MBBS YEAR 1

FunMed (Fundamentals of Medicine)

Types of Collagen

Collagen is the most abundant protein in mammals, making up approximately 25-35% of the body's protein content.

• Type I collagen: Found predominantly in bone, comprising about 90% of bone matrix. It provides tensile strength to tissues and is also found in tendons, skin, ligaments, cornea, and many interstitial connective tissues
• Type II collagen: The principal component of cartilage. It forms fibrils that provide tensile strength while allowing the tissue to bear compressive loads

Osmolarity and Solutions

• Hypertonic solutions: Have higher osmolarity than the reference solution (typically cell cytoplasm). They cause cell shrinkage as water moves out of cells via osmosis

Microbiology

• E. coli: Gram-negative bacterium with rod-shaped morphology. The Gram staining distinction is based on cell wall composition: Gram-positive bacteria have a thick peptidoglycan layer that retains crystal violet dye, while Gram-negative bacteria have a thin peptidoglycan layer and an outer membrane containing lipopolysaccharides
• H. pylori: Gram-negative bacterium that colonizes the stomach and causes gastric ulcers. Treatment involves triple therapy consisting of one proton pump inhibitor (PPI) plus two antibiotics to eradicate the infection

Immunoglobulins and Their Functions

Antibodies are glycoproteins produced by B cells that recognize specific antigens:

• IgA: A dimeric immunoglobulin found in secretions including tears, gastric fluid, mucus, colostrum, and breast milk. It provides mucosal immunity and prevents pathogen attachment to epithelial surfaces
• IgE: A monomeric immunoglobulin involved in allergic responses, asthma, and antiparasitic activity. It binds to Fc receptors on mast cells and basophils, triggering degranulation when cross-linked by allergens
• IgG: The most abundant antibody in serum. A monomeric immunoglobulin that crosses the placenta, providing passive immunity to the fetus. It has the longest half-life of all antibodies and is involved in complement activation, opsonization, and antibody-dependent cell-mediated cytotoxicity (ADCC)
• IgD: A monomeric immunoglobulin that functions as an antigen receptor on naive B cells and is involved in B cell activation
• IgM: A pentameric immunoglobulin that is the first antibody produced during an immune response. It is highly efficient at complement activation and agglutination due to its multiple antigen-binding sites

Cancer, Oncogenes, and Tumor Suppressor Genes

DNA Repair Disorders

• Xeroderma pigmentosum: Autosomal recessive disorder caused by defects in nucleotide excision repair. Patients have extreme sensitivity to UV light and a high predisposition to skin cancers
• Constitutional mismatch repair deficiency syndrome (CMMRD): Caused by biallelic mutations in MutS and MutL enzymes that are critical for DNA mismatch repair. Results in early- onset cancers, especially brain tumors and hematological malignancies
• Inherited BRCA2 repair associated mutations: Affect homologous recombination repair mechanisms, increasing the risk of breast, ovarian, prostate, and pancreatic cancers

Chromosomal Disorders

• Edwards syndrome (Trisomy 18): Characterized by an extra chromosome 18, resulting in severe developmental abnormalities and early mortality
• Patau syndrome (Trisomy 13): Results from an extra chromosome 13, causing severe congenital anomalies including holoprosencephaly, polydactyly, and heart defects
• Down syndrome (Trisomy 21): Can occur in three forms:
  • Classic: Complete trisomy of chromosome 21
  • Robertsonian translocation: Involves chromosome 14 and 21
  • Mosaic: Only some cells have the extra chromosome, typically resulting in milder phenotypic expression
• Klinefelter syndrome (47, XXY): Males with an extra X chromosome, characterized by tall stature, gynecomastia, and hypogonadism
• Turner syndrome (45, XO): Females with only one X chromosome, characterized by short stature, webbed neck, and ovarian dysgenesis

Cell Cycle Regulators

• p16, p21, p27: Cyclin-dependent kinase inhibitor (CDKI) proteins that regulate the G1/S transition by inhibiting CDKs
• p53: Critical tumor suppressor that regulates both G1/S and G2/M checkpoints. It responds to DNA damage by inducing cell cycle arrest, DNA repair, or apoptosis if repair is not possible
• Rb (retinoblastoma protein): Tumor suppressor that regulates the G1/S transition by sequestering E2F transcription factors
• BRCA1 and BRCA2: Tumor suppressors involved in DNA double-strand break repair through homologous recombination

Genetic Mechanisms in Cancer

• Proto-oncogene to oncogene: Involves gain-of-function mutations that enhance cellular proliferation and survival
• Tumor suppressor gene mutations: Involve loss-of-function mechanisms, typically requiring mutations in both alleles (two-hit hypothesis)
• Methylation: An epigenetic mechanism commonly affecting cytosine residues in CpG islands. Hypermethylation of tumor suppressor gene promoters can silence their expression, contributing to carcinogenesis

Joint Types and Classification

Fibrous Joints

Characterized by fibrous connective tissue between bones with little or no movement:

• Sutures: Found between skull bones; allow minimal movement until ossification is complete
• Gomphosis: Peglike articulation of tooth in socket; held by periodontal ligament
• Syndesmosis: Connected by interosseous ligament/membrane; allows slight movement (e.g., tibiofibular joint)

Cartilaginous Joints

Connected by cartilage with limited movement:

• Primary (synchondroses): Temporary hyaline cartilage joints like epiphyseal plates and costochondral joints
• Secondary (symphyses): Contains fibrocartilage disc between bones; examples include pubic symphysis and intervertebral discs

Synovial Joints

Characterized by synovial fluid, articular cartilage, and a joint capsule allowing free movement:

• Condyloid joints: Allow biaxial movement (flexion/extension, abduction/adduction) as seen in metacarpal-phalangeal and radiocarpal joints
• Planar joints: Allow gliding movements between flat bone surfaces, found between tarsal bones and at the acromioclavicular joint
• Saddle joints: Allow biaxial movement with reciprocally concave-convex surfaces, exemplified by the carpometacarpal joint of the thumb
• Hinge joints: Allow uniaxial movement (flexion/extension) like the elbow
• Pivot joints: Allow rotation around a single axis, as seen in the atlantoaxial joint (C1-C2)
• Ball and socket joints: Allow multiaxial movement including circumduction, found at the hip and shoulder

CR (Cardiovascular/Respiratory)

Autonomic Regulation of Blood Pressure

Sympathetic and Parasympathetic Effects

• Sympathetic stimulation: Increases heart rate and mean arterial pressure through beta-1 adrenergic receptor activation
• Parasympathetic stimulation: Decreases heart rate and mean arterial pressure through muscarinic receptor activation by acetylcholine

Baroreceptor System

The baroreceptor reflex provides rapid neural control of blood pressure:

Sensors

• Located in the carotid sinus, aortic arch, and arterial vessels
• When arterial pressure increases, vascular wall tension increases, activating mechanosensitive PIEZO channels, causing Na^+ and Ca^{2+} influx, membrane depolarization, and action potential generation

Neural Pathways

• Afferent signals travel via the sinus nerve (branch of glossopharyngeal nerve) and vagus nerve to the nucleus of the solitary tract (NTS) in the medulla
• When BP increases: NTS activates the nucleus ambiguus, increasing parasympathetic outflow via the vagus nerve to the SA node, reducing heart rate and cardiac output, thereby lowering mean arterial pressure
• When BP decreases: NTS activates the vasomotor center, increasing sympathetic outflow via the reticulospinal tract, causing vasoconstriction and increased heart rate, thereby increasing peripheral resistance and mean arterial pressure

Renin-Angiotensin-Aldosterone System (RAAS)

Long-term regulation of blood pressure through:

• Renin release from juxtaglomerular apparatus in response to decreased renal perfusion
• Angiotensinogen conversion to angiotensin I by renin
• Angiotensin I conversion to angiotensin II by ACE
• Angiotensin II causes vasoconstriction and aldosterone release
• Aldosterone promotes Na^+ and water retention

Hypertension Management

Antihypertensive therapy is guided by patient characteristics:

• Patients under 55 or with type II diabetes: First-line treatment with ACE inhibitors, which block the conversion of angiotensin I to angiotensin II. If cough develops (common side effect), switch to angiotensin receptor blockers (ARBs)
• Patients over 55 or of Afro-Caribbean descent without diabetes: First-line treatment with calcium channel blockers, which reduce vascular smooth muscle contraction

Asthma Pharmacology

Beta-2 Agonists

• Short-acting beta agonists (SABAs): Such as salbutamol (albuterol), provide rapid bronchodilation for symptom relief by activating β_2-adrenergic receptors on airway smooth muscle
• Long-acting beta agonists (LABAs): Such as salmeterol, provide sustained bronchodilation (12+ hours) and are used as maintenance therapy, typically in combination with inhaled corticosteroids

Adrenergic Receptors

Alpha Adrenergic Receptors

• \alpha_1 receptors: Located on vascular smooth muscle; activation (by phenylephrine) causes vasoconstriction and increases blood pressure through Gq protein-mediated phospholipase C activation and intracellular calcium increase
• \alpha_2 receptors: Located presynaptically on sympathetic nerve terminals; activation (by clonidine) inhibits norepinephrine release via Gi protein-mediated inhibition of adenylyl cyclase. Also inhibits insulin release from pancreatic beta cells

Beta Adrenergic Receptors

• \beta_1 receptors: Located primarily in the heart; activation increases heart rate, conduction velocity, and contractility through Gs protein-mediated activation of adenylyl cyclase
• \beta_2 receptors: Located in bronchial smooth muscle; activation causes bronchodilation through Gs protein-mediated relaxation of smooth muscle

Autonomic Nervous System

Sympathetic Division

Neurochemistry:

• Preganglionic neurons use acetylcholine as neurotransmitter
• Postganglionic neurons primarily use norepinephrine (except sweat glands where ACh is used)

Primary functions:

• Pupil dilation via radial muscle contraction
• Inhibition of salivation
• Bronchial relaxation for increased airflow
• Cardiac acceleration and increased blood pressure
• Decreased gastrointestinal peristalsis and secretion
• Enhanced glucose production and release from liver
• Stimulation of adrenal medulla to release epinephrine and norepinephrine
• Inhibition of bladder contraction
• Stimulation of ejaculation and orgasm

Neuroanatomy:

• Cell bodies located in lateral horn of spinal cord segments T1-L2
• Postganglionic neuron cell bodies located in paravertebral ganglia (sympathetic chain)
• Pre- and postganglionic neurons synapse in paravertebral or prevertebral ganglia

Adrenoreceptor functions:

• Stimulatory effects:
  • \alpha_1: Causes vasoconstriction of blood vessels
  • \beta_1: Increases heart rate and contractility
• Inhibitory effects:
  • \alpha_2: Inhibits overall sympathetic activity (negative feedback)
  • \beta_2: Causes bronchodilation and vasodilation

Pulmonary Physiology

Lung Volumes and Capacities

• Tidal volume (TV): Volume of air moved in and out during quiet breathing (~500ml in adults)
• Inspiratory reserve volume (IRV): Additional volume of air that can be forcefully inhaled after normal inspiration (~3000ml)
• Expiratory reserve volume (ERV): Additional volume of air that can be forcefully exhaled after normal expiration (~1200ml)
• Residual volume (RV): Volume of air remaining in lungs after maximal exhalation (~1200ml)
• Forced vital capacity (FVC): Total volume of air that can be exhaled after maximal inhalation (IRV + TV + ERV, ~4700ml)

Respiratory Muscles

Inspiration

• Quiet inspiration:
  • Diaphragm: Principal muscle of inspiration; contracts and flattens, increasing vertical dimension of thoracic cavity
  • External intercostal muscles: Elevate ribs, increasing anteroposterior and transverse dimensions of thoracic cavity
• Forced inspiration: Additional recruitment of accessory muscles:
  • Pectoralis minor and major: Elevate ribs when arms are fixed
  • Serratus anterior: Elevates ribs when scapula is fixed

Expiration

• Quiet expiration: Largely passive process involving elastic recoil of lungs and relaxation of inspiratory muscles
• Forced expiration: Active process involving:
  • Internal intercostal muscles: Depress ribs
  • Anterior abdominal muscles (rectus abdominis, external/internal obliques, transversus abdominis): Contract to increase intra-abdominal pressure
  • Quadratus lumborum: Fixes last rib and stabilizes diaphragm attachments

Mechanics

• Diaphragm moves upward during relaxation (expiration) and downward during contraction (inspiration)
• Rib cage moves down and in during expiration, up and out during inspiration

Lung Compliance and Recoil

Compliance refers to the ease with which lungs expand under pressure:

• Lung compliance = Change in volume / Change in transpulmonary pressure
• Higher recoil forces correlate with lower compliance

Reduced Compliance Conditions

• Pulmonary fibrosis: Excessive collagen deposition in lung parenchyma
• Lung collapse (atelectasis): Loss of air volume increases surface tension
• Increased pulmonary venous pressure: As in left heart failure, causes fluid accumulation

Increased Compliance Conditions

• Emphysema: Destruction of elastic fibers and alveolar walls
• Aging: Natural loss of elastic fibers with age

Edema Formation

Edema results from an imbalance in Starling forces governing fluid movement across capillaries. The Starling equation governs net fluid filtration:
JV(NFP) = K[(Pc – Pi) – σ(Πc- Πi)]
Where:

• JV = net fluid movement
• K = filtration coefficient
• P_c = capillary hydrostatic pressure
• P_i = interstitial hydrostatic pressure
• \sigma = reflection coefficient
• Π_c = capillary oncotic pressure
• Π_i = interstitial oncotic pressure

Causes of Edema

• Increased capillary hydrostatic pressure: Seen in heart failure, venous obstruction, and excessive sodium retention
• Decreased plasma oncotic pressure: Results from hypoalbuminemia in conditions like liver disease, nephrotic syndrome, and protein-losing enteropathy
• Increased capillary permeability: Occurs in inflammation, allergic reactions, burns, and sepsis
• Lymphatic obstruction: Due to malignancy, filariasis, or post-surgical complications

Cardiac Preload and Afterload

• Preload: The tension or load on ventricular muscle at the end of diastole, indexed by End Diastolic Volume (EDV). Increased preload leads to increased active tension and stronger contraction according to the Frank-Starling mechanism, which states that the heart will pump what it receives
• Afterload: The load against which the heart must eject blood, determined primarily by aortic pressure and systemic vascular resistance. Increasing afterload (within physiological limits) increases stroke volume by enhancing contraction force, but excessive afterload can decrease stroke volume by impeding ejection

Gas Exchange and Partial Pressures

Partial pressure represents the pressure exerted by a specific gas in a mixture as if it alone occupied the entire volume at the same temperature

• Oxygen gradient: Partial pressure of O_2 is lower in blood (40 mmHg in venous blood) than in alveoli (104 mmHg), creating a gradient that drives oxygen diffusion from alveoli into blood
• Carbon dioxide gradient: Partial pressure of CO2 is higher in blood (46 mmHg in venous blood) than in alveoli (40 mmHg), driving CO2 diffusion from blood into alveoli
• High altitude effects: Decreased atmospheric pressure at altitude reduces the partial pressure of inspired oxygen, leading to lower alveolar PO_2, reduced hemoglobin saturation, and potential altitude sickness characterized by hypoxemia, dyspnea, headache, and nausea

Physiological Laws

• Laplace's Law: Tension = Pressure × Radius
  • Smaller vessels can withstand higher pressures due to reduced wall tension
  • Explains why aneurysms (dilated vessel segments) are prone to rupture — the increased radius requires greater wall tension to contain the same pressure
• Frank-Starling Law: The force of myocardial contraction is proportional to initial muscle fiber length (preload)
  • As ventricular filling increases, myofilaments are stretched to optimal overlap, increasing contractile force
  • This mechanism allows the heart to adjust output based on venous return
• Boyle's Law: P1V1 = P2V2 (pressure and volume are inversely related at constant temperature)
  • As alveoli expand during inspiration, pressure decreases, drawing air in
  • During expiration, alveolar volume decreases, pressure increases, pushing air out
• Poiseuille's Law: Flow = (\frac{π × ΔP × r^4}{8 × η × L})
  • Flow is proportional to the fourth power of radius (r^4)
  • Small changes in vessel radius cause dramatic changes in blood flow
  • Explains the powerful effect of vasoconstriction and vasodilation on peripheral resistance

