention in body tissues Weight gain Musculoskeletal symptoms (e.g., muscle cramps, joint pain & ↓ muscle tone) Published June 19, 2013, revised November 23, 2025 on www.thecalgaryguide.com Normal or ↓ TSH levels when T3/T4 levels are low Authors: Sophia Khan, Ayden Hansen, Jessica Revington, Rupali Manek, Jaye Platnich Reviewers: Shahab Marzoughi, Gurreet Bhandal, Raafi Ali, Matthew Harding, Mark Elliott, Hanan Bassyouni*, Breanna McSweeney* * MD at time of publication **See corresponding Calgary Guide slides ↓ T3 levels lead to ↓ lipoprotein lipase (lipid metabolism enzyme) activity ↑ Triglyceride levels in blood ↓ TH levels & ↓ metabolic rate impair cold tolerance & thermogenesis (heat production) mechanisms Cold extremities (e.g. hands, feet) ↓ Cold tolerance ↓ Activation of the T3- mediated low- density lipoprotein (LDL) receptor gene ↓ LDL receptor expression for LDL clearance ↑ LDL cholesterol levels in the blood ↓ T3/T4 levels ↓ coagulation factor synthesis by the liver ↓ T3/T4 levels disrupt the menstrual cycle & cause anovulation (absence of ovulation) Legend: Hyperlipidemia Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications