B Pharmacy Sem 4: Pathophysiology

Subject 5. Pathophysiology

1. Cell Injury, Adaptation & Death (Hypoxia, Free Radicals, Apoptosis)
2. Inflammation & Repair (Acute & Chronic; Mediators; Wound Healing)
3. Cardiovascular Disorders (Atherosclerosis, Hypertension, Heart Failure)
4. Respiratory Disorders (COPD, Asthma, Pneumonia)
5. Gastrointestinal Disorders (Peptic Ulcer, Hepatitis, IBD)
6. Renal & Hepatic Disorders (Glomerulonephritis, Cirrhosis)
7. Endocrine & Metabolic Disorders (Diabetes Mellitus, Thyroid Diseases)

Unit 1: Cell Injury, Adaptation & Death (Hypoxia, Free Radicals, Apoptosis)

A detailed exploration of how cells respond to stress and damage—covering reversible and irreversible injury, adaptive changes, mechanisms of hypoxic and oxidative damage, programmed cell death, and their implications in disease.

1.1 Definitions & Concepts

1.1.1 Cell Injury

• Reversible Injury: Cellular dysfunction without structural disruption; removal of stress restores normal function.

• Irreversible Injury: Structural damage beyond recovery, culminating in cell death.

1.1.2 Cellular Adaptations

• Hypertrophy: Increase in cell size (e.g., cardiac myocytes in hypertension).

• Hyperplasia: Increase in cell number (e.g., endometrial proliferation under estrogen).

• Atrophy: Reduction in size and function (e.g., muscle wasting in disuse).

• Metaplasia: Replacement of one differentiated cell type with another (e.g., Barrett’s esophagus: squamous → columnar epithelium).

1.2 Mechanisms of Hypoxic Injury

1.2.1 Definition of Hypoxia

• Insufficient O₂ to meet cellular metabolic demands; common causes include ischemia, anemia, and respiratory failure.

1.2.2 Pathophysiology

1. ATP Depletion

   • Impaired oxidative phosphorylation → drop in ATP → failure of Na⁺/K⁺‐ATPase → cellular swelling.

2. Ion Homeostasis Disruption

   • Na⁺ and Ca²⁺ influx; K⁺ efflux; ER and mitochondrial swelling.

3. Anaerobic Glycolysis

   • Lactic acid accumulation → intracellular acidosis → ribosomal detachment and reduced protein synthesis.

4. Membrane Damage

   • Increased cytosolic Ca²⁺ activates phospholipases and proteases.

1.2.3 Morphological Features

• Reversible: Cellular swelling, plasma membrane blebs, mitochondrial swelling.

• Irreversible: Dense mitochondrial matrix, rupture of lysosomes, nuclear chromatin clumping (pyknosis), karyorrhexis, karyolysis.

1.3 Free Radical–Mediated Injury

1.3.1 Reactive Oxygen Species (ROS)

• Examples: Superoxide (O₂·⁻), hydrogen peroxide (H₂O₂), hydroxyl radical (·OH).

1.3.2 Sources

• Endogenous: Mitochondrial electron transport leakage, NADPH oxidases, peroxisomal fatty acid oxidation.

• Exogenous: Ionizing radiation, xenobiotics (e.g., CCl₄ metabolism), inflammation (neutrophil respiratory burst).

1.3.3 Mechanisms of Damage

1. Lipid Peroxidation of membranes → loss of integrity.

2. Protein Oxidation → enzyme inactivation, structural protein damage.

3. DNA Damage → strand breaks, base modifications, mutagenesis.

1.3.4 Antioxidant Defenses

• Enzymatic: Superoxide dismutase (SOD), catalase, glutathione peroxidase.

• Non‑Enzymatic: Glutathione, vitamins C and E, ceruloplasmin.

1.4 Cell Death Pathways

1.4.1 Necrosis

• Definition: Passive, uncontrolled cell death with inflammation.

• Features: Cell swelling, plasma membrane rupture, enzymatic digestion, inflammatory response.

• Patterns: Coagulative (ischemia in heart/kidney), liquefactive (brain infarcts, abscesses), caseous (tuberculosis), fat necrosis (pancreatitis), fibrinoid (immune vascular injury).

1.4.2 Apoptosis

• Definition: Active, regulated “programmed” cell death without inflammation.

• Morphology: Cell shrinkage, chromatin condensation, membrane blebbing, formation of apoptotic bodies, phagocytosis by macrophages.