Pulmonary Function Testing

FEV1/FVC Ratio

• Definition: Ratio of forced expiratory volume in 1 second to forced vital capacity
• Normal values: Above 70-80% in healthy individuals
• Diagnostic significance:
  • Reduced in obstructive lung diseases like asthma and COPD
  • Normal or increased in restrictive lung diseases

ECG Interpretation

Chest Leads Placement

• V1: 4th intercostal space, right sternal border
• V2: 4th intercostal space, left sternal border
• V3: Midway between V2 and V4
• V4: 5th intercostal space, left midclavicular line
• V5: Same level as V4, left anterior axillary line
• V6: Same level as V5, left midaxillary line

ECG Intervals

• P wave: < 0.08 seconds (2 small boxes); represents atrial depolarization
• P-R interval: 0.12-0.20 seconds (3-5 small boxes); represents atrioventricular conduction time
• QRS complex: 0.08-0.12 seconds (2-3 small boxes); represents ventricular depolarization
• Q-T interval: 0.35-0.43 seconds, dependent on heart rate; represents total time for ventricular depolarization and repolarization

Cardiac Anatomy

The right ventricle occupies most of the anterior cardiac surface, making it most vulnerable to anterior penetrating chest trauma

Vascular Histology

• Arteries: Have the thickest tunica media, comprised primarily of smooth muscle and elastic fibers for pressure resistance and regulation of blood flow
• Veins: Have the thickest tunica adventitia, composed of connective tissue providing structural support while allowing distensibility for volume accommodation

Antidiuretic Hormone (ADH)

• Stimulus: Increased blood osmolarity is sensed by osmoreceptors in the subfornical organ, which activates the hypothalamic paraventricular and supraoptic nuclei
• Production: ADH (vasopressin) is synthesized in the hypothalamus and stored in the posterior pituitary
• Actions:
  1. Increases water permeability in collecting ducts by inserting aquaporin-2 channels, reducing urine volume and producing more concentrated urine
  2. Enhances collecting duct permeability to urea, facilitating water reabsorption
  3. Stimulates sodium reabsorption in the thick ascending limb of Henle's loop by increasing NKCC (Na-K-2Cl) cotransporter activity, increasing medullary interstitial osmolarity and promoting water reabsorption from collecting ducts

Allergic Response

Increased IL-4 production is characteristic of allergic reactions and asthma. IL-4 promotes:

• B cell isotype switching to IgE production
• Development of Th2 lymphocytes
• Goblet cell hyperplasia and mucus hypersecretion
• Eosinophil recruitment and activation

MET (Metabolism)

Micronutrients and Deficiency States

Fat-Soluble Vitamins

• Vitamin A (Retinol): Essential for vision (rhodopsin formation), epithelial cell integrity, and immune function. Deficiency causes night blindness, xerophthalmia, and Bitot's spots
• Vitamin D (Cholecalciferol): Essential for calcium and phosphate homeostasis. Deficiency causes:
  • In children: Rickets - poor mineralization of growing bones leading to bowed legs, rachitic rosary, and craniotabes
  • In adults: Osteomalacia - demineralization of mature bone causing bone pain and fractures
• Vitamin E (Tocopherol): Antioxidant that protects cell membranes. Deficiency causes peripheral neuropathy, ataxia, and hemolytic anemia
• Vitamin K: Essential for synthesis of clotting factors II, VII, IX, X, protein C, and protein S. Deficiency causes coagulopathy manifesting as easy bruising, mucosal bleeding, and prolonged PT/INR

Water-Soluble Vitamins

Water-soluble vitamins often serve as enzymatic cofactors:

