# Normal Physiology Exam Answers 2025-2026 (2nd Semester, Summer Session) --- ## RENAL PHYSIOLOGY --- ### Q1. Describe glomerular filtration process. Factors affecting GFR. **Glomerular Filtration** is the first step in urine formation. It is a passive, non-selective process by which fluid is forced from the glomerular capillaries into the Bowman's capsule (glomerular capsule) to form the **glomerular filtrate (ultrafiltrate)**. #### The Filtration Barrier The filtration barrier has three layers: 1. **Fenestrated capillary endothelium** - pores ~70-100 nm; prevents passage of blood cells 2. **Glomerular basement membrane (GBM)** - thick layer of collagen and proteoglycans; negatively charged (repels albumin and anionic proteins) 3. **Podocyte layer (epithelial cells)** - foot processes with slit diaphragms ~25-65 nm; final size barrier #### Driving Forces (Starling Forces) Filtration is governed by the **net filtration pressure (NFP)**: **NFP = (Pgc - Pbs) - (πgc - πbs)** Where: - Pgc = glomerular capillary hydrostatic pressure (~55 mmHg) - **favors** filtration - Pbs = Bowman's space hydrostatic pressure (~15 mmHg) - **opposes** filtration - πgc = glomerular capillary oncotic pressure (~30 mmHg) - **opposes** filtration - πbs = oncotic pressure in Bowman's space (~0 mmHg) - negligible **NFP = (55 - 15) - (30 - 0) = 10 mmHg** (favoring filtration) #### Glomerular Filtration Rate (GFR) - Normal GFR = **125 mL/min** (180 L/day) in adults - Formula: **GFR = Kf × NFP** - Kf = filtration coefficient (hydraulic conductivity × surface area) #### Factors Affecting GFR **1. Glomerular capillary hydrostatic pressure (Pgc)** - Increased by: dilation of afferent arteriole, constriction of efferent arteriole → increased GFR - Decreased by: constriction of afferent arteriole (sympathetic stimulation), hypotension → decreased GFR **2. Renal blood flow (RBF)** - Increased blood flow → increased GFR - Decreased by hemorrhage, dehydration, heart failure → decreased GFR **3. Oncotic pressure of plasma (πgc)** - Increased plasma proteins (e.g., multiple myeloma) → decreased GFR - Decreased plasma proteins (e.g., liver disease, malnutrition) → increased GFR **4. Bowman's capsule pressure (Pbs)** - Increased by: urinary tract obstruction, renal edema → decreased GFR **5. Filtration coefficient (Kf)** - Reduced by: glomerulonephritis, diabetes (thickening/scarring of GBM) → decreased GFR **6. Autoregulation of GFR** - The kidney maintains GFR relatively constant (MAP 80-180 mmHg) via: - **Myogenic mechanism**: afferent arteriole stretches → vasoconstriction - **Tubuloglomerular feedback (TGF)**: macula densa senses NaCl → releases adenosine → afferent arteriole constriction **7. Hormonal and neural factors** - **Angiotensin II**: constricts efferent > afferent → maintains GFR when BP falls - **Prostaglandins (PGE2, PGI2)**: dilate afferent → increase GFR (important in low-flow states) - **Sympathetic stimulation**: constricts afferent → decreases GFR (fight-or-flight) - **ANP (atrial natriuretic peptide)**: dilates afferent, constricts efferent → increases GFR --- ### Q2. Describe the mechanism of tubular reabsorption in different parts of the nephron. Tubular reabsorption returns approximately **178.5 L/day** of the 180 L filtered back into the blood. It is selective and occurs via active transport, passive diffusion, osmosis, and co-transport. #### Proximal Convoluted Tubule (PCT) - 65-70% reabsorption - **Sodium (Na+)**: Actively transported out by Na+/K+-ATPase on basolateral membrane; creates electrochemical gradient for Na+ entry on luminal side via co-transporters - **Glucose**: 100% reabsorbed by Na+-glucose co-transporter (SGLT2 and SGLT1); threshold ~180 mg/dL - **Amino acids**: 100% reabsorbed via Na+-dependent co-transporters - **Bicarbonate (HCO3-)**: ~80% reabsorbed; H+ secreted by Na+/H+ antiporter, combines with HCO3- → H2CO3 → CO2 + H2O (catalyzed by carbonic anhydrase); CO2 diffuses in - **Water**: Follows osmotically - ~65% reabsorbed via aquaporin-1 (AQP1) - **Chloride**: Passively follows Na+ via paracellular and transcellular routes - **Urea**: ~50% passively reabsorbed along concentration gradient - **Phosphate**: Reabsorbed by Na+-phosphate co-transporter; inhibited by PTH #### Loop of Henle - **Descending thin limb**: Permeable to water (AQP1), impermeable to solutes → water leaves → tubular fluid becomes concentrated - **Ascending thin limb**: Impermeable to water, permeable to NaCl → passive NaCl reabsorption - **Thick ascending limb (TAL)**: Na+-K+-2Cl- (NKCC2) co-transporter reabsorbs NaCl; **impermeable to water** → generates hyperosmotic medullary interstitium; urine becomes dilute here (~100 mOsm) - This is the site of action of **loop diuretics (furosemide)** #### Distal Convoluted Tubule (DCT) - **Na+** reabsorbed by Na+-Cl- co-transporter (NCC); site of action of **thiazide diuretics** - **Calcium**: Actively reabsorbed; stimulated by PTH - **Magnesium**: Reabsorbed - **Impermeable to water** in absence of ADH #### Collecting Duct (CD) - **Principal cells**: - Na+ reabsorbed through ENaC channels (stimulated by aldosterone) - K+ secreted - Water reabsorption via AQP2 channels (inserted in response to ADH/vasopressin) - **Alpha-intercalated cells**: Secrete H+ (acid-base balance) - **Beta-intercalated cells**: Secrete HCO3- #### Summary Table of Reabsorption | Segment | Na+ | Water | Key Transporters | |---------|-----|-------|-----------------| | PCT | 65% | 65% | NHE3, Na+/K+-ATPase, SGLT2 | | Thin descending | - | 15% | AQP1 | | Thick ascending | 25% | 0% | NKCC2 | | DCT | 5% | 0% | NCC | | Collecting duct | 3% | Variable (ADH) | ENaC, AQP2 | --- ### Q3. Renal function tests. Normal ranges. Renal function tests (RFTs) assess the kidney's ability to filter, reabsorb, secrete, and maintain homeostasis. #### 1. Blood Urea Nitrogen (BUN) - **Normal**: 7-20 mg/dL (2.5-7.1 mmol/L) - Urea is the end product of protein catabolism - Elevated (azotemia) in: renal failure, dehydration, high protein diet, GI bleeding - BUN:Creatinine ratio >20:1 suggests pre-renal cause #### 2. Serum Creatinine - **Normal**: Males 0.7-1.2 mg/dL; Females 0.5-1.0 mg/dL - Creatinine is a breakdown product of creatine phosphate in muscle - Freely filtered, minimally secreted → good marker of GFR - Elevated in: acute/chronic kidney disease, muscle disorders #### 3. GFR / eGFR (Estimated GFR) - **Normal**: >90 mL/min/1.73m² (decreases with age) - Calculated by CKD-EPI or MDRD equations using serum creatinine, age, sex, race - Measured by inulin clearance (gold standard) or creatinine clearance #### 4. Creatinine Clearance (CrCl) - **Normal**: Males 97-137 mL/min; Females 88-128 mL/min - Formula: CrCl = (U[Cr] × V) / P[Cr] - U[Cr] = urine creatinine concentration, V = urine flow rate, P[Cr] = plasma creatinine #### 5. Urine Analysis (Urinalysis) - **Color**: Pale to dark yellow (normal) - **pH**: 4.5-8.0 - **Specific gravity**: 1.001-1.035 - **Protein**: <150 mg/day (negative dipstick) - **Glucose**: Negative (absent unless plasma glucose >180 mg/dL) - **Ketones**: Negative - **RBCs**: <3/HPF - **WBCs**: <5/HPF - **Casts**: Occasional hyaline casts normal; RBC casts = glomerulonephritis; WBC casts = pyelonephritis #### 6. Serum Electrolytes - **Na+**: 136-145 mEq/L - **K+**: 3.5-5.0 mEq/L - **Cl-**: 98-106 mEq/L - **HCO3-**: 22-26 mEq/L #### 7. Serum Uric Acid - **Normal**: Males 3.5-7.2 mg/dL; Females 2.6-6.0 mg/dL #### 8. Cystatin C - **Normal**: 0.52-0.98 mg/L - More sensitive than creatinine; not affected by muscle mass #### 9. Urine Osmolality - **Normal**: 50-1200 mOsm/kg - After overnight fast: >800 mOsm/kg - Measures concentrating ability of kidney #### 10. Urine Protein:Creatinine Ratio - **Normal**: <0.2 - >3.5 indicates nephrotic range proteinuria --- ### Q4. Explain physiology of micturition reflex. **Micturition (urination)** is the process of expelling urine from the urinary bladder. It involves a coordinated interaction between the autonomic and somatic nervous systems. #### Anatomy - **Detrusor muscle**: Smooth muscle of bladder wall; contracts during urination - **Internal urethral sphincter (IUS)**: Smooth muscle; involuntary; under sympathetic control - **External urethral sphincter (EUS)**: Skeletal muscle; voluntary; pudendal nerve (S2-S4) #### Phases of Micturition **1. Storage/Filling Phase (Urine fills bladder)** - Sympathetic nervous system (T10-L2) is active: - Norepinephrine → beta-3 adrenergic receptors on detrusor → **relaxation** (allows filling) - Alpha-1 receptors on IUS → **contraction** (prevents leaking) - Somatic pudendal nerve → **EUS contracts** (voluntary) - Bladder fills at ~50 mL; first urge ~150-200 mL; strong urge ~400-500 mL - Compliance of bladder allows filling without large pressure increase **2. Voiding/Micturition Reflex** When bladder reaches ~300-400 mL: - **Stretch receptors** in bladder wall activated → afferent signals via pelvic nerve (S2-S4) → spinal cord → pontine micturition center (PMC, Barrington's nucleus) - If conditions are appropriate (socially acceptable), cerebral cortex permits voiding: - Parasympathetic activation (S2-S4) via pelvic nerve: - Muscarinic M3 receptors on detrusor → **contraction** - Inhibition of IUS (relaxation) - Sympathetic inhibition → detrusor relaxation removed - Somatic pudendal nerve inhibited → **EUS relaxes** (voluntary release) - Abdominal and perineal muscles contract (Valsalva) → increases intra-abdominal pressure - Urine expelled **3. Guarding Reflex (between voidings)** - During filling, spinal pathways generate guarding reflex that contracts EUS - Prevents voiding until cortical centers permit #### Neural Control Centers - **Sacral micturition center (S2-S4)**: Basic reflex arc; responsible for parasympathetic control - **Pontine micturition center (PMC)**: Coordinates relaxation of EUS with detrusor contraction; essential for normal voiding - **Cerebral cortex/frontal lobe**: Voluntary suppression and initiation of voiding - **Hypothalamus**: Integration of emotional state #### Clinical Relevance - **Neurogenic bladder**: Spinal cord injury above sacral level → loss of voluntary control - **Overflow incontinence**: Detrusor underactivity (diabetic neuropathy) - **Urgency incontinence**: Detrusor overactivity --- ### Q5. Explain functions of the kidney. The kidneys perform vital homeostatic, excretory, and endocrine functions: #### 1. Excretion of Metabolic Waste Products - Urea (protein metabolism), creatinine, uric acid, bilirubin metabolites - Drug metabolites and xenobiotics #### 2. Regulation of Water Balance - Controls urine volume (50-1500 mL/day depending on fluid intake) - ADH (vasopressin) regulates water reabsorption in collecting duct (AQP2) - Prevents dehydration and overhydration #### 3. Regulation of Electrolyte Balance - **Na+**: Aldosterone increases Na+ reabsorption; ANP decreases it - **K+**: Aldosterone increases K+ secretion; key role in cardiac rhythm - **Ca2+**: PTH and vitamin D regulate; important for bone, nerve, muscle - **Phosphate**: PTH promotes phosphate excretion - **Mg2+**, **Cl-**, **HCO3-** balance maintained #### 4. Acid-Base Regulation - Excretes H+ ions (as NH4+ and titratable acid) - Reabsorbs HCO3- (filtered bicarbonate recovered in PCT) - Generates new HCO3- via ammoniogenesis - Maintains blood pH 7.35-7.45 #### 5. Blood Pressure Regulation - **Renin-Angiotensin-Aldosterone System (RAAS)**: JG cells release renin → angiotensin II → vasoconstriction + aldosterone → Na+ and water retention → increased BP - **Prostaglandins**: Vasodilators; counterbalance vasoconstriction - **Kallikrein-kinin system**: Bradykinin → vasodilation - **ANP receptor**: Kidneys respond to ANP by increasing Na+/water excretion #### 6. Erythropoiesis Regulation - Peritubular cells produce **erythropoietin (EPO)** in response to hypoxia - EPO stimulates RBC production in bone marrow - Chronic kidney disease → EPO deficiency → anemia #### 7. Vitamin D Activation - 25-hydroxyvitamin D (calcidiol) converted to **1,25-dihydroxyvitamin D3 (calcitriol)** by 1-alpha-hydroxylase in proximal tubule cells - Calcitriol → increases intestinal Ca2+ absorption - Stimulated by PTH, low phosphate; inhibited by high Ca2+, FGF-23 #### 8. Gluconeogenesis - Kidneys contribute ~10-20% of total gluconeogenesis (especially during prolonged fasting) - Use glutamine as substrate #### 9. Catabolism of Small Proteins and Peptides - Insulin, PTH, glucagon filtered and degraded in tubular cells #### 10. Regulation of Plasma Osmolality - Responds to ADH (hypothalamic osmoreceptors) to retain water - Normal plasma osmolality: 280-295 mOsm/kg --- ### Q6. Properties and composition of normal urine. #### Physical Properties | Property | Normal Value | |---------|-------------| | Volume | 1000-1500 mL/24 hours (range: 800-2000 mL) | | Color | Pale yellow to amber (from urochrome/urobilin) | | Transparency | Clear (fresh urine) | | Odor | Faintly aromatic (fresh); ammonia-like (standing) | | Specific gravity | 1.001-1.035 (typically ~1.015-1.025) | | pH | 4.5-8.0 (average ~6.0) | | Osmolality | 50-1200 mOsm/kg | | Reaction | Slightly acidic (reflects diet) | #### Chemical Composition (per 24 hours) **Organic components:** - **Urea**: 25-35 g/day (largest organic component; ~50% of total solutes) - **Creatinine**: 1.0-1.8 g/day (males), 0.8-1.5 g/day (females) - **Uric acid**: 0.5-1.0 g/day - **Amino acids**: ~1 g/day - **Glucose**: none (absent; trace only) - **Proteins**: <150 mg/day (trace albumin, Tamm-Horsfall protein) - **Hormones and metabolites**: 17-ketosteroids, catecholamines, etc. - **Urobilinogen**: 0.1-1.0 mg/dL **Inorganic components (electrolytes):** - **Na+**: 40-220 mEq/day (varies with diet) - **K+**: 25-100 mEq/day - **Cl-**: 110-250 mEq/day - **Ca2+**: <300 mg/day (males), <250 mg/day (females) - **Phosphate**: 0.4-1.3 g/day - **Mg2+**: 10-40 mEq/day - **NH4+**: 30-50 mEq/day - **Sulfate**: 1.1-1.5 g/day #### Microscopic Examination (per High Power Field) - **RBCs**: 0-3/HPF - **WBCs**: 0-5/HPF - **Epithelial cells**: Few - **Casts**: Occasional hyaline casts (normal) - **Bacteria**: None (sterile) - **Crystals**: Few uric acid or phosphate crystals (may be normal) --- ### Q7. Describe the physiology of urine formation. Urine formation involves three processes occurring sequentially in the nephron: #### Step 1: Glomerular Filtration - **Site**: Glomerulus/Bowman's capsule - Blood enters via afferent arteriole → glomerular capillaries → filtrate forced across filtration barrier into Bowman's space - **GFR**: 125 mL/min; 180 L/day - Filtrate composition: similar to plasma but without large proteins and cells - The filtrate contains: water, Na+, K+, Cl-, HCO3-, glucose, amino acids, urea, creatinine, uric acid #### Step 2: Tubular Reabsorption - **Site**: Entire tubular system (PCT, loop of Henle, DCT, collecting duct) - The tubules reabsorb ~99% of the filtered fluid - **Active reabsorption**: glucose, amino acids, Na+, K+, HCO3-, phosphate - **Passive reabsorption**: water (osmosis), Cl-, urea - **Key mechanisms**: - Na+/K+-ATPase on basolateral membrane creates driving force - Specific co-transporters and channels on luminal membrane - Transcellular and