• Pathways:

  1. Intrinsic (Mitochondrial): Stress → Bcl‑2 family regulation → cytochrome c release → caspase‑9 activation.

  2. Extrinsic (Death Receptor): Fas/FasL or TNF receptor engagement → caspase‑8 activation.

• Execution: Caspase‑3 cleaves cellular substrates (e.g., ICAD), leading to DNA fragmentation (180–200 bp ladders).

1.5 Integration in Disease

1.5.1 Hypoxic Injury in Myocardial Infarction

• Prolonged ischemia → irreversible necrosis of cardiomyocytes → loss of contractile tissue.

1.5.2 Oxidative Stress in Liver Injury

• CCl₄ metabolism → ·CCl₃ radicals → lipid peroxidation → centrilobular necrosis.

1.5.3 Apoptosis in Chronic Disease

• Excessive apoptosis in neurodegenerative disorders (e.g., Parkinson’s).

• Insufficient apoptosis in cancer leading to uncontrolled proliferation.

1.6 Key Points for Exams

1. Define & Differentiate: Reversible vs. irreversible injury; necrosis vs. apoptosis.

2. Mechanism Sketch: Draw steps of intrinsic apoptotic pathway, labeling mitochondrial events and caspases.

3. Clinical Correlation: Explain cellular changes in early and late myocardial ischemia.

4. Free Radical Defense: List enzymatic and non‑enzymatic antioxidants and their roles.

5. Adaptive Change: Provide one example each of hypertrophy, hyperplasia, atrophy, and metaplasia, with underlying stimulus.

Unit 2: Inflammation & Repair (Acute & Chronic; Mediators; Wound Healing)

An exhaustive exploration of the body’s response to injury—including the cellular and molecular events of acute and chronic inflammation, the principal mediators involved, and the stages and regulation of tissue repair and wound healing.

2.1 Inflammation: Purpose & Types

2.1.1 Definition

• Inflammation: Complex tissue reaction to harmful stimuli (infection, necrosis, foreign bodies) intended to eliminate the cause, clear debris, and initiate repair.

2.1.2 Classification

2.2 Acute Inflammation

2.2.1 Vascular Events

1. Vasoconstriction (brief) → Vasodilation (increased blood flow; heat/redness)

2. Increased Vascular Permeability → plasma exudation (swelling/pain)

2.2.2 Cellular Events

1. Leukocyte (Neutrophil) Recruitment

   • Margination & Rolling: Selectin‑mediated transient binding on endothelium

   • Adhesion: Integrin–ICAM/VCAM interactions

   • Transmigration (Diapedesis): PECAM‑1–mediated passage between endothelial cells

2. Leukocyte Activation & Phagocytosis

   • Recognition & Attachment: Opsonins (C3b, IgG)

   • Engulfment: Pseudopod formation, phagosome

   • Killing & Degradation:

     • Oxygen‑dependent: NADPH oxidase → superoxide → MPO halide system → HOCl

     • Oxygen‑independent: Lysozyme, major basic protein, defensins

2.2.3 Exudate Types

2.3 Mediators of Inflammation

2.3.1 Plasma‑Derived Mediators

2.3.2 Cell‑Derived Mediators

2.4 Chronic Inflammation

2.4.1 Cellular Infiltrate & Features

• Mononuclear Cells: Macrophages, lymphocytes, plasma cells

• Tissue Destruction: Persistent injury by cytokines and enzymes

• Repair: Simultaneous angiogenesis and fibrosis

2.4.2 Granulomatous Inflammation

• Definition: Aggregates of activated macrophages (epithelioid cells) often with multinucleated giant cells.

• Etiologies: Mycobacterium tuberculosis, schistosomiasis, sarcoidosis.

• Morphology: Central caseation (tuberculous) vs. non‑caseating (sarcoid).

2.5 Tissue Repair & Wound Healing

2.5.1 Regeneration vs. Repair

• Regeneration: Restoration of normal architecture by proliferation of residual cells and stem cells (e.g., liver).

• Repair (Scar Formation): Replacement with connective tissue when regeneration impossible.

2.5.2 Phases of Wound Healing

1. Hemostasis & Inflammation (Days 0–3)

   • Vasoconstriction, platelet plug, clot formation releasing PDGF, TGF‑β

   • Neutrophils → macrophages clear debris

2. Proliferative Phase (Days 3–14)

   • Angiogenesis: VEGF‑driven new capillaries

   • Fibroplasia & ECM Deposition: TGF‑β stimulates collagen (Type III) and proteoglycan synthesis

   • Re‑epithelialization: Keratinocyte migration over granulation tissue

3. Maturation & Remodeling (Weeks 2–months)

   • Collagen Remodeling: Type III replaced by stronger Type I collagen; crosslinking increases tensile strength

   • Scar Maturation: Decreased vascularity, myofibroblast‑mediated wound contraction

2.5.3 Factors Influencing Healing

• Local: Infection, ischemia, mechanical stress

• Systemic: Nutrition (vitamin C, protein), diabetes, corticosteroids, age

2.6 Clinical Correlations

2.6.1 Chronic Ulcer Formation

• Defective proliferation or excessive protease activity impedes granulation → non‑healing ulcers.