• Vitamin C (Ascorbic acid): Required for collagen synthesis, antioxidant function, and iron absorption. Deficiency causes scurvy - characterized by poor wound healing, gingival bleeding, perifollicular hemorrhages, and joint pain
• Vitamin B1 (Thiamine): Cofactor for pyruvate dehydrogenase and transketolase. Deficiency causes:
  • Beriberi: Peripheral neuropathy, high-output heart failure, edema
  • Wernicke-Korsakoff syndrome: Characterized by the triad of horizontal nystagmus, cerebellar ataxia, and ophthalmoplegia (Wernicke's), which may progress to irreversible anterograde amnesia and confabulation (Korsakoff's)
• Vitamin B2 (Riboflavin): Component of FAD and FMN. Deficiency causes angular stomatitis, glossitis, and dermatitis
• Vitamin B3 (Niacin): Component of NAD and NADP. Deficiency causes pellagra, characterized by the "4 Ds": dermatitis, diarrhea, dementia, and death if untreated
• Vitamin B6 (Pyridoxine): Cofactor in amino acid metabolism. Deficiency causes peripheral neuropathy, sideroblastic anemia, and seizures
• Vitamin B9 (Folate): Required for nucleic acid synthesis and methylation reactions. Deficiency causes megaloblastic anemia and neural tube defects during pregnancy
• Vitamin B12 (Cobalamin): Cofactor for methionine synthase and methylmalonyl-CoA mutase. Deficiency causes megaloblastic anemia, subacute combined degeneration of the spinal cord (posterior and lateral columns), and peripheral neuropathy

Rate-Limiting Enzymes

Rate-limiting enzymes control the pace of metabolic pathways and are key regulatory points:

• HMG-CoA reductase: Rate-limiting enzyme in cholesterol synthesis; target of statin medications
• Phosphofructokinase-1: Rate-limiting enzyme in glycolysis
• Pyruvate kinase: Final rate-limiting step in glycolysis
• Carnitine palmitoyltransferase-1: Rate-limiting step in fatty acid oxidation
• Acetyl-CoA carboxylase: Rate-limiting enzyme in fatty acid synthesis

Nutrient Absorption Phases

Nutrient absorption occurs in three sequential phases:

1. Luminal Phase: Ingested food undergoes chemical and enzymatic breakdown through:
   • Acidic hydrolysis in the stomach
   • Alkaline hydrolysis in the small intestine
   • Enzymatic digestion by secretions from gastric mucosa, pancreas, and small bowel epithelium
2. Mucosal Phase: Pre-digested nutrients are absorbed by the brush border membrane of enterocytes through:
   • Active transport (glucose, amino acids)
   • Facilitated diffusion (fructose)
   • Passive diffusion (short-chain fatty acids)
   • Endocytosis (vitamin B12-intrinsic factor complex)
3. Post-absorptive Phase: Absorbed nutrients are transported to the body via:
   • Portal circulation: Water-soluble nutrients, amino acids, monosaccharides
   • Lymphatic system (via chylomicrons): Fat-soluble vitamins and long-chain fatty acids in triglycerides

Gastroesophageal Reflux Disease (GORD)

GORD involves the retrograde movement of gastric contents from the fundus into the distal esophagus

Pathophysiology

• Lower Esophageal Sphincter (LES) Dysfunction: Inappropriate transient relaxations of the LES allow acid reflux
• Hiatal Hernia: Protrusion of stomach into thorax through diaphragmatic hiatus, compromising LES function
• Esophageal Hypersensitivity: Heightened perception of acid reflux, even with normal acid exposure
• Delayed Gastric Emptying: Increases volume of gastric contents available for reflux

Treatment

• Proton Pump Inhibitors (PPIs): First-line pharmacologic therapy; irreversibly inhibit H+/K+ ATPase in gastric parietal cells
• Antacids: Provide symptom relief by neutralizing stomach acid; products like Gaviscon (sodium alginate and potassium bicarbonate) form a physical barrier against reflux
• Surgery: Fundoplication for refractory cases or large hiatal hernias; creates a mechanical barrier to reflux by wrapping the fundus around the distal esophagus

Inflammatory Bowel Disease and Related Conditions

Irritable Bowel Syndrome (IBS)

• An umbrella term for functional gastrointestinal disorders (FGIDs) with unknown organic pathology
• Characterized by abdominal pain associated with altered bowel habits
• Upper GI manifestations include GORD, dyspepsia, bloating, and pain
• Lower GI manifestations include abdominal pain, constipation, and motility-related diarrhea
• Diagnosis is based on Rome IV criteria and exclusion of organic disease

