Midterm Notes - Patho PDF

Modules 1-6 1 Inﬂammatory Response Inﬂammation is a critical component of the innate immune system, triggered by virtually any injury to vascularized tissues. It is a rapid and non-speciﬁc process aimed at containing the damage, eliminating pathogens, and initiating healing. The key features of the inﬂammatory response include: Activation: Occurs within seconds of tissue injury. Vascular changes: Vasodilation increases blood ﬂow to the site, causing redness and heat. Increased capillary permeability allows ﬂuid and cells to leak into the tissues, causing swelling and pain. Cellular events: Leukocytes, particularly neutrophils and macrophages, are recruited to the site of injury by chemotactic factors. They engulf and destroy pathogens and cellular debris through phagocytosis. Cytokines: Intercellular signaling molecules that regulate the immune response. Pro- inﬂammatory cytokines, such as TNF-α and IL-1, amplify the inﬂammatory response. Anti- inﬂammatory cytokines, such as IL-10 and TGF-β, dampen the response. Characteristics: Acute Inﬂammation: Characterized by redness, swelling, heat, pain, and loss of function. Key processes include vasodilation, increased vascular permeability, and leukocyte recruitment to the site of injury. Chronic Inﬂammation: Can result from unresolved acute inﬂammation or from persistent triggers such as infections, autoimmune diseases, or environmental toxins. Persistent inﬂammation, tissue destruction, and attempts at repair. This often leads to ﬁbrosis and scarring. o Characterized by the inﬁltration of lymphocytes and macrophages, followed by ﬁbroblast proliferation, connective tissue formation, and epithelial cell proliferation, potentially leading to scar or polyp formation. Granulomatous Chronic Inﬂammation: Macrophages and eosinophils wall oS and isolate a foreign body or infected area by forming a granuloma. This is commonly seen in infections caused by certain bacteria, fungi, and parasites, as well as autoimmune conditions. Cells Involved in Inﬂammation Mast cells: Located near epithelial surfaces and blood vessels, they immediately release histamine upon activation, causing vasodilation and increased vascular permeability. They also release chemokines, attracting other immune cells. o Mast cells also release cytokines like TNF-α, IL-4, IL-5, IL-6, and IL-13, which further amplify the inﬂammatory response and activate other immune cells Macrophages: Resident in tissues and recruited from the bloodstream, they engulf pathogens and cellular debris. They also release pro-inﬂammatory cytokines and present antigens to T helper cells, initiating the adaptive immune response. o Pro-inﬂammatory cytokines, such as TNF-α, IL-1, and IL-6, amplify inﬂammation, promote leukocyte recruitment, and induce systemic eSects like fever Modules 1-6 2 Dendritic cells: A specialized type of macrophage (antigen-presenting cells (APCs)) that bridge the innate and adaptive immune systems. They capture antigens in tissues, migrate to lymph nodes, and present antigens to T cells. Neutrophils: The most abundant leukocytes in the bloodstream, they are rapidly recruited to the site of inﬂammation and are highly eSective phagocytes. They also release enzymes and toxic reactive oxygen species (ROS) that kill pathogens but can contribute to tissue damage. o neutrophil extracellular traps (NETs), composed of DNA and antimicrobial peptides, which can trap pathogens but also contribute to inﬂammation and tissue damage Eosinophils: Primarily involved in defense against parasites, they also regulate vascular mediators released by mast cells. They are implicated in allergic reactions and can contribute to tissue damage. Innate Immune System The innate immune system is the body's ﬁrst line of defense against injury and infection. It provides an immediate, non-speciﬁc response to a wide range of threats, and consists of: Physical barriers: such as skin and mucous membranes, which prevent pathogens from entering the body. Biochemical barriers: such as antimicrobial peptides found in secretions like sweat and saliva. The human microbiome: a collection of beneﬁcial microorganisms that reside on body surfaces and compete with harmful pathogens. Cells: including mast cells, macrophages, and dendritic cells, which recognize and respond to pathogens and cellular damage. Adaptive Immune System The adaptive immune system provides a more speciﬁc and long-lasting response to pathogens, involving: T lymphocytes (T cells): Mature in the thymus and diSerentiate into: o T helper (Th) cells: Orchestrate the immune response by releasing cytokines that activate other immune cells. o T cytotoxic (Tc) cells: Directly kill infected or cancerous cells. o T regulatory (Treg) cells: Suppress the immune response, preventing excessive inﬂammation and autoimmunity. B lymphocytes (B cells): Mature in the bone marrow and diSerentiate into: o Plasma cells: Produce antibodies, which are proteins that speciﬁcally target and neutralize pathogens. o Memory B cells: Provide long-term immunity by remembering past encounters with speciﬁc pathogens. Interaction Between Systems: Innate and adaptive systems work together to protect the body. The inﬂammatory response initiated by the innate immune system creates an environment that attracts and activates cells of the adaptive immune system. Antigen-presenting cells of the innate immune system present antigens to T cells, triggering the adaptive immune response. Modules 1-6 3 Products of the adaptive immune response, such as antibodies and cytokines, can enhance the eSectiveness of the innate immune system. Hypersensitivity Reactions Hypersensitivity reactions are exaggerated or misdirected immune responses to an antigen, resulting in damage to the host. These reactions are classiﬁed into four types: Type I: IgE-Mediated Hypersensitivity Type I reactions, also known as immediate hypersensitivity reactions, are mediated by IgE antibodies. They occur within minutes to a few hours after exposure to an allergen. Common examples include allergic rhinitis (hay fever), asthma, and anaphylaxis. Pathophysiology: 1. Sensitization: The ﬁrst exposure to an allergen leads to the activation of Th2 cells, which release IL-4 and IL-13, stimulating B cells to produce IgE antibodies. 2. IgE Binding: IgE antibodies bind to high-aSinity receptors (FcεRI) on the surface of mast cells and basophils. 3. Re-exposure and Degranulation: Upon subsequent exposure to the same allergen, the allergen cross-links the IgE bound to mast cells, triggering their degranulation. 4. Release of Mediators: Degranulation releases preformed mediators like histamine, leukotrienes, and prostaglandins. 5. Clinical Manifestations: These mediators cause vasodilation, increased vascular permeability, bronchoconstriction, mucus secretion, and tissue damage, leading to symptoms like sneezing, wheezing, itching, and hives. Cells involved: Th2 cells: Orchestrate the immune response by releasing IL-4, IL-5, and IL-13, which drive IgE production, eosinophil recruitment, and airway inﬂammation. B cells: DiSerentiate into plasma cells that produce IgE antibodies speciﬁc to the allergen. Mast cells: Release histamine and other inﬂammatory mediators upon degranulation, causing the immediate symptoms of allergic reactions. Eosinophils: Contribute to tissue damage, particularly in the respiratory system, by releasing cytotoxic substances. Type II: Tissue-Speciﬁc Hypersensitivity Type II reactions, or tissue-speciﬁc reactions, involve antibodies directed against antigens on the surface of speciﬁc cells or tissues. Leads to cell destruction or dysfunction through mechanisms like: Complement-mediated lysis: Activation of the complement system leads to the formation of the membrane attack complex, which damages the cell membrane and causes cell lysis. Antibody-dependent cellular cytotoxicity (ADCC): Antibodies (IgG) bind to target cells, marking them for destruction by immune cells such as natural killer (NK) cells, macrophages, and neutrophils. Antireceptor antibodies: Antibodies bind to cell surface receptors, either blocking or stimulating their function. Modules 1-6 4 Examples include: Graves disease: Autoantibodies stimulate thyroid-stimulating hormone receptors, leading to hyperthyroidism. Myasthenia gravis: Autoantibodies block acetylcholine receptors at the neuromuscular junction, causing muscle weakness. Autoimmune hemolytic anemia: Autoantibodies target red blood cells, leading to their