2.6.2 Fibrosis in Chronic Disease

• Liver cirrhosis: Chronic hepatitis → stellate cell activation → excess ECM → nodular architecture.

2.6.3 Therapeutic Modulation

• NSAIDs: Inhibit COX → reduce prostaglandin‑mediated pain and swelling but may impair mucosal healing.

• Anti‑TNF Agents: Block chronic inflammation in rheumatoid arthritis and inflammatory bowel disease.

2.7 Key Points for Exams

1. Outline Steps: Neutrophil recruitment cascade with adhesion molecules and chemokines.

2. Compare: Serous vs. fibrinous exudates—composition and examples.

3. Draw: Granuloma structure labeling epithelioid cells and giant cells.

4. Phases Sketch: Timeline of wound healing showing key cellular events.

5. Mediator Roles: Match five mediators (e.g., bradykinin, LTB₄, histamine) to their functions.

Unit 3: Cardiovascular Disorders (Atherosclerosis, Hypertension & Heart Failure)

An in-depth exploration of major cardiovascular pathologies—detailing their definitions, etiologies, pathogenesis, clinical features, complications, and therapeutic implications.

3.1 Atherosclerosis

3.1.1 Definition & Clinical Significance

• Atherosclerosis: Chronic inflammatory disease of medium- and large-sized arteries characterized by intimal lipid accumulation, fibrous cap formation, and plaque development.

• Consequences: Myocardial infarction, stroke, peripheral arterial disease, aneurysm.

3.1.2 Risk Factors

• Non-modifiable: Age, male sex (until menopause), family history/genetics (e.g., familial hypercholesterolemia).

• Modifiable:

  • Lipid Abnormalities: ↑ LDL-cholesterol, ↓ HDL-cholesterol.

  • Hypertension: Endothelial injury from high shear stress.

  • Smoking: Oxidative endothelial damage.

  • Diabetes Mellitus: Glycation of proteins, dyslipidemia.

  • Obesity & Sedentary Lifestyle: Pro-inflammatory adipokines.

3.1.3 Pathogenesis (Response-to-Injury Hypothesis)

1. Endothelial Dysfunction

   • Triggered by hypertension, hyperlipidemia, smoking → ↑ permeability, leukocyte adhesion molecule expression (VCAM-1, ICAM-1).

2. Lipoprotein Entry & Modification

   • LDL infiltrates intima, becomes oxidized (oxLDL) by ROS → chemotactic for monocytes.

3. Monocyte Recruitment & Differentiation

   • Monocytes adhere, transmigrate → macrophages expressing scavenger receptors ingest oxLDL → foam cells.

4. Fatty Streak Formation

   • Aggregates of foam cells visible even in adolescence; reversible at this stage.

5. Smooth Muscle Cell (SMC) Migration & Proliferation

   • SMCs from media migrate to intima under PDGF and TGF-β influence, secrete extracellular matrix (collagen, proteoglycans) to form fibrous cap.

6. Plaque Progression & Complications

   • Necrotic lipid core, calcification, neovascularization.

   • Plaque Rupture or Erosion → thrombosis → acute vessel occlusion.

   • Aneurysm Formation: Destruction of media in the aorta.

3.1.4 Clinical Manifestations

• Coronary Artery Disease: Angina pectoris, myocardial infarction.

• Cerebrovascular Disease: Transient ischemic attacks, stroke.

• Peripheral Arterial Disease: Claudication, non-healing ulcers.

• Aortic Aneurysm/Dissection: Pulsatile abdominal mass, sudden chest pain.

3.2 Hypertension

3.2.1 Definition & Classification

• Hypertension: Sustained elevation of arterial blood pressure ≥ 140/90 mm Hg (ESC/ESH now defines ≥ 140/90; ACC/AHA ≥ 130/80).

• Types:

  • Primary (Essential): ~95% of cases; multifactorial (genetic, environmental).

  • Secondary: Renal disease, endocrine causes (pheochromocytoma, Cushing’s), coarctation of the aorta, medications.

3.2.2 Pathophysiology

• Cardiac Output (CO) × Systemic Vascular Resistance (SVR) determines BP.