paracellular pathways #### Step 3: Tubular Secretion - **Site**: PCT, thick ascending limb, DCT, collecting duct - Substances moved from peritubular capillaries INTO tubular lumen - **Secreted substances**: - H+ (acid-base regulation) - K+ (in collecting duct; controlled by aldosterone) - NH4+ (ammonia buffer) - Organic anions and cations (drug metabolites, uric acid) - Creatinine (small amount) #### Concentration and Dilution Mechanism **Countercurrent Multiplier (Loop of Henle)**: - Thick ascending limb actively pumps NaCl into medullary interstitium (but is impermeable to water) - This creates a hyperosmotic medullary gradient (from ~300 mOsm in cortex to ~1200 mOsm at papilla) - Descending limb equilibrates with hypertonic interstitium by losing water → tubular fluid becomes concentrated **Countercurrent Exchanger (Vasa Recta)**: - Peritubular capillaries (vasa recta) flow alongside loop of Henle in opposite directions - This exchange prevents "washing out" the medullary gradient - Maintains hyperosmotic medulla **Role of ADH (Antidiuretic Hormone / Vasopressin)**: - ADH released from posterior pituitary in response to increased plasma osmolality or decreased blood volume - ADH binds V2 receptors on collecting duct principal cells → inserts AQP2 water channels → water reabsorbed from collecting duct into hyperosmotic medullary interstitium → concentrated urine (up to 1200 mOsm/kg) - Without ADH → dilute urine (50-100 mOsm/kg) - diabetes insipidus **Role of Aldosterone**: - Released from adrenal cortex in response to Ang II, high K+ - Acts on principal cells of collecting duct → increases ENaC expression → more Na+ reabsorbed → water follows → K+ and H+ secreted → increases blood volume #### Final Urine - Volume: ~1-2 L/day - Composition: concentrated waste products - pH adjusted by H+ secretion - Drained by ureters to bladder for storage and eventual micturition --- ## GASTROINTESTINAL PHYSIOLOGY --- ### Q8. Digestion in the stomach. Digestive and non-digestive functions of the stomach. #### Anatomy Relevant to Function The stomach has four regions: cardia, fundus, body, and antrum (pylorus). The mucosa contains: - **Chief cells** (fundus/body): Pepsinogen → pepsin - **Parietal cells** (fundus/body): HCl and intrinsic factor - **G-cells** (antrum): Gastrin - **D-cells**: Somatostatin (inhibitory) - **ECL cells**: Histamine (stimulates parietal cells) - **Mucus neck cells**: Mucus and HCO3- (protection) #### Digestion in the Stomach **Mechanical digestion:** - **Receptive relaxation**: Vagally mediated relaxation of fundus accommodates 1-1.5 L of food - **Mixing waves**: Peristaltic contractions mix food with gastric juice → **chyme** - **Grinding**: Antrum grinds solid food into particles <1-2 mm - **Gastric emptying**: Pyloric sphincter controls release of chyme into duodenum at ~3 mL/min **Chemical digestion:** - **Protein digestion**: - HCl denatures proteins, activates pepsinogen → **pepsin** - Pepsin (endopeptidase) cleaves peptide bonds adjacent to aromatic amino acids (Phe, Tyr, Trp) - Active at pH 1-3; inactivated at pH >5 - Produces peptides (not amino acids) - **Fat digestion**: - **Lingual lipase** (from tongue salivary glands): active in stomach; cleaves short/medium chain triglycerides - **Gastric lipase**: active at pH 3-6; contributes ~10-30% of fat digestion - **Carbohydrate digestion**: - Salivary amylase continues briefly in stomach until inactivated by HCl - Minimal carbohydrate digestion in stomach #### Digestive Functions of the Stomach 1. Storage of ingested food 2. Mixing food with gastric juice to form chyme 3. Regulated delivery of chyme to duodenum 4. Initiation of protein digestion (pepsin + HCl) 5. Some fat digestion (gastric lipase) 6. Denatures food proteins #### Non-Digestive Functions of the Stomach 