destruction. Cells involved: B cells: Produce antibodies against tissue-speciﬁc antigens. Macrophages: Phagocytose opsonized cells. Neutrophils: Release cytotoxic substances, contributing to tissue damage. NK cells: Kill target cells through ADCC. Type III: Immune Complex-Mediated Hypersensitivity Type III reactions are triggered by the formation of immune complexes, which are aggregates of antigen and antibody. These complexes circulate in the bloodstream and deposit in tissues, causing damage through: Complement activation: Immune complexes activate the complement cascade, generating inﬂammatory mediators that attract neutrophils to the site. Neutrophil-mediated damage: Neutrophils attempt to phagocytose immune complexes and release lysosomal enzymes, causing tissue damage. Examples include: Systemic lupus erythematosus (SLE): Autoantibodies against various cellular components form immune complexes that deposit in tissues like the kidneys, skin, and joints, causing widespread inﬂammation. Rheumatoid arthritis: Immune complexes deposit in the joints, leading to chronic inﬂammation and damage. Cells involved: B cells: Produce antibodies that form immune complexes. Neutrophils: Recruited to the site of immune complex deposition, release enzymes that damage tissues. Type IV: Cell-Mediated Hypersensitivity Type IV reactions, also known as delayed hypersensitivity reactions, are mediated by T cells rather than antibodies. These reactions are delayed, taking 24 to 72 hours to develop after antigen exposure. Pathophysiology: 1. Antigen presentation: Antigen-presenting cells present the antigen to T cells. 2. T cell activation: T helper 1 (Th1) cells release cytokines like interferon-gamma (IFN-γ), which activate macrophages. Cytotoxic T cells (Tc cells) directly kill target cells. 3. Macrophage-mediated damage: Activated macrophages release lysosomal enzymes and toxic oxygen species, causing tissue damage. Examples include: Modules 1-6 5 Contact dermatitis: A skin reaction to allergens like poison ivy, nickel, and latex. Tuberculin skin test: A positive reaction indicates previous exposure to tuberculosis and involves a delayed-type hypersensitivity response to tuberculin protein. Graft rejection: T cells recognize foreign antigens on transplanted tissues and attack them. Cells involved: Th1 cells: Release IFN-γ, activating macrophages and promoting inﬂammation. Tc cells: Directly kill target cells expressing the speciﬁc antigen. Macrophages: Activated by Th1 cytokines, release enzymes and toxic substances that cause tissue damage Cachexia Cachexia is a complex metabolic disorder characterized by muscle wasting and atrophy, sometimes accompanied by a loss of white adipose tissue. This leads to muscle weakness and fatigue. Energy Imbalance: A key characteristic of cachexia is an abnormal energy balance where energy input doesn't meet the body's needs. o This can be caused by decreased energy input, increased energy output, or both. o Patients with cachexia often consume fewer calories. Role of Inﬂammation: Cachexia symptoms also appear during acute or chronic inﬂammation. o The energy imbalance is furthered by pro-inﬂammatory cytokines like TNF-α and IL-1. Other Contributing Factors: Substances released directly from tumor cells Chemotherapeutic agents The unusual metabolic needs of growing tumors Hormonal changes that aSect appetite, including increased appetite-suppressing hormones and decreased appetite-stimulating hormones Infection Concepts Factors inﬂuencing a microorganism's ability to cause infection: o Communicability: Ability to spread from one individual to others and cause disease. o Immunogenicity: Ability to induce an immune response. o Infectivity: Ability to invade and multiply in the host. o Mechanism of action: How the microorganism damages tissue. o Pathogenicity: Ability to produce disease. o Portal of entry: Route of infection (e.g., direct contact, inhalation, ingestion, bites). o Toxigenicity: Ability to produce toxins. o Virulence: Capacity to cause severe disease. o ID50: Estimated number of organisms or viral particles required to produce infection in 50% of a population. Transmission: Endogenous microorganisms: Already present in the body and part of the normal microbiome. Modules 1-6 6 Exogenous microorganisms: Transmitted from an external source, like contaminated water, food, or from another human, animal, or insect. Risk Factors: Age: The very young and the very old have weaker immune systems. Compromised immunity: Individuals with weakened immune systems, such as those with HIV/AIDS or undergoing chemotherapy, are more susceptible to infections. Underlying health conditions: Chronic diseases like diabetes or heart disease can increase the risk of infection. Environmental factors: Exposure to contaminated water, food, or environments can increase the risk of infection. MODULE 2 Epidermis: The outermost layer of the skin, serving as a defensive barrier that constantly regenerates. Keratinocytes: The predominant cells of the epidermis. They produce keratin (hair skin and nails), an insoluble protein that gives skin its strength and resilience, acting as a barrier against mechanical stress and water loss. Keratinocytes originate in the basal layer (stratum basale) of the epidermis and gradually move upward, undergoing diSerentiation and ﬂattening as they form the diSerent layers of the epidermis. This process is called keratinization or corniﬁcation, and it takes about 30 days for a keratinocyte to reach the surface and be shed. Melanocytes: found in stratum basale layer, these cells produce the pigment melanin. Derived from amino acid (tyrosine) through an oxidation reaction. Absorbs UV light, which stimulates melanocytes to increase melanin production to prevent DNA damage to cells below the epidermis. Vitiligo is a condition where there is a loss of melanocytes, resulting in patches of depigmented skin. Langerhans Cells: specialized dendritic cells reside in the epidermis and originate in the bone marrow. Langerhans cells, presenting antigens to T cells to initiate adaptive immune response. Merkel Cells: sensory cells - touch receptors. They are most concentrated around hair follicles. Dermis: The deeper layer, sometimes called the "true skin". This layer is composed of connective tissue, houses hair follicles, sebaceous glands, sweat glands, blood vessels, lymphatic vessels, and nerves. Fibroblasts: These cells are responsible for producing the connective tissue matrix and collagen that make up the structural framework of the dermis. Mast Cells: Involved in immune responses, mast cells release histamine and other inﬂammatory mediators, contributing to allergic reactions and other inﬂammatory processes in the skin. Modules 1-6 7 Macrophages: These phagocytic cells engulf and digest cellular debris, pathogens, and other foreign substances, playing a critical role in wound healing and immune defense within the dermis. Subcutaneous Layer: The lowest layer, composed primarily of adipose tissue (fat). This layer also contains macrophages, ﬁbroblasts, blood vessels, lymphatics, nerves, and hair follicle roots. Adipocytes: The primary cell type in the subcutaneous layer, these cells store fat, providing insulation, cushioning, and energy storage Bacterial Skin Infections Most likely causative micro-organisms: Staphylococcus aureus (including community-acquired methicillin-resistant S. aureus [CA-MRSA]), followed by streptococci. Folliculitis: results from infection of the hair follicles, often by Staphylococcus aureus. Bacterial multiplication and secreted factors lead to lesions like papules, pustules, and surrounding erythema. Cellulitis: involves infection of the dermis and subcutaneous tissue, commonly caused by Staphylococcus aureus, group A Streptococcus, and Streptococcus pyogenes. Risk factors: diabetes, edema, peripheral vascular disease, tinea pedis, insect bites, and immune suppression are risk factors. Manifests as erythema, warmth, edema, and pain without a deﬁned border. Impetigo: more prevalent in children aged 2-5 years, particularly in hot and humid climates, is a superﬁcial infection caused by Staphylococcus aureus and/or Streptococcus pyogenes. Superﬁcial skin lesions that rupture creating a thin, ﬂat, honey coloured crust. Bacterial toxins damage the skin barrier, leading to blister formation in either non-bullous (caused by both staph and strep) or bullous (mainly caused by staph) forms Viral Skin Infections Most likely causative micro-organisms: Herpes simplex virus (HSV) types 1 and 2, varicella- zoster virus (VZV), human papillomavirus (HPV), measles virus, rubella virus. Pathophysiology: Viruses infect skin cells, causing cell death and triggering an inﬂammatory response. o Varicella-Zoster Virus causes both chickenpox (varicella) and shingles (herpes zoster). The virus spreads via airborne droplets or contact. Chickenpox is marked by an itchy, blistering rash. Shingles arises when the virus, dormant in nerve ganglia after chickenpox, reactivates (during a state of immunosuppression), producing a painful rash along a nerve path – dermatome – generally one sided (thoracic or lumbar most common sites affected). o Herpes Simplex Virus (HSV) can cause a variety of infections. HSV-1 typically leads to cold sores, while HSV-2 often causes genital lesions and is usually transmitted sexually. Transmission: o Direct contact: HSV, VZV, and HPV. o Respiratory droplets: Measles and rubella. Risk Factors: Weakened immune systems, close contact with infected individuals, unprotected sex. Modules 1-6 8 Fungal Skin Infections Dermatophytes (trichophyton, microsporum) are a group of fungi that cause superficial skin lesions, feeding on keratin. Mycoses: Fungal disorders caused by fungi that thrive on keratin. These infections can be categorized based on location: o Tinea infections are classified by their location on the body, examples including tinea capitis (scalp), tinea corporis (body), tinea pedis (feet), and tinea unguium (nails). The sources note that these infections are diagnosed using culture, microscopic examination o Candidiasis (candida albicans) results from infection by the yeast-like fungus Candida albicans, which can impact skin and mucous membranes. In immunosuppressed individuals, this fungus, normally commensal, becomes pathogenic Transmission: Direct contact with infected individuals, animals, or contaminated surfaces. Risk Factors: Warm, moist environments, immunocompromised, prolonged ABX use, diabetes. Skin Cancer Most likely causative micro-organisms: While infections, like HPV, can increase the risk of some skin cancers, the main cause of most skin cancers is chronic exposure to ultraviolet (UV) radiation from the sun or tanning beds. Pathophysiology: UV radiation damages DNA in skin cells, leading to mutations that can cause uncontrolled cell growth and the development of skin cancer. Types: o Basal cell carcinoma (BCC): the most common type, originates from basal cells in the epidermis. It often appears on sun-exposed areas and has various subtypes and presentations. Often appears as a pearly or waxy bump, a ﬂat, ﬂesh-colored or brown scar- like lesion, or a bleeding or scabbing sore that heals and returns. o Squamous cell carcinoma (SCC): arises from epidermal keratinocytes, linked to sun exposure. It can either be localized (in situ) or invade other tissues. Can look like a ﬁrm, red nodule, a ﬂat lesion with a scaly, crusted surface, or a sore that doesn't heal or heals and returns. o Melanoma: Can develop from an existing mole or appear as a new dark spot on the skin. The ABCDE rule is used to assess moles: Asymmetry, Border irregularity, Color variation, Diameter greater than 6 mm, evolving (changing in size, shape, or color). Nevi (moles), originating from melanocytes, may transition into malignant melanoma - multiple/changing Risk Factors: o Excessive sun exposure: The most signiﬁcant risk factor. o Fair skin, freckles, and light hair. o Family history of skin cancer. o Weakened immune system. o Exposure to certain chemicals. Psoriasis Modules 1-6 9 Chronic inflammatory skin disorder driven by immune system dysregulation, leading to accelerated skin cell turnover and the formation of characteristic plaques. The typical turnover time for epidermal cells is 26-30 days, but in psoriasis, this is shortened to 3-4 days, resulting in thickened plaques. Characteristics: scaly, thick, silvery, elevated, well-demarcated lesions, usually found on the scalp, elbows, or knees, with plaque psoriasis being the most common type. The specific antigenic trigger in psoriasis remains unknown, but its interaction with the immune system is understood. An unknown antigen activates dendritic cells, which then activate Th1 and Th17 cells. These activated T cells migrate to the skin and release cytokines (like IL-17, IFN-γ, and TNF-α) and chemokines, attracting more immune cells and contributing to epidermal inflammation. Excess production of TNF-α, IL-17, and IL-23 by immune cells in individuals with psoriasis leads to the rapid growth of skin cells, resulting in the formation of plaques. Thickening of the dermis and epidermis is caused by keratinocyte hyperproliferation and altered differentiation. Treatment: include biologic medications that target specific cytokines or T cells involved Risk Factors: o Family history: Genetics plays a strong role. o Infections: Strep throat or other infections can trigger psoriasis ﬂares. o Stress: Can worsen symptoms. o Medications: Certain medications, such as lithium and beta-blockers, can trigger psoriasis. Inﬂammatory Disorders of the Skin Most likely causative micro-organisms: Inﬂammatory skin disorders are a common category of skin conditions that can arise from various triggers, including immune reactions, irritants, and underlying medical problems. Dermatitis (eczema) - skin inﬂammation, characterized by pruritus, lesions with indistinct borders, and epidermal changes. Lesions can take the form of erythema, papules, or scales. Atopic Dermatitis (AD) is a chronic inﬂammation of the skin, relapsing, itchy eczema often linked to a family history of asthma or allergic rhinitis and is associated with high IgE levels. AD often begins in infancy or childhood. It involves impaired skin barrier function, often due to ﬁlaggrin gene mutations, resulting in erythema, pruritus, scaling, and licheniﬁcation. Allergic Contact Dermatitis (ACD) is a delayed hypersensitivity reaction (Type IV) triggered by allergens like microorganisms, metals, chemicals, drugs, or plant oils. This immune response to a speciﬁc allergen causes an inﬂammatory reaction at the site of contact. Urticaria (Hives) is a type I hypersensitivity reaction caused by allergens like medications, foods, and environmental triggers. Histamine release from mast cells causes the endothelial cells of the skin to contract - causes blood vessels to leak ﬂuid - forming wheals, welts, or hives. MODULE 3 Diastole: time in the cardiac cycle the represents ﬁlling of the blood into a chamber of the heart (relaxed) Systole: time in the cardiac cycle that represents the ejection of blood from a chamber of the heart (contraction) Modules 1-6 10 Preload: the volume and pressure inside the ventricle at the end of diastole Afterload: resistance the ventricle must overcome to eject blood during systole. Determined by the pressure in the aorta for the left ventricle and the pressure in the pulmonary artery for the right ventricle. Contractility: the intrinsic ability of the heart muscle to contract, independent of preload and afterload. Increased contractility leads to a greater force of contraction for a given preload. Frank-Starling Law: states that the force of ventricular contraction increases as the myocardial ﬁbers are stretched, up to a certain limit. This means that an increase in preload (ventricular ﬁlling) leads to a greater stroke volume, but only up to a point. The Frank-Starling mechanism helps to match cardiac output to venous return Atherosclerosis – EXAM QUESTIONS Atherosclerosis is a form of arteriosclerosis caused by the build-up of lipid-laden macrophages in the artery wall, leading to plaque formation. This process can aSect vascular systems throughout the body. Atherosclerosis is a primary cause of peripheral artery disease, coronary artery disease (CAD), and cerebrovascular disease. Pathophysiology: Atherosclerosis is an inﬂammatory disease that starts with damage to the endothelial cells lining artery walls. The lesions progress from endothelial injury and dysfunction to a fatty streak to a ﬁbrotic plaque to a complicated lesion Risk Factors: Smoking: Damages blood vessels and increases LDL cholesterol levels. Hypertension: Puts stress on artery walls, making them more susceptible to damage. Diabetes: High blood sugar levels can damage blood vessels. High cholesterol: Especially high LDL cholesterol. Family history of heart disease Obesity: Increases the risk of other risk factors, like high cholesterol and diabetes