• Essential Hypertension Mechanisms:

  • Renin–Angiotensin–Aldosterone System (RAAS) Overactivity → vasoconstriction, sodium retention.

  • Sympathetic Nervous System (SNS) Hyperactivity → increased heart rate and vasoconstriction.

  • Endothelial Dysfunction: ↓ nitric oxide, ↑ endothelin.

  • Salt Sensitivity & Volume Expansion: Genetic predisposition to sodium retention.

3.2.3 Target Organ Damage (“Hypertensive End-Organ Damage”)

• Heart: Left ventricular hypertrophy (LVH), ischemic heart disease, heart failure.

• Brain: Stroke, hypertensive encephalopathy.

• Kidneys: Hypertensive nephrosclerosis → chronic kidney disease.

• Eyes: Hypertensive retinopathy (arteriolar narrowing, “cotton-wool” spots).

• Vessels: Accelerated atherosclerosis, aneurysm risk.

3.2.4 Clinical Presentation & Diagnosis

• Often Asymptomatic (“Silent Killer”) identified on routine BP measurement.

• Symptoms: Headache, dizziness, visual disturbances in severe cases.

• Work-up:

  • Multiple readings, ambulatory BP monitoring.

  • Laboratory: Serum creatinine, electrolytes, fasting glucose, lipid profile.

  • ECG/Echocardiography: LVH, diastolic dysfunction.

  • Urinalysis: Proteinuria.

3.2.5 Management Principles

• Lifestyle: Weight loss, dietary sodium restriction (< 2.3 g/day), DASH diet, exercise, alcohol moderation.

• Pharmacotherapy (individualized):

  • Thiazide Diuretics (e.g., hydrochlorothiazide)

  • ACE Inhibitors (e.g., enalapril) or ARBs (e.g., losartan)

  • Calcium Channel Blockers (e.g., amlodipine)

  • Beta-Blockers (e.g., metoprolol)

  • Mineralocorticoid Receptor Antagonists (e.g., spironolactone) in resistant cases.

3.3 Heart Failure

3.3.1 Definition & Classification

• Heart Failure (HF): Syndrome in which the heart cannot pump blood at a rate commensurate with metabolic demands or can do so only with elevated filling pressures.

• Types:

  • HFrEF (reduced EF ≤ 40%; “systolic HF”)

  • HFpEF (preserved EF ≥ 50%; “diastolic HF”)

  • Acute vs. Chronic; Left, Right, or Biventricular.

3.3.2 Etiologies

• Ischemic Heart Disease (most common)

• Hypertension

• Valvular Disease (e.g., aortic stenosis)

• Cardiomyopathies (dilated, hypertrophic)

• Myocarditis, toxins (alcohol, chemotherapy), arrhythmias.

3.3.3 Pathophysiology & Compensatory Mechanisms

1. Reduced Cardiac Output → tissue hypoperfusion.

2. Neurohormonal Activation: SNS ↑, RAAS ↑, vasopressin ↑ → initial compensation but maladaptive long-term.

3. Ventricular Remodeling: Myocyte hypertrophy, fibrosis, chamber dilation or stiffening.

4. Congestion:

   • Left HF → pulmonary edema, dyspnea, orthopnea.

   • Right HF → systemic venous congestion, hepatomegaly, peripheral edema, ascites.

3.3.4 Clinical Features & Diagnosis

• Symptoms: Exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue.

• Signs: Elevated JVP, crackles, S3 gallop, peripheral edema, hepatomegaly.

• Investigations:

  • Echocardiography: EF assessment, chamber size, wall motion, diastolic function.

  • BNP/NT-proBNP: Biomarkers elevated with increased cardiac wall stress.

  • Chest X-ray: Cardiomegaly, pulmonary congestion.

3.3.5 Management Strategies

• General Measures: Sodium restriction, fluid management, weight monitoring, exercise.

• Pharmacotherapy:

  • ACE Inhibitors/ARBs

  • Beta-Blockers (bisoprolol, carvedilol)

  • Mineralocorticoid Receptor Antagonists

  • Diuretics (loop diuretics for congestion)

  • ARNI (sacubitril/valsartan) in HFrEF

• Device Therapy: ICD for sudden death prevention; CRT for dyssynchrony.

• Advanced: Heart transplantation, LV assist devices.

3.4 Key Points for Exams

1. Atherosclerosis Pathway: Illustrate foam-cell formation and fibrous cap development, naming key mediators (PDGF, TGF-β).