1. **Intrinsic factor secretion** (parietal cells): essential for vitamin B12 absorption in terminal ileum 2. **Bactericidal action**: HCl kills most ingested bacteria (pH <2) 3. **Hematopoietic**: indirect via B12 absorption enabling RBC maturation 4. **Endocrine function**: secretes gastrin (G-cells), ghrelin (hunger hormone from fundus/body) 5. **Reservoir**: stores food and regulates its delivery to small intestine 6. **Renin secretion**: in infants - curdles milk protein (casein) 7. **Activation of vitamin D**: some conversion occurs #### Regulation of Gastric Function (Three Phases) 1. **Cephalic phase** (~30% of acid secretion): - Triggered by sight, smell, taste, thought of food - Vagal (parasympathetic) stimulation → ACh → parietal cells (HCl) + chief cells (pepsinogen) - Vagal → G-cells → gastrin → HCl 2. **Gastric phase** (~60%): - Food in stomach → distension → vagal and local ENS reflexes → HCl and gastrin - Amino acids and peptides → directly stimulate G-cells → gastrin 3. **Intestinal phase** (~10%): - Chyme in duodenum with protein/fat → small initial HCl secretion, then inhibition - **Inhibition**: secretin, CCK, GIP released by duodenum in response to acid/fat → inhibit gastric secretion --- ### Q9. Digestion in the oral cavity. Saliva: amount, composition, properties, physiological role. Regulation of salivation. #### Digestion in the Oral Cavity The oral cavity initiates digestion through: 1. **Mechanical**: teeth (mastication) break food into smaller particles; increases surface area 2. **Chemical**: salivary enzymes begin carbohydrate and fat digestion 3. **Lubrication**: saliva moistens food → bolus formation for swallowing **Swallowing (Deglutition)**: - Voluntary phase: tongue pushes bolus to pharynx - Pharyngeal phase: involuntary; soft palate closes nasopharynx; epiglottis closes larynx; pharyngeal peristalsis - Esophageal phase: primary and secondary peristaltic waves carry bolus to stomach #### Saliva: Amount - **Normal production**: 1000-1500 mL/day (range 500-2000 mL) - At rest: ~0.5 mL/min (predominantly submandibular) - During stimulation: up to 7 mL/min - **Salivary glands**: parotid (25%; watery, rich in amylase), submandibular (70%; mixed), sublingual (5%; mucous) #### Saliva: Composition **Water**: 99.5% **Organic components**: - **Salivary amylase (ptyalin)**: cleaves alpha-1,4-glycosidic bonds in starch → maltose, dextrins; active pH 6.7-7.0 - **Lingual lipase**: secreted by lingual glands (von Ebner's glands); active in stomach - **Mucin (glycoprotein)**: lubricates, protects mucosa - **Lysozyme**: bactericidal; cleaves peptidoglycan in bacterial cell walls - **Lactoferrin**: bacteriostatic; chelates iron - **IgA (secretory)**: immunological protection - **Proline-rich proteins**: protect teeth enamel, bind tannins - **Kallikrein**: produces bradykinin (vasodilation of salivary glands) - **Blood group antigens** (in secretors) - **Urea, uric acid, amino acids**: small amounts **Inorganic components**: - Na+: 2-20 mEq/L (hypotonic compared to plasma at low flow; approaches plasma at high flow) - K+: 10-36 mEq/L (higher than plasma) - Cl-: 10-40 mEq/L - HCO3-: 20-60 mEq/L (increases with flow rate) - Ca2+, Mg2+, phosphate, fluoride #### Properties of Saliva 1. **Hypotonic** to plasma (Na+ and Cl- are reabsorbed by ducts) 2. **pH**: 6.2-7.4 (average ~7.0; HCO3- acts as buffer) 3. **Viscous** (due to mucins) 4. **Slightly alkaline** when stimulated #### Physiological Role of Saliva 1. **Digestion**: Salivary amylase begins starch digestion; lingual lipase initiates fat digestion 2. **Lubrication**: Mucins lubricate food → eases swallowing; protects oral mucosa 3. **Solvent function**: Dissolves food chemicals for taste receptor stimulation 4. **Oral hygiene and antimicrobial**: lysozyme, lactoferrin, IgA