Physical inactivity Unhealthy diet: A diet high in saturated and trans fats can raise cholesterol levels. Progression: Injured endothelial cells become inﬂamed. These cells cannot produce normal amounts of antithrombotic and vasodilating cytokines, and they start to express adhesion molecules that attract macrophages and other inﬂammatory and immune cells. Macrophages release numerous inﬂammatory cytokines like tumor necrosis factor-alpha (TNF-α), interferons, interleukins, and C-reactive protein. Macrophages also release enzymes that further injure the vessel wall. Oxidized LDL, which is generated by the inﬂammatory process, causes additional adhesion molecule expression and draws in monocytes that turn into macrophages. When enough foam cells (macrophages that have engulfed oxidized LDL) accumulate, they form a fatty streak. Fatty streaks, in turn, produce more toxic oxygen free radicals and secrete inﬂammatory mediators, leading to more damage to the vessel wall. Plaque Rupture: A complicated plaque occurs when an unstable plaque ruptures. Plaque rupture occurs because of inﬂammatory cytokines, enzymes, wall stress, and neurohumoral changes. When rupture happens, exposure of the underlying tissue causes platelets to adhere and the clotting cascade Modules 1-6 11 to begin, resulting in rapid thrombus formation. The thrombus may completely block the vessel, leading to ischemia and infarction Hypertension Persistently high blood pressure (a blood pressure reading of 140/90 mmHg or higher). Often asymptomatic in the early stages, which is why it's often called the "silent killer." Pathophysiology: Several mechanisms contribute to the pathophysiology of hypertension, including changes in the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS), and natriuretic peptides. Inﬂammation, endothelial dysfunction, obesity-related hormones, and insulin resistance also contribute. Increased vascular volume is caused by a decrease in the kidney's excretion of salt. Secondary hypertension is caused by an identiﬁable underlying condition, like kidney disease or hormonal disorders. Complicated Hypertension: As hypertension becomes more severe and chronic, it can cause damage to blood vessels and tissues, leading to target organ damage in the heart, kidneys, brain, and eyes. Risk Factors: o Age: Blood pressure tends to rise with age. o Family history: Genetics plays a role. o Race: African Americans are at increased risk. o Obesity: Increases the workload on the heart. o Physical inactivity. o Unhealthy diet: High in sodium and low in potassium. o Excessive alcohol consumption. o Stress: Can temporarily raise blood pressure. o Smoking: Constricts blood vessels and increases blood pressure. Acute Coronary Syndromes Acute coronary syndromes occur when there is a sudden blockage in a coronary artery, usually due to thrombus formation over a ruptured atherosclerotic plaque Pathophysiology: Unstable angina and myocardial infarction (MI) are acute coronary syndromes. Both conditions involve the same process of plaque progression, disruption, and subsequent clot formation. The diSerence lies in the stability of the thrombus and the duration of vessel occlusion. Unstable angina occurs when the thrombus is unstable and disperses within 20 minutes, resulting in transient ischemia. Myocardial infarction occurs when the thrombus is more stable and occludes the vessel for a longer period, leading to sustained ischemia, myocyte necrosis, and death Prinzmetal/Variant Angina an uncommon type of angina, due to reduced blood ﬂow to the myocardium – coronary artery spasm. Often occurs during sleep or rest. Cannot be controlled by attempts to reduce myocardial O2 demand. Can by relieved by nitroglycerin and with the use of calcium channel blockers. Modules 1-6 12 Non-ST-segment elevation myocardial infarction (NSTEMI): typically involves infarction of the myocardium directly beneath the endocardium, referred to as subendocardial MI. This occurs when the thrombus breaks apart before causing complete tissue necrosis. The ECG ﬁndings in NSTEMI typically show ST segment depression and T wave inversion, without ST segment elevation ST-segment elevation myocardial infarction (STEMI): thrombus completely blocks the coronary artery, leading to a transmural infarction that extends from the endocardium to the epicardium. This complete blockage results in a larger area of damage and more severe cardiac dysfunction. STEMI is characterized by ST segment elevation on the ECG. Characteristics: o Chest pain (angina): crushing/squeezing sensation, radiate to the arms, jaw, neck, back o Shortness of breath o Sweating o Nausea o Light headedness Risk Factors: The same as for atherosclerosis, including smoking, high cholesterol, hypertension, diabetes, family history of heart disease, obesity, and physical inactivity. Deep Vein Thrombosis Deep venous thrombosis (DVT) - Three factors promote venous thrombosis, also known as the triad of Virchow: (1) venous stasis, (2) venous endothelial damage, and (3) hypercoagulable states. Venous stasis occurs when conditions limit blood ﬂow through the veins. For example, immobility prevents the muscular pump from increasing blood ﬂow from the lower extremity to the inferior vena cava and right atrium. Heart failure also causes venous stasis because increased diastolic ﬁlling pressures reduce venous return. Venous endothelial damage can occur from trauma, caustic intravenous medications, or invasive venous procedures. The healthy endothelium serves as a barrier between the blood and the prothrombotic sub-endothelium. It also expresses anticoagulant factors. When damaged, endothelial cells lose their anticoagulant properties and express adhesion molecules that activate inﬂammatory cells and platelets. Hypercoagulable states can be transient or prolonged. Ex: pregnancy with both hyper- coagulability and venous stasis. Active cancer is a cause of hypercoagulability because cancer cells produce tissue factor which activates coagulation, ﬁbrin synthesis, and platelet activation. Characteristics: o Swelling in the aSected leg o Pain in the leg, especially when standing or walking o Warmth and redness in aSected area Risk Factors: o Prolonged immobility: Such as during long ﬂights or bed rest Modules 1-6 13 o Surgery: Especially orthopedic surgery o Pregnancy o Certain medications: Such as hormone replacement therapy and birth control pills. o Inherited clotting disorders o Obesity o Smoking Heart Failure Left-sided Heat Failure Systolic heart failure (left sided), arises when the heart struggles to pump out enough blood to meet the body's needs, characterized by an ejection fraction of 40% or less. Several factors can trigger HFrEF: Decreased Contractility: caused by conditions that impair the heart muscle's ability to contract eSectively, such as myocardial infarction, myocarditis, and certain types of cardiomyopathy. Increased Preload: the volume of blood within the left ventricle at the end of diastole. When contractility decreases, less blood is pumped out, leading to a rise in preload. Mitral valve disease and renal failure can also contribute to increased preload. Increased Afterload: the resistance the left ventricle faces when pumping blood out into the aorta. Hypertension and aortic valve disease increase afterload, putting extra strain on the heart. As the heart attempts to compensate for reduced cardiac output, a complex chain of events ensues, often making the situation worse: Reduced blood ﬂow to the kidneys triggers the renin-angiotensin-aldosterone system (RAAS), leading to increased peripheral vascular resistance and ﬂuid retention, further increasing afterload and preload. Baroreceptors detect the drop in blood pressure and activate the sympathetic nervous system (SNS), causing vasoconstriction and the release of antidiuretic hormone (ADH), which also contributes to ﬂuid retention and increased afterload. RAAS – in systolic heart failure RASS will result in direct vasoconstriction (afterload) through the production of angiotensin II and increase the blood volume (pre load) by stimulating renal sodium and water retention via aldosterone. Right-Sided Heart Failure Occurs when the right ventricle cannot pump blood eSectively into the pulmonary circulation. One common cause is left-sided heart failure. The increased pressure in the left side of the heart backs up into the pulmonary circulation, making it harder for the right ventricle to pump blood out. The right ventricle eventually