2. Hypertension Classification: Differentiate primary vs. secondary causes, and list three systemic complications.

3. HF Mechanisms: Contrast HFrEF vs. HFpEF pathophysiology and hemodynamics.

4. Clinical Correlation: Describe orthopnea mechanism in left-sided HF.

5. Therapeutic Rationale: Explain how ACE inhibitors improve remodeling in HFrEF.

Unit 4: Respiratory Disorders (COPD, Asthma & Pneumonia)

A thorough examination of prevalent respiratory pathologies—detailing definitions, etiologies, pathophysiologic mechanisms, clinical manifestations, complications, and therapeutic strategies.

4.1 Chronic Obstructive Pulmonary Disease (COPD)

4.1.1 Definition & Clinical Significance

• COPD: Progressive airflow limitation that is not fully reversible, associated with abnormal inflammatory response to noxious particles or gases.

• Components: Chronic bronchitis (airway inflammation) and emphysema (alveolar wall destruction).

• Global Impact: 3rd leading cause of death worldwide.

4.1.2 Risk Factors

• Smoking: Primary cause (> 80% of cases).

• Environmental Exposures: Biomass fuel, occupational dusts/chemicals.

• Genetic: α₁‑Antitrypsin deficiency (panacinar emphysema in non‑smokers).

4.1.3 Pathogenesis

1. Chronic Inflammation

   • Infiltration by neutrophils, macrophages, CD8⁺ T‑cells → release of proteases and ROS.

2. Protease–Antiprotease Imbalance

   • Excess elastase activity → alveolar septal destruction (emphysema).

3. Oxidative Stress

   • Cigarette smoke and activated inflammatory cells generate ROS → tissue injury.

4. Airflow Limitation

   • Small airway remodeling: fibrosis, mucous gland hyperplasia → increased resistance.

4.1.4 Clinical Features

• Symptoms:

  • Chronic productive cough (≥ 3 months in ≥ 2 consecutive years).

  • Dyspnea on exertion progressing to at rest.

• Examination:

  • Barrel chest, prolonged expiration, wheezes/crackles.

  • Hyperresonance on percussion (emphysema).

• Spirometry:

  • Post‑bronchodilator FEV₁/FVC < 0.70 confirms airflow obstruction.

  • GOLD staging based on FEV₁ % predicted.

4.1.5 Complications & Acute Exacerbations

• Exacerbations: Often triggered by infections (viral/bacterial) or pollutants—worsening dyspnea, sputum change, hypoxia.

• Cor Pulmonale: Right‑heart failure secondary to pulmonary hypertension.

• Respiratory Failure: Type II (hypercapnic) in late-stage disease.

4.1.6 Management

4.2 Asthma

4.2.1 Definition & Epidemiology

• Asthma: Chronic inflammatory disorder of airways with variable airflow obstruction and bronchial hyperresponsiveness.

• Prevalence: Affects ~300 million globally; often begins in childhood but can occur at any age.

4.2.2 Pathophysiology

1. Airway Inflammation

   • Eosinophils, mast cells, Th₂ lymphocytes → release of cytokines (IL‑4, IL‑5, IL‑13).

2. Airway Hyperresponsiveness

   • Exaggerated bronchoconstrictive response to stimuli (allergens, exercise, cold air).

3. Remodeling

   • Chronic changes: subepithelial fibrosis, smooth muscle hypertrophy, goblet cell hyperplasia.

4.2.3 Clinical Features

• Symptoms: Episodic wheezing, chest tightness, cough (often nocturnal), dyspnea.

• Triggers: Allergens (dust mites, pollen), exercise, cold air, NSAIDs, infections.

• Spirometry:

  • ↑ Variability in FEV₁ (> 12% and 200 mL improvement after bronchodilator).

• Peak Expiratory Flow (PEF): Diurnal variability > 20%.

4.2.4 Severity Classification

4.2.5 Management

• Relievers:

  • Short‑acting β₂‑agonists (SABA: albuterol) for acute symptoms

• Controllers:

  • Inhaled corticosteroids (ICS) mainstay

  • Long‑acting β₂‑agonists (LABA) in combination with ICS

  • Leukotriene receptor antagonists (montelukast)

  • Biologics for severe asthma: anti‑IgE (omalizumab), anti‑IL‑5 (mepolizumab), anti‑IL‑4Rα (dupilumab)

• Non‑pharmacologic: Trigger avoidance, allergen immunotherapy.

4.3 Pneumonia

4.3.1 Definition & Classification

• Pneumonia: Infection of pulmonary parenchyma leading to alveolar inflammation and consolidation.

• Types:

  • Community‑Acquired (CAP) vs. Hospital‑Acquired (HAP) and Ventilator‑Associated (VAP)

  • Typical (bacterial: Streptococcus pneumoniae) vs. Atypical (Mycoplasma, Chlamydophila, Legionella).