Inflammatory Bowel Disease (IBD)

Umbrella term for chronic inflammatory conditions of the lower GI tract, primarily:

• Crohn's disease
• Ulcerative colitis
  Etiology involves genetic susceptibility, environmental triggers, and dysregulated immune response

Crohn's Disease

• Can affect any part of the GI tract from mouth to anus, but commonly affects terminal ileum
• Characterized by transmural inflammation (affecting all layers of bowel wall)
• Discontinuous "skip lesions" with normal mucosa between affected areas
• Clinical features include abdominal pain, fatigue, fever, blood in stool, and inflammatory diarrhea
• Complications include strictures, fistulas, abscesses, and increased risk of colorectal cancer
• Histologically shows non-caseating granulomas in 50% of cases

Ulcerative Colitis

• Limited to the colon and rectum
• Characterized by continuous inflammation limited to the mucosa and submucosa
• Typically begins in the rectum and extends proximally
• Clinical features include bloody diarrhea, tenesmus, urgency, and abdominal pain
• Complications include toxic megacolon, perforation, massive hemorrhage, and increased risk of colorectal cancer
• Histologically shows crypt abscesses and goblet cell depletion

Treatment of IBD

• Mild to moderate symptoms: 5-aminosalicylates, corticosteroids
• Severe symptoms: Immunosuppressants (azathioprine, 6-mercaptopurine), biological therapies (anti-TNF agents like infliximab, adalimumab)
• Surgery: Required in 30-40% of ulcerative colitis patients and up to 70% of Crohn's disease patients over their lifetime

Diarrhea Classification

Diarrhea can be classified based on pathophysiological mechanisms:

• Osmotic diarrhea: Results from presence of poorly absorbable solutes in the intestinal lumen that retain water. Examples include lactose intolerance (lactase deficiency) and malabsorption syndromes
• Secretory diarrhea: Results from active secretion of ions and fluid into the intestinal lumen. Typically caused by enterotoxins such as those produced by E. coli and Vibrio cholerae (activates adenylate cyclase)
• Inflammatory diarrhea: Results from mucosal damage and inflammation. Seen in conditions like Crohn's disease, ulcerative colitis, and infectious colitis
• Motility diarrhea: Results from altered intestinal motility, typically accelerated transit. Seen in functional GI disorders like IBS

Gastric Secretion and Regulation

Gastric Epithelial Cell Types

• Surface mucus cells: Secrete mucus, trefoil peptides, and bicarbonate to protect gastric epithelium from acid and pepsin
• Mucus neck cells: Serve as stem cell compartment for epithelial renewal
• Parietal cells: Secrete hydrochloric acid (via H+/K+-ATPase) and intrinsic factor (essential for vitamin B12 absorption)
• Enterochromaffin-like (ECL) cells: Secrete histamine, which stimulates parietal cells
• Chief cells: Secrete pepsinogen (precursor to pepsin), chymosin (rennin), and gastric lipase
• G cells: Located in pyloric antrum; secrete gastrin in response to proteins, amino acids, calcium, and gastric distension
• D cells: Secrete somatostatin, which inhibits acid secretion

Regulation of Acid Secretion

Parietal cells and ECL cells in the gastric corpus and body are connected to the enteric nervous system (ENS) and respond to various stimuli:

• Acetylcholine (ACh): Released from vagal nerve endings; binds to M3 receptors on parietal cells and ECL cells, stimulating acid secretion and histamine release, respectively
• Gastrin ("the booster"): Released from G cells in response to proteins; acts on CCK2 receptors on both ECL cells and parietal cells to stimulate acid secretion. G cells sense digested proteins before the pyloric sphincter and release gastrin into the bloodstream
• Somatostatin ("the brake"): Released from D cells; inhibits acid production by binding to somatostatin receptors on parietal and ECL cells. D cells are activated by excess acid (negative feedback) and have both paracrine and endocrine functions
• Enteric nervous system: When activated by stress, the ENS stimulates G cells and inhibits D cells, increasing gastric acid production. This explains stress-induced peptic ulcer disease
• Parietal cell receptors:
  • Stimulatory: Gastrin receptors, M3 muscarinic receptors, histamine H2 receptors
  • Inhibitory: Somatostatin receptors, prostaglandin E receptors