weakens and fails. Right-sided heart failure can also develop independently of left-sided problems, typically due to lung diseases such as chronic obstructive pulmonary disease (COPD), cystic ﬁbrosis, and acute respiratory distress syndrome (ARDS). These diseases often lead to pulmonary hypertension, which increases the resistance the right ventricle must overcome. Modules 1-6 14 Pulmonary hypertension can arise from several factors, including: Hypoxic Pulmonary Vasoconstriction: When lung tissue is poorly oxygenated, blood vessels in the lungs constrict to redirect blood ﬂow to areas with better ventilation. If this happens chronically or extensively, it can lead to sustained pulmonary hypertension. Inﬂammation: Many lung diseases involve inﬂammation, which can cause thickening and narrowing of pulmonary blood vessels, contributing to pulmonary hypertension. In cor pulmonale, a speciﬁc type of right-sided heart failure caused by lung disease, the persistently elevated pulmonary artery pressure overloads the right ventricle. This leads to right ventricular hypertrophy initially, followed by decreased compliance, dilation, and ultimately failure Risk Factors: o Coronary artery disease: The most common cause. o High blood pressure. o Diabetes. o Obesity. o Valvular heart disease: Problems with the heart valves. o Cardiomyopathy: Diseases of the heart muscle. o Congenital heart defects: Heart defects present at birth. Renin Angiotensin Aldosterone System (RAAS): **know this** is a crucial hormonal cascade involved in regulating blood pressure and ﬂuid balance. Its activation results in a series of physiological responses, primarily vasoconstriction, sodium and water retention, and sympathetic nervous system stimulation, aimed at restoring blood pressure and volume. Pathophysiology 1. Renin Release: When blood pressure drops or sodium levels decrease, the JGA releases renin into the bloodstream. 2. Angiotensin I Formation: Renin cleaves angiotensinogen, producing angiotensin I 3. Angiotensin II Conversion: ACE converts angiotensin I into the active hormone angiotensin II 4. Angiotensin II E_ects: Angiotensin II exerts its eSects by binding to speciﬁc receptors (AT1 and AT2) on various tissues. a. Vasoconstriction: Angiotensin II binding to AT1 receptors causes vasoconstriction, increasing peripheral vascular resistance and raising blood pressure. b. Aldosterone Secretion: Angiotensin II stimulates the adrenal cortex to release aldosterone. c. Sodium and Water Retention: Aldosterone acts on the kidneys to increase sodium and water reabsorption, further increasing blood volume and blood pressure. d. Sympathetic Nervous System Activation: Angiotensin II also enhances sympathetic nervous system activity, contributing to vasoconstriction and increased heart rate. e. Growth Factor Activity: Angiotensin II can act as a growth factor, promoting hypertrophy and remodeling of the heart and blood vessels. These eSects contribute to the long-term consequences of hypertension and heart failure. Modules 1-6 15 f. AT2 Receptor E_ects: Binding of angiotensin II to AT2 receptors has opposing eSects, including vasodilation, decreased remodeling, anti-inﬂammatory, and antioxidant properties. 5. Feedback Regulation: The RAAS is tightly regulated by negative feedback mechanisms. Increased blood pressure and sodium levels inhibit renin release, preventing excessive activation of the system. MODULE 4 Hypercapnia – ↑PaCO2 in the blood Triggers reﬂex to increase ventilation, vasodilation Hypoxemia – ↓PaO2 in arterial blood – can present as cyanosis Acute respiratory failure – hypoxemia or hypercapnia with a pH ≤ 7.25 Respiratory acidosis: Occurs when the lungs can't remove enough carbon dioxide (CO2) from the body, leading to an increase in the acidity of the blood. Respiratory alkalosis: Occurs when the lungs remove too much CO2, leading to a decrease in the acidity of the blood. Metabolic acidosis: Occurs when there is an excess of acid in the body or a loss of bicarbonate (a base) from the body. Metabolic alkalosis: Occurs when there is a loss of acid or an excess of bicarbonate in the body. Modules 1-6 16 Ventilation-Perfusion Mismatch (V/Q ratio) Correction of V/Q ratio through the pulmonary arterioles Arterioles relax if PACO2 is low or PAO2 is high Arterioles constrict if PACO2 is high or PAO2 is low o Otherwise known as hypoxic pulmonary vasoconstriction Chronic Obstructive Pulmonary Disease Characterized by persistent airﬂow limitation that is usually progressive and is associated with an enhanced chronic inﬂammatory response in the airways to noxious particles or gases. Chronic inﬂammation causes structural changes and narrowing of the small airways in the lungs. Emphysema: is a chronic inﬂammatory condition characterized by abnormal permanent enlargement of the gas-exchange airways accompanied by destruction of alveolar walls without obvious ﬁbrosis. o Inspired irritants lead to inﬂammation in the airway wall, which is predominantly mediated by Th1 cells and is characterized by macrophage, neutrophil, and lymphocyte inﬁltration. Loss of elastin ﬁbers reduces lung recoil (increases compliance), makes bronchioles less stable and more prone to collapse, making it more diSicult to expire. o Macrophages and neutrophils release proteolytic enzymes that destroy alveoli, reducing the surface area of the lungs and impairing oxygen extraction. Alpha-1 antitrypsin deﬁciency can lead to pulmonary emphysema even in nonsmokers due to chronic lung inﬂammation Modules 1-6 17 o Air trapping contributes to retention of C)2 (hypercapnia) and results in respiratory acidosis Chronic bronchitis: is deﬁned as hypersecretion of mucus and chronic productive cough that lasts for at least 3 months of the year for at least 2 consecutive years. o Inspired irritants trigger inﬂammation in the airway wall, predominantly mediated by Th1 cells (macrophage and cytotoxic T cell inﬁltration) & increased release of IL-1β and TNF-α. o These cytokines stimulate increased mucus production by increasing the size and number of mucous glands and goblet cells in airway epithelium. o The mucus becomes thicker than normal, and ciliary function is impaired, further reducing mucus clearance. Goblet cell hyperplasia decreases the diameter of the lumen. o Bacteria become embedded in airway secretions, reproduce, and cause infections/injury. Inﬂammation is exacerbated, further increasing mucus production. Both emphysema and chronic bronchitis are characterized by expiratory ﬂow limitation due to a loss of elastic tissue in emphysema and excessive mucus production and airway narrowing in chronic bronchitis. Air trapping and alveolar destruction in COPD lead to ventilation/perfusion mismatches, resulting in hypoxia and hypercapnia. Overtime the lungs begin to hyperinﬂate, which makes the respiratory muscles less eSective. Over time, hypoxia can cause structural changes in the pulmonary vasculature, including thickening of the tunica intima and vascular smooth muscle cell hyperplasia. These vascular changes lead to pulmonary hypertension, which can cause right-sided heart failure (cor pulmonale) and possibly even death. Asthma Asthma is an inﬂammatory disorder of the airways characterized by bronchial hyperresponsiveness, airway inﬂammation, and airway remodeling. Genetic and environmental factors contribute to the pathogenesis of asthma. The most common type of asthma is allergic asthma. Antigen-presenting cells (dendritic cells & macrophages) grab inhaled allergens in the airways. T helper cells activated when presented with the allergen and initiate an immune response. Modules 1-6 18 The immune response during asthma is predominantly mediated by Th2 cells which secrete cytokines IL-4, IL-5, IL-8, and IL-13. B cells activated by Th2 cells and diSerentiate into plasma cells. Plasma cells synthesize and secrete IgE antibodies. IgE antibodies bind to high-aSinity receptors on the surface of mast cells, B cells, basophils, eosinophils, and macrophages. Early Phase of Inﬂammation Allergen binds to IgE antibodies on the surface of mast cells, the mast cells degranulate. The degranulation of mast cells triggers release of histamine, bradykinin, prostaglandins, and leukotrienes. Histamine causes: Bronchoconstriction, Increased capillary permeability, Edema of the airways Bradykinin stimulates mucus secretion Prostaglandins cause: Bronchoconstriction, Vasodilation, Increased capillary permeability Leukotrienes cause: Bronchoconstriction, Recruitment