4.3.2 Pathogenesis

1. Pathogen Inhalation/Aspiration into alveoli.

2. Host Defense Overcome: Impaired mucociliary clearance, macrophage dysfunction.

3. Inflammatory Response: Neutrophil infiltration, exudate filling alveoli → impaired gas exchange.

4.3.3 Clinical Features

• Symptoms: Fever, productive cough with purulent sputum, pleuritic chest pain, dyspnea.

• Signs: Tachypnea, crackles, bronchial breath sounds, egophony, dullness to percussion.

4.3.4 Diagnosis & Investigations

• Chest X‑ray: Lobar consolidation (typical) vs. interstitial infiltrates (atypical).

• Sputum Gram Stain & Culture

• Blood Cultures (in severe CAP)

• PCR & Urinary Antigens: Legionella and S. pneumoniae antigen tests.

• Severity Assessment: CURB‑65 score (Confusion, Urea, Respiratory rate, Blood pressure, age ≥ 65) to guide inpatient vs. outpatient management.

4.3.5 Management

4.4 Key Points for Exams

1. COPD Pathogenesis: Explain protease–antiprotease imbalance and its role in emphysema.

2. Asthma Definition: Differentiate variable vs. irreversible airflow obstruction.

3. Spirometric Criteria: State the diagnostic thresholds for COPD and asthma reversibility.

4. Pneumonia Classification: Use CURB‑65 to determine management setting and empiric antibiotics.

5. Therapeutic Rationale: Justify the use of ICS + LABA in moderate persistent asthma.

Unit 5: Gastrointestinal Disorders (Peptic Ulcer Disease, Hepatitis & Inflammatory Bowel Disease)

An in‑depth exploration of key GI pathologies—covering definitions, etiologies, pathogenesis, clinical presentations, complications, diagnostic approaches, and therapeutic strategies.

5.1 Peptic Ulcer Disease (PUD)

5.1.1 Definition & Epidemiology

• Peptic Ulcer: Break in the mucosal lining of the stomach or duodenum extending through the muscularis mucosae.

• Prevalence: Affects ~10% of the population; duodenal ulcers more common than gastric.

5.1.2 Etiology & Risk Factors

• Helicobacter pylori infection (~70–90% of duodenal, 50–70% of gastric ulcers)

• NSAIDs: Inhibit prostaglandin synthesis → reduced mucosal protection

• Acid Hypersecretion: Zollinger–Ellison syndrome (gastrinoma)

• Lifestyle: Smoking, stress, alcohol

5.1.3 Pathogenesis

1. Mucosal Defense Disruption

   • ↓ Mucus–bicarbonate barrier, ↓ epithelial cell restitution, ↓ mucosal blood flow.

2. Acid–Pepsin Injury

   • Gastric acid and pepsin degrade exposed tissue.

3. H. pylori Mechanisms

   • Urease production → ammonia neutralizes acid locally, cytotoxins (CagA, VacA) induce inflammation.

4. NSAID Mechanisms

   • COX‑1 inhibition → ↓ prostaglandin E₂ → impaired mucosal blood flow and repair.

5.1.4 Clinical Features

• Symptoms: Epigastric burning pain—

  • Duodenal: Pain 2–5 h after meals; relieved by food (“pain–food–pain” pattern).

  • Gastric: Pain aggravated by meals; weight loss.

• Alarm Signs: Melena, hematemesis, anemia, weight loss, dysphagia.

5.1.5 Complications

• Bleeding: Erosion into submucosal vessels.

• Perforation: Sudden severe abdominal pain; peritonitis.

• Gastric Outlet Obstruction: Edema or scarring of pylorus.

5.1.6 Diagnosis

• Endoscopy: Visualization & biopsy for H. pylori and malignancy exclusion.

• Noninvasive H. pylori Tests: Urea breath test, stool antigen, serology.

5.1.7 Management

• Eradication Therapy (for H. pylori)

  • PPI + clarithromycin + amoxicillin (or metronidazole) for 10–14 days

• Acid Suppression

  • Proton‑pump inhibitors (omeprazole) or H₂‑blockers (ranitidine)

• NSAID Management

  • Discontinue or switch to COX‑2 selective; co‑prescribe PPI or misoprostol.

5.2 Hepatitis

5.2.1 Definition & Classification

• Hepatitis: Inflammation of the liver parenchyma.

• Types:

  • Viral: A, B, C, D, E (blood‑borne vs. fecal–oral routes)

  • Nonviral: Alcoholic, autoimmune, drug‑induced, metabolic (e.g., NAFLD/NASH)

5.2.2 Viral Hepatitis Pathogenesis

• HAV/HEV: Acute, self‑limiting; no chronic stage.