destroy bacteria; washing action 5. **Dental protection**: HCO3- neutralizes acid produced by bacteria → prevents caries; Ca2+, phosphate, fluoride remineralize enamel; mucins form protective pellicle 6. **Speech**: moistens mouth/lips for articulation 7. **Buffering**: HCO3- maintains oral pH 8. **Excretory**: small amounts of drugs, viruses, antibodies excreted 9. **Taste enhancement**: dissolves tastants 10. **Wound healing**: EGF (epidermal growth factor) in saliva promotes wound healing #### Regulation of Salivation Salivation is primarily under **autonomic nervous control** (no hormonal phase): **Parasympathetic stimulation (dominant)** - via CN VII (chorda tympani → submandibular/sublingual) and CN IX (glossopharyngeal → parotid): - ACh → muscarinic M3 receptors → **large volume watery saliva** rich in enzymes - Also causes vasodilation of gland blood vessels (bradykinin, VIP) **Sympathetic stimulation** - via superior cervical ganglion: - Norepinephrine → beta-adrenergic → **small volume viscous/mucous saliva**; also vasoconstriction **Stimuli that increase salivation (unconditioned and conditioned reflexes)**: - Taste (especially sour/acidic - most potent), smell, chewing, sight/thought of food (conditioned reflex) - Nausea (watery salivation before vomiting) - Tactile stimulation of oral mucosa **Stimuli that decrease salivation**: - Sleep, dehydration, fear (sympathetic dominance), atropine (muscarinic blocker) - Irradiation of salivary glands **Salivatory center**: Located in medulla oblongata (superior and inferior salivatory nuclei) --- ### Q10. Gastric juice: composition, properties. Physiological role of hydrochloric acid. #### Composition and Properties of Gastric Juice - **Volume**: 2-3 liters/day - **pH**: 1.5-3.5 (basal); can reach pH 1-2 during maximal stimulation - **Color**: colorless to pale yellow - **Specific gravity**: 1.002-1.004 **Components:** 1. **Hydrochloric acid (HCl)**: - Secreted by **parietal cells** (oxyntic cells) in fundus and body - Concentration: up to 155-160 mEq/L (pure parietal secretion) - H+/K+-ATPase (proton pump) on apical membrane pumps H+ into lumen in exchange for K+ - Cl- transported via Cl-/HCO3- exchanger on basolateral side, then Cl- exits apically via channels - Stimulated by: ACh (vagus), gastrin, histamine (via H2 receptors) - Inhibited by: somatostatin, secretin, GIP, prostaglandins 2. **Pepsinogens (I and II)**: - Secreted by **chief cells** (zymogenic cells) - Pepsinogen → pepsin (autocatalytic, at pH <5) - Pepsin: endopeptidase, cleaves aromatic amino acid bonds, active pH 1.5-3.5 - Stimulated by ACh, secretin 3. **Intrinsic factor (IF)**: - Secreted by **parietal cells** - Glycoprotein; binds vitamin B12 in duodenum - IF-B12 complex absorbed in terminal ileum by specific receptors - Essential for B12 absorption; deficiency → pernicious anemia 4. **Mucus and HCO3-** (mucous neck cells and surface mucous cells): - Forms a protective gel layer (~0.2 mm) on gastric mucosa - HCO3- trapped in mucus maintains pH ~7 at cell surface despite luminal pH 2 - Prostaglandins stimulate mucus and HCO3- production 5. **Gastric lipase**: - Secreted by chief cells - Active at pH 2-7; digests ~10-30% of dietary fat - Particularly important in infants 6. **Gastrin** (G-cells, antrum/duodenum): - Hormone, not digestive enzyme 7. **Water**: 99% of gastric juice #### Physiological Role of Hydrochloric Acid (HCl) 1. **Protein denaturation**: Unfolds tertiary protein structure → increases accessibility to proteolytic enzymes 2. **Activation of pepsinogen**: HCl converts inactive pepsinogen → active pepsin (also autocatalytic at pH 1-3) 3. **Antibacterial/sterilization**: pH <2 kills most ingested bacteria and pathogens (protection against food-borne infections); prevents gastric and small bowel