of neutrophils and eosinophils to the bronchioles, Stimulation of mucus secretion Bronchoconstriction, edema, and mucus hypersecretion narrow the airway lumen and obstruct airﬂow. This leads to the common asthma symptoms: wheeze, non-productive cough, dyspnea, tachycardia, tachypnea, shortness of breath, prolonged expiration, and tightness in the chest. Airway obstruction makes it diSicult to exhale. Air becomes trapped in alveoli distal to obstructed areas, which decreases ventilation to these alveoli. The body attempts to compensate by decreasing perfusion of these alveoli, but perfusion ventilation mismatches still occur, leading to hypoxia. Lung receptors are activated and promote hyperventilation. At this point, arterial O2 is low but CO2 levels are normal or low. Chemoreceptors also become activated, increasing respiratory rate (tachypnea) Late Phase of Inﬂammation The late asthmatic response follows the early response and is characterized by chemotactic recruitment of eosinophils, neutrophils, and lymphocytes. Eosinophils release proinﬂammatory cytokines and cytotoxic mediators that further promote: Vascular leakage Mucus hypersecretion Bronchoconstriction Airway hyperresponsiveness Airway Remodeling Over time, untreated chronic inﬂammation or repeat asthma exacerbations can cause airway remodeling. This further perpetuates asthma. Structural changes include: o Smooth muscle cell hypertrophy and hyperplasia (increase in cell size and number) o Increased extracellular matrix deposition (subepithelial ﬁbrosis) (thickening and scarring of the tissue beneath the epithelium) o Goblet cell hyperplasia Modules 1-6 19 o Epithelial cell proliferation o Increased vascularity Cystic Fibrosis Pathophysiology: An autosomal recessive genetic disorder that aSects the epithelial cells that produce mucus, sweat, and digestive juices. The mutated cystic ﬁbrosis transmembrane conductance regulator (CFTR) gene causes these ﬂuids to become thick and sticky, clogging up tubes and ducts in the body, particularly in the lungs and pancreas. Mutations in CFTR gene cause abnormal expression of the CFTR protein, which is a chloride channel present on the surface of epithelial cells lining the airways, bile ducts, pancreas, sweat ducts, paranasal sinuses, and vas deferens (testes tube). Without adequate CFTR function, chloride and water transport across epithelial membranes is impaired, resulting in thick, dehydrated mucus secretions. In the lungs, CF leads to mucus plugging, chronic inﬂammation, and chronic infection of the small airways. o Mucus plugging occurs due to increased production of mucus from goblet cells, altered mucus properties, and impaired mucociliary clearance. o Thick mucus, along with bacteria and neutrophil by-products, adheres to the airway epithelium. o Neutrophils are present in excess in the airways and release oxidants and proteases, damaging lung structural proteins. o Microorganisms induce airway cells to produce inﬂammatory mediators that destroy immunoglobulin G (IgG) and complement components, contributing to chronic infection Characteristics: o Persistent cough with thick mucus. o Frequent lung infections. o Wheezing or shortness of breath. o Poor growth or weight gain. o Salty-tasting skin. o Greasy, bulky stools. Respiratory Infections Most likely causative micro-organisms: Viruses: Inﬂuenza virus, respiratory syncytial virus (RSV), rhinoviruses, adenoviruses, parainﬂuenza viruses, coronaviruses Bacteria: Streptococcus pneumoniae, Haemophilus inﬂuenzae, Moraxella catarrhalis, Legionella pneumophila, Mycoplasma pneumoniae, Chlamydophila pneumoniae Fungi: Pneumocystis jirovecii, Aspergillus, Cryptococcus Pneumonia lower resp inﬂection caused by: bacteria, viruses, fungi, protozoa, or parasites. Either hospital acquired or community. Pathogens pass defenses in the upper airway to reach lower airway. Most common cause: S. pneumoniae Modules 1-6 20 Alveolar macrophages are ﬁrst point of contact o Recognize pathogens using surface receptors (Toll-like) o Release proinﬂammatory cytokines TNF-alpha, IL-1, etc. o Promotes inﬂux of other inﬂammatory cells (neutrophils) Alveolar macrophages and neutrophils engulf and destroy pathogens using proteilytic enzymes, antimicrobial proteins, and reactive oxygen species. Tuberculosis (TB) \ caused by Mycobacterium tuberculosis – high contagious through droplets. The inﬂammatory response isolates colonies of bacilli by enclosing them in tubercles surrounded by scar tissue. TB bacilli can survive within macrophages, escaping immune defenses causing latent TB. M. tuberculosis contained by inﬂammatory and immune response system. Results in latent TB infection (LTBI) with on evidence of disease. Inspired bacilli lodge in upper lobes of the lungs; can also migrate to lymph nodes Alveolar macrophages & neutrophils engulf bacilli – macrophage release interferon Bacterium can resist lysosomal killing in macrophages Body attempts to isolate bacilli by forming granulomatous lesion (tubercle) Infected tissue in tubercle dies = caseation necrosis (cheese-like material) Tubercule surrounded by collagen, walling oS bacilli – response takes 10 days LTBI may last the lifetime of the host – asymptomatic and non-contagious Impairment of the immune system can lead to reactivation and progression of disease Lung Cancers Non-small cell lung cancer (NSCLC): The most common type, includes several subtypes, such as adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Squamous Cell Carcinoma (NSCLC) – slow growth, central location, metastasize late Located near hila, can project into bronchi Symptoms of non-productive cough or hemoptysis common – increased risk of pneumonia Adenocarcinoma (NSCLC) - slow/mod growth, peripheral location, metastasizes early, most common in non-smokers Peripherally located in lung parenchyma Often asymptomatic, but can present with pleuritic pain Typical adenoma transition (hyperplasia > carcinoma in situ > minimally invasive > invasive carcinoma) EGFR+ treated with tyrosine kinase inhibitors Large-cell carcinoma (NSCLC) – rapid growth, central, metastasize early and widespread Commonly arise centrally (distort trachea & carina) Tumour cells are large and undiSerentiated Grow rapidly, metastasize early - poor prognosis with metastasis Small cell lung cancer (SCLC): Grows rapidly and spreads quickly to other parts of the body. Strongest correlation to smoking Neuroendocrine tumor (small cell carcinoma) Modules 1-6 21 Most located centrally (hilar / mediastinal) Metastasize very early (mediastinum, lymph nodes, brain, BM) Arise from pulmonary neuroendocrine cells o Cells containing neurosecretory granules responsible for making neurotransmitters, growth factors, and vasoactive substances o Neoplastic syndromes often ﬁrst signs / symptoms of cancer Genetic abnormalities in bronchial cells MODULE 5 Inﬂammatory Bowel Disease (IBD) Most likely causative micro-organism: IBD is thought to be caused by an aberrant immune response to intestinal microbiota in a genetically susceptible host rather than a speciﬁc micro-organism. Crohn's Disease: Inﬂammation can aSect any portion of the GI tract from mouth to perianal area. Typically occurs in the terminal ileum and proximal colon. Inﬂammation is discontinuous ("skip lesions"), transmural, and aSects the entire thickness of the GI wall. This leads to ulceration, and severe inﬂammation can cause perforations or ﬁstulae. Characterized by a predominantly Th1 T Helper cell mediated immune response NOD2/CARD15 gene (chromosome 16): o involved in bacterial recognition and defense against foreign intruders o loss of function mutation associated with increased risk of developing CD Ulcerative Colitis: primary lesion begins with inﬂammation at the base of the crypt of Lieberkühn in the large intestine. The disease begins in the rectum and may extend proximally to the entire colon. Lesions are limited to mucosal epithelium, not transmural, and no skip lesions. § Characterized by a predominantly Th2 T helper cell mediated immune response Risk factors: The exact cause of IBD is unknown. Risk factors include smoking, low ﬁber-high carbohydrate diet, medications such as NSAIDs, and an altered intestinal microbiome. Irritable Bowel Syndrome (IBS) Disorder of brain-gut interaction characterized by recurrent abdominal pain with altered bowel habits. Although the pathophysiology of IBS is unknown, several mechanisms may be involved: Visceral hypersensitivity: This means that the nerves in the gut are more