• HBV/HCV/D: Can progress to chronic hepatitis, cirrhosis, hepatocellular carcinoma.

• HBV: Partially double‑stranded DNA; integrates into host genome.

• HCV: RNA flavivirus with high genetic variability; immune evasion leads to chronicity.

5.2.3 Clinical Features

• Acute: Malaise, anorexia, nausea, RUQ discomfort, jaundice, dark urine, pale stools.

• Chronic: Often asymptomatic until advanced fibrosis; fatigue, hepatomegaly, elevated transaminases.

5.2.4 Diagnostics

• Serology:

  • HAV IgM, HBV surface antigen (HBsAg), HCV antibody + HCV RNA PCR.

• Liver Function Tests: ↑ AST/ALT (viral > 1,000 U/L in acute), ↑ bilirubin, ↓ albumin in chronic.

• Imaging & Biopsy: Ultrasound elastography for fibrosis; histology for staging.

5.2.5 Management

• Acute Viral: Supportive; no specific antivirals for HAV/HEV.

• Chronic HBV: Nucleos(t)ide analogs (entecavir, tenofovir) or interferon‑α.

• Chronic HCV: Direct‑acting antivirals (sofosbuvir + velpatasvir) achieving > 95% SVR.

• Nonviral:

  • Alcohol cessation, corticosteroids/immunosuppressants for autoimmune hepatitis, weight loss and insulin sensitizers for NASH.

5.3 Inflammatory Bowel Disease (IBD)

5.3.1 Definition & Types

• IBD: Chronic, relapsing inflammatory disorders of the GI tract.

• Major Forms:

  • Ulcerative Colitis (UC): Continuous mucosal inflammation confined to colon and rectum.

  • Crohn’s Disease (CD): Transmural, segmental (“skip lesions”) inflammation anywhere from mouth to anus.

5.3.2 Etiology & Pathogenesis

• Genetic Susceptibility: NOD2 mutation in CD, HLA‑DRB1 in UC.

• Immune Dysregulation:

  • CD: Th1/Th17‑mediated; ↑ IL‑12, TNF.

  • UC: Th2‑like response; ↑ IL‑5, IL‑13.

• Microbiome Alterations: Dysbiosis with loss of protective commensals.

• Barrier Dysfunction: Increased intestinal permeability leading to antigen exposure.

5.3.3 Clinical Features

5.3.4 Diagnosis

• Endoscopy: Colonoscopy with biopsy—crypt abscesses in UC; granulomas in CD (not always).

• Imaging: MR-enterography for small‑bowel CD.

• Laboratory: ↑ CRP/ESR; fecal calprotectin correlates with inflammation.

5.3.5 Management

• Induction of Remission:

  • UC: 5‑ASA (mesalazine), corticosteroids.

  • CD: Corticosteroids, budesonide (ileocaecal disease).

• Maintenance:

  • Thiopurines (azathioprine), methotrexate.

  • Biologics: Anti‑TNF (infliximab), anti‑integrin (vedolizumab), anti‑IL‑12/23 (ustekinumab).

• Surgery:

  • UC: Proctocolectomy is curative.

  • CD: Resection of diseased segment; not curative—high recurrence.

5.4 Key Points for Exams

1. PUD Pathogenesis: Contrast H. pylori‑mediated vs. NSAID‑induced ulcer mechanisms.

2. Hepatitis Markers: Match serologic markers (IgM, HBsAg, HCV RNA) to acute vs. chronic infection.

3. IBD Differentiation: List four features distinguishing UC from CD in terms of pathology and presentation.

4. Treatment Rationale: Explain the use of bile acid sequestrants in PUD and direct‑acting antivirals in HCV.

5. Complication Management: Outline the approach to toxic megacolon in UC, including initial medical and surgical considerations.

Unit 6: Renal & Hepatic Disorders (Glomerulonephritis & Cirrhosis)

An in‑depth examination of key renal and hepatic pathologies—detailing definitions, etiologies, pathogenesis, clinical manifestations, diagnostic approaches, complications, and therapeutic principles.

6.1 Glomerulonephritis

6.1.1 Definition & Classification

• Glomerulonephritis (GN): Inflammatory injury of the renal glomeruli resulting in hematuria, proteinuria, and variable loss of renal function.

• Classification:

  • Acute vs. Chronic GN

  • Primary (renal‐limited) vs. Secondary (systemic diseases)

  • Histologic patterns: Proliferative (e.g., post‑streptococcal), membranous, rapidly progressive (crescentic), IgA nephropathy.