Vitamin B12 Absorption

The absorption of vitamin B12 (cobalamin) involves multiple steps and proteins:

1. In saliva, B12 binds to haptocorrin (R-binder/transcobalamin I), protecting it from acid degradation in the stomach
2. In the stomach, parietal cells secrete intrinsic factor (IF)
3. In the duodenum, pancreatic enzymes digest haptocorrin, releasing B12 to bind with IF
4. The B12-IF complex travels to the terminal ileum where it is absorbed via receptor-mediated endocytosis by cubilin receptors on enterocytes
5. Within enterocytes, B12 binds to transcobalamin II for transport in the bloodstream to tissues.

Celiac Disease

Pathophysiology

Celiac disease is an autoimmune enteropathy triggered by gluten ingestion in genetically susceptible individuals:

• The gliadin component of gluten is resistant to complete digestion and is modified by tissue transglutaminase (tTG)
• Modified gliadin is recognized by HLA-DQ2 or HLA-DQ8 molecules on antigen-presenting cells, which present it to CD4+ T cells
• Activated CD4+ T cells produce proinflammatory cytokines that damage enterocytes
• The disease is associated with IgA deficiency in 2-3% of patients

Diagnosis

• Serological testing: IgA anti-tissue transglutaminase (anti-tTG) antibodies have high sensitivity and specificity
• Total serum IgA: Must be measured alongside anti-tTG antibodies because IgA deficiency can cause false-negative results. In IgA-deficient patients, IgG-based testing (IgG DGP or IgG tTG) should be used.
• Duodenal biopsy: Gold standard for diagnosis, showing characteristic histological changes

Histopathology

• Villous atrophy: Flattening of villi, reducing absorptive surface area
• Crypt hyperplasia: Increased depth of crypts and cellular proliferation
• Intraepithelial lymphocytosis: Increased CD8+ T lymphocytes within the epithelium (>25-30 per 100 enterocytes)
• Lamina propria inflammation: Increased plasma cells and lymphocytes

Cori Cycle

The Cori cycle (lactic acid cycle) describes the metabolic pathway connecting skeletal muscle and liver during anaerobic exercise:

1. In skeletal muscle during intense exercise, glucose is metabolized to lactate via anaerobic glycolysis when oxygen is limited
2. Lactate is released into the bloodstream and transported to the liver, where it is converted back to glucose through gluconeogenesis
3. This newly synthesized glucose returns to the circulation and is available for uptake by muscle tissue, completing the cycle
4. The cycle requires energy input in the liver (6 ATP per glucose molecule regenerated), which is supplied primarily by fatty acid oxidation
5. For the cycle to function, pyruvate must be preserved (not converted to acetyl-CoA). Fatty acids inhibit the pyruvate dehydrogenase complex, preventing pyruvate-to-acetyl-CoA conversion and ensuring pyruvate remains available for gluconeogenesis

Body Fluid Compartments

Water Content by Age and Sex

• Infants: ~80% of body weight is water
• Adult males: ~60% of body weight is water
• Adult females: ~50% of body weight is water (lower due to higher fat content)

Extracellular vs. Intracellular Fluid

• Extracellular fluid (ECF): ~15% of body weight
  • Primarily contains Na^+, Cl^-, and HCO_3^-
  • Plasma and interstitial fluid are the main components
• Intracellular fluid (ICF): ~40% of body weight
  • Primarily contains K^+ and phosphate (PO_4^{3-}
  • Higher protein content than ECF
    The mnemonic "a cell is an island with a banana tree, surrounded by sea" helps remember: cells (islands) have high K^+ (bananas/potassium) surrounded by Na^+ (sea/salt water).

Cholera

Pathophysiology

Vibrio cholerae produces cholera toxin, which alters intestinal ion transport:

Structure:

AB5 toxin with:

• B subunit pentamer: Binds to GM1 ganglioside receptors on enterocytes, facilitating entry of the A subunit
• A subunit: Contains enzymatic activity

Mechanism:

• The A subunit activates adenylate cyclase, converting ATP