sensitive to stimuli, such as stretching or gas, than they are in people without IBS. Abnormal GI motility: Individuals with diarrhea-predominant IBS have rapid colonic transit times, while those with constipation-predominant IBS have delayed transit times. Altered gut microbiota: composition of bacteria in the gut may be diSerent in people with IBS. Immune activation: There is evidence that the immune system may be involved in IBS, although the exact role is not clear. Psychosocial factors: Stress and anxiety can worsen IBS symptoms. Modules 1-6 22 Clinical manifestations of IBS vary from mild to debilitating and can be grouped into three categories: diarrhea-predominant IBS (IBS-D), constipation-predominant IBS (IBS-C), and mixed IBS (IBS-M). Gastroesophageal reﬂux disease (GERD) The reﬂux of chyme from the stomach into the esophagus, or more proximal regions of the digestive system, causing noticeable symptoms or complications. Prevalence is approx 18-27% in North America. Chyme is normally retained within the stomach by the lower esophageal sphincter (LES). o Patients with GERD exhibit reduced resting pressures of the LES. The LES undergoes periods of relaxation in healthy individuals. o Relaxation often occurs after a meal and is stimulated by fats in the duodenum. o These periods of relaxation are more frequent in patients with GERD. Risk factors: Sliding hiatal hernia, Obesity, Smoking, Alcohol, Drugs or chemicals that relax the LES (e.g., anticholinergics, nitrates, calcium channel blockers, nicotine). Certain foods (coSee, mints, citrus fruits, fats). Things that increase abdominal pressure (e.g., vomiting, coughing, lifting, bending, pregnancy) Barrett's Esophagus: A small percentage of patients with GERD exhibit abnormal repair processes following exposure to acidic chyme. squamous epithelium lining the esophagus is replaced by metaplastic columnar epithelium. o increases the patient’s risk of developing esophageal adenocarcinoma. Hiatal Hernia Characterized by a protrusion or bulging of an abdominal structure into the thoracic cavity. Sliding hiatal hernia (type 1): The proximal portion of the stomach moves into the thoracic cavity through the esophageal hiatus Contributed to by a congenitally short esophagus, ﬁbrosis, excessive vagal nerve stimulation, or weakening of the diaphragmatic muscles at the gastroesophageal junction Lying in the supine position causes the lower esophagus and stomach to be pulled into the thorax Reﬂux is common Paraesophageal hiatal hernia (type 2): A herniation of the greater curvature of the stomach through a secondary opening in the diaphragm alongside the esophagus moves into the thorax above the diaphragm Reﬂux is uncommon Strangulation of the hernia is a major complication Risk Factors: o Age: More common in people over 50. o Obesity: Increases pressure in the abdomen. o Pregnancy. o Smoking. o Straining: Such as during bowel movements or lifting heavy objects. Peptic Ulcer Disease Modules 1-6 23 Most likely causative micro-organism: Helicobacter pylori Pathophysiology: Open sores that develop on the lining of the stomach (gastric ulcers) or the upper part of the small intestine (duodenal ulcers). H. pylori infection can damage the protective mucus layer of the stomach and duodenum, allowing stomach acid to irritate the lining. NSAIDs can also damage the lining. Characteristics: o Burning pain in the stomach. o Feeling of fullness or bloating. o Nausea and vomiting. o Loss of appetite. o Black or tarry stools (a sign of bleeding). Duodenal Ulcer: Most common location of peptic ulcers Typically caused by exposure of the proximal duodenum to higher than normal concentrations of HCl or pepsin o Can be due to NSAIDs, H. pylori, increased acid/pepsin production, rapid gastric emptying, decreased duodenal bicarbonate secretion HCl and pepsin damage the mucosal barrier and promote ulceration Gastric Ulcer: Gastric ulcers are less common than duodenal ulcers and are caused by the breakdown of mucosal defenses and injury from agents such as H. pylori infection, NSAIDs, and other medications. Transmission: H. pylori is transmitted through the fecal-oral route, usually acquired in childhood. Risk factors: H. pylori infection, use of NSAIDs, corticosteroids, bisphosphonates, potassium chloride, and ﬂuorouracil. Other risk factors include smoking, alcohol consumption, and certain disease processes that can make the gastric lining a hypersecretory environment. Diarrhea/Constipation Most likely causative micro-organism: Many infectious organisms can cause diarrhea, including viruses like rotavirus and bacteria like Escherichia coli, Vibrio cholera, and Clostridioides diDicile. Osmotic diarrhea occurs when a nonabsorbable substance in the intestine draws excess water into the intestinal lumen by osmosis, increasing stool weight and volume. This results in large- volume diarrhea. Causes: Large oral doses of poorly absorbed ions such as magnesium, sulfate, and phosphate. Excessive ingestion of synthetic, non-absorbable sugars. Introduction of full-strength tube feeding formulas. Dumping syndrome. Lactase deﬁciency. Pancreatic enzyme or bile salt deﬁciency. Small intestine bacterial overgrowth. Celiac disease. Modules 1-6 24 Secretory diarrhea is a form of large-volume diarrhea caused by excessive mucosal secretions of chloride or bicarbonate-rich ﬂuid or the inhibition of sodium absorption. Causes: Viruses (e.g., rotavirus). Bacterial enterotoxins (e.g., Escherichia coli, Vibrio cholerae). Exotoxins (e.g., overgrowth of Clostridium diDicile following antibiotic therapy). Small bowel bacterial overgrowth. Motility diarrhea results from increased intestinal motility, reducing the time available for ﬂuid absorption. Constipation: Functional constipation involves a normal rate of stool passage but diSiculty with stool evacuation. Slow-transit constipation (STC) involves impaired colonic motor activity with infrequent bowel movements. IBS-C is associated with chronic constipation and abdominal pain. Hepatitis The most common form of hepatitis is viral hepatitis, which is caused by one of the hepatitis viruses (A, B, C, D, E or G), the Epstein-Barr virus or the varicella virus. Hepatitis can also be caused by alcohol abuse, drugs, toxins, trauma, fat buildup and autoimmune disorders. Pathophysiology: The pathologic lesions of hepatitis include hepatic cell necrosis, scarring, and KupSer cell hyperplasia. Cellular injury is promoted by cell-mediated immune mechanisms, release of inﬂammatory mediators, and persistent inﬂammation. Transmission: Transmission varies depending on the type of hepatitis: Hepatitis A (ass): transmitted through the fecal-oral route. Hepatitis B (blood/bitches): transmitted through contact with infected blood or body ﬂuids. Hepatitis C: primarily transmitted through contact with infected blood. Risk factors: Risk factors vary depending on the type of hepatitis: Hepatitis A: travel to areas with poor sanitation and close contact with an infected person. Hepatitis B: unprotected sex, sharing needles, and exposure to infected blood. Hepatitis C: sharing needles and receiving blood transfusions before 1992. Hepatitis A (Ass and Ah) Previously known as infectious hepatitis because virus is transmitted by fecal oral route in contaminated food or water o Can also be transmitted by blood transfusions Once ingested, the virus crosses the intestinal barrier and infects hepatocytes in the liver Virus replicates in hepatocytes and subsequently shed into bile – allowing transmission to others Virally infected hepatocytes are attacked by the immune system causing hepatitis In most patients, hepatitis A causes self-limiting inﬂammation, and the patients develop life-long immunity to the virus – does not cause chronic hepatitis In severe cases, hepatitis A can cause liver failure and even death, but typically hepatitis A infections are less severe than hepatitis B or C infections Hepatitis B (Blood) Modules 1-6 25 Transmitted through contact with infected blood o Sharing needles and other drug equipment o Multiple sexual partners o Can be passed from mother to infant if mother becomes infected during 3rd trimester o Co-infection with hepatitis C and D and HIV are common Eight genotypes (A through H) with many sub-genotypes In 70% of patients the infection is asymptomatic and self limiting Progresses to chronic hepatitis in 15-30% of cases o Immune system cannot clear the virus Major cause of cirrhosis and hepatocellular carcinoma Can lead to acute