6.1.2 Etiologies & Examples

6.1.3 Pathogenesis

1. Immune Complex–Mediated Injury

   • Circulating complexes or in situ antigen–antibody binding → complement activation (C5a) → neutrophil recruitment.

2. Cell‑Mediated Injury

   • ANCA‑associated vasculitis: Neutrophil activation against endothelial targets.

3. Podocyte & GBM Damage

   • Membrane thickening (membranous GN), crescents from Bowman’s capsule epithelial proliferation (rapidly progressive GN).

6.1.4 Clinical Features

• Acute GN:

  • Hematuria (cola‑colored urine), oliguria, hypertension, mild proteinuria (< 3.5 g/day).

  • Edema (periorbital) from salt retention.

• Nephrotic Syndrome (when heavy proteinuria) overlaps:

  • Proteinuria > 3.5 g/day, hypoalbuminemia, generalized edema, hyperlipidemia.

6.1.5 Diagnosis

• Urinalysis: RBC casts, proteinuria quantification.

• Serology:

  • Complement levels (↓ C3 in immune complex GN).

  • ANA, anti‑dsDNA (lupus); ANCA; anti‑GBM.

• Renal Biopsy: Light microscopy, immunofluorescence (granular vs. linear deposits), electron microscopy (sub‑epithelial “humps” in post‑streptococcal).

6.1.6 Management

• Supportive: Salt restriction, diuretics for edema, blood pressure control (ACE inhibitors to reduce proteinuria).

• Immunosuppression:

  • Corticosteroids ± cyclophosphamide in rapidly progressive GN.

  • Mycophenolate or rituximab in membranous GN.

• Plasmapheresis: In anti‑GBM disease and severe vasculitis.

6.2 Cirrhosis

6.2.1 Definition & Stages

• Cirrhosis: End‑stage of chronic liver injury characterized by diffuse fibrosis, regenerative nodules, and disruption of normal architecture.

• Compensated vs. Decompensated cirrhosis (ascites, variceal bleeding, encephalopathy).

6.2.2 Etiologies

6.2.3 Pathogenesis

1. Chronic Hepatocyte Injury → apoptosis, inflammatory cytokines (TNF, TGF‑β).

2. Activation of Hepatic Stellate Cells → myofibroblast transformation, collagen deposition in space of Disse.

3. Regenerative Hyperplasia → nodular architecture encased by fibrous septae.

4. Vascular Remodeling → intrahepatic portal hypertension.

6.2.4 Clinical Features

• Portal Hypertension:

  • Splenomegaly, thrombocytopenia.

  • Varices (esophageal, gastric) → bleeding risk.

  • Ascites: Albumin‐rich fluid in peritoneum.

• Hepatic Insufficiency:

  • Jaundice, coagulopathy (↓ clotting factors), hypoalbuminemia → edema.

  • Hepatic encephalopathy: Confusion, asterixis from ammonia accumulation.

• Complications: Hepatorenal syndrome, hepatopulmonary syndrome, hepatocellular carcinoma.

6.2.5 Diagnosis

• Laboratory: ↑ AST/ALT (milder than acute hepatitis), ↑ bilirubin, ↑ INR, ↓ albumin.

• Imaging: Ultrasound elastography for liver stiffness, nodularity on CT/MRI.

• Endoscopy: Screen for varices.

• Liver Biopsy: Confirms etiology and fibrosis stage.

6.2.6 Management

• Address Underlying Cause:

  • Abstinence from alcohol, antiviral therapy for HBV/HCV, weight loss for NASH.

• Portal Hypertension Management:

  • Nonselective β‑blockers (propranolol) to reduce portal pressure.

  • Endoscopic variceal ligation for high‑risk varices.

• Ascites & Edema:

  • Sodium restriction, diuretics (spironolactone + furosemide), large‑volume paracentesis with albumin.

• Encephalopathy:

  • Lactulose, rifaximin to reduce ammonia.

• Liver Transplantation: Definitive in decompensated cirrhosis (MELD score guidance).

6.3 Key Points for Exams

1. GN Classification: Match histopathologic pattern (e.g., subepithelial humps) to disease type.

2. Cirrhosis Pathogenesis: Diagram stellate cell activation and fibrogenesis.

3. Clinical Correlates: Describe how hypoalbuminemia contributes to ascites formation.

4. Diagnostic Criteria: List the minimal diagnostic work‑up for a patient with suspected glomerulonephritis.

5. Therapeutic Rationale: Explain why ACE inhibitors reduce proteinuria in GN and β‑blockers prevent variceal bleeding in cirrhosis.