fulminating hepatitis characterized by massive hepatocyte necrosis and liver failure Hepatitis C (Contaminate) Transmitted through contact with infected blood and contaminated needles In 50-80% of cases, acute inﬂammatory response is unable to clear the virus Chronic inﬂammation ensues and is accompanied by ﬁbrosis 20-30% of patients go on to develop cirrhosis Most common cause of chronic liver disease in the Western world Clinical Course of Viral Hepatitis The clinical course of viral hepatitis usually consists of three phases, preceded by an incubation phase. Incubation phase: The length of this phase varies depending on the virus. Prodromal (preicteric) phase: o Begins approximately 2 weeks after exposure and ends with the appearance of jaundice o Symptoms include fatigue, anorexia, malaise, nausea, vomiting, headache, hyperalgia, cough, and low-grade fever o The infection is highly transmissible during this phase. Icteric phase: o Begins 1 to 2 weeks after the prodromal phase and lasts 2 to 6 weeks o Jaundice, dark urine, and clay-colored stools are common o The liver is enlarged, smooth, and tender o Fatigue and abdominal pain may persist or become more severe Recovery phase: o Begins with the resolution of jaundice o Symptoms gradually improve and liver function tests return to normal o Can take several months for complete recovery MODULE 6 Urinary Tract Obstructions Upper Urinary Tract Obstruction: Modules 1-6 26 Nephrolithiasis - Kidney stones (calculi) are a common cause of upper urinary tract obstructions. Stones form when salts in the urine become supersaturated, precipitate, and grow into crystals. Most common stone type: Calcium Oxalate and Calcium Phosphate They can obstruct the calyces, ureteropelvic junction, or ureterovesical junction. Lower Urinary Tract Obstruction: In the lower urinary tract, obstructions can result from anatomical issues like: Prostate enlargement Urethral stricture Severe pelvic organ prolapse Neurogenic Bladder: Neurogenic bladder, a dysfunction in bladder control due to nerve damage, can also cause lower urinary tract obstructions. This can happen due to lesions in the spinal cord or sacral peripheral nerves. Compensatory Mechanisms and Post-obstructive Diuresis: The body attempts to compensate for urinary tract obstruction. Compensatory Hypertrophy and Hyperfunction: When one kidney is obstructed, the unaSected kidney may try to compensate by increasing in size and function. Post-obstructive Diuresis: After an obstruction is relieved, there may be a period of increased urine production (diuresis) as the body restores ﬂuid and electrolyte balance.13 This can lead to dehydration if not managed properly. Urinary Incontinence Stress incontinence: Urine leakage with sudden increases in intra-abdominal pressure, such as during coughing, sneezing, laughing, or exercise. Most common in women younger than 60 and men who have had prostate surgery. Urge incontinence: Urine loss accompanied by a strong, sudden urge to urinate. This type is most common in older adults and may be associated with neurologic disorders or decreased bladder wall compliance. Overﬂow incontinence: Involuntary urine loss due to bladder overdistention. This may be caused by neurologic lesions, polyneuropathies, urethral obstruction (such as an enlarged prostate), or detrusor underactivity. Functional incontinence: Urine leakage resulting from cognitive impairment (such as dementia) or physical limitations that prevent timely toileting. Urinary Tract Infections (UTIs) Cystitis and Pyelonephritis UTIs occur when pathogens infect any part of the urinary tract, from the urethra to the kidneys. UTIs are typically caused by the retrograde movement of bacteria from the gut into the urethra and bladder. Cystitis is an infection of the bladder, while pyelonephritis is an infection of one or both upper urinary tracts (kidneys). Causative Microorganisms: Modules 1-6 27 The most common cause of UTIs is Escherichia coli ( E. coli). Other causative organisms include Klebsiella, Proteus, Pseudomonas, Staphylococcus saprophyticus, fungi, viruses, and parasites. Pathophysiology of Cystitis: Bacteria, typically E. coli, enter the urethra and ascend to the bladder. Uropathic E. coli have ﬁmbriae that allow them to adhere to the uroepithelium, resisting the ﬂushing action of urine. Infection triggers an inﬂammatory response in the bladder wall, leading to redness, pus formation, and potentially ulceration or necrosis. Pathophysiology of Pyelonephritis: Infection usually ascends from the bladder up the ureters to the kidneys Alternatively, bacteria can spread to the kidneys through the bloodstream Inﬂammation primarily aSects the renal pelvis, calyces, and medulla In severe cases, abscesses can form in the medulla and extend to the cortex Clinical Manifestations: Cystitis (lower): Frequency, dysuria, urgency Lower abdominal and/or suprapubic pain Hematuria and cloudy urine may also occur Pyelonephritis (upper): Symptoms of cystitis may precede systemic signs Fever, chills, nausea, vomiting Flank or groin pain Glomerular Disorders. Glomerulonephritis An inﬂammation of the glomeruli, the ﬁltering units of the kidneys. It can be acute or chronic and is categorized as primary or secondary. Primary glomerulonephritis originates in the glomeruli themselves, often triggered by infections or immune responses. Secondary glomerulonephritis develops because of systemic diseases like DM, HTN, or lupus. Risk Factors: Acute Glomerulonephritis: Infections, particularly those caused by group A beta-hemolytic streptococci Immune disorders, such as IgA nephropathy Exposure to certain toxins or drugs Chronic Glomerulonephritis: Systemic diseases like diabetes mellitus, hypertension, and systemic lupus erythematosus Prolonged or recurrent episodes of acute glomerulonephritis Family history of kidney disease Pathophysiology of Glomerulonephritis: Modules 1-6 28 Glomerulonephritis is caused by immune responses that damage the glomerular ﬁltration membrane. Immune complexes can deposit in the glomeruli, activating complement and triggering an inﬂammatory response that damages the ﬁltration barrier. This damage leads to: o Increased permeability, allowing proteins and red blood cells to leak into the urine o Reduced glomerular ﬁltration rate o Fluid retention, leading to edema and hypertension o Potential progression to chronic kidney disease Clinical Manifestations of Glomerulonephritis: Hematuria with red blood cell casts, resulting in brown-tinged urine Proteinuria, often accompanied by hypoalbuminemia Edema, particularly around the eyes (periorbital) and in the legs (pedal) Hypertension In severe cases, oliguria and renal failure Nephrotic Syndrome: Characterized by massive proteinuria (more than 3.5 g per day), hypoalbuminemia, edema, hyperlipidemia, and lipiduria. It is caused by increased permeability of the glomerular ﬁltration membrane, leading to signiﬁcant protein loss in the urine.20 Minimal change nephropathy, membranous glomerulonephritis, and focal segmental glomerulosclerosis are primary causes of nephrotic syndrome. Nephritic Syndrome: Marked by hematuria (with red blood cell casts), hypertension, edema, and oliguria. It typically occurs with infection-related glomerulonephritis, rapidly progressive crescentic glomerulonephritis, and lupus nephritis. Acute and Chronic Kidney Injury Pathophysiology: Acute Kidney Injury (AKI): characterized by a sudden decline in kidney function, caused by a decrease in blood ﬂow to the kidneys, direct damage to the kidneys, or blockage - urinary tract. Chronic Kidney Disease (CKD): is a progressive loss of kidney function over time, often caused by conditions like diabetes, high blood pressure, and glomerular diseases. Main characteristics: AKI: AKI is characterized by a rapid decline in kidney function, often accompanied by a decrease in urine output and an accumulation of waste products in the blood. CKD: CKD is characterized by a gradual loss of kidney function over time, eventually leading to end-stage renal disease (ESRD), requiring dialysis or transplantation. Risk factors: Modules 1-6 29 AKI: Risk factors include pre-existing kidney disease, diabetes, high blood pressure, heart failure, liver disease, older age, and exposure to certain medications and toxins. CKD: Risk factors include diabetes, high blood pressure, glomerular diseases, family history of kidney disease, older age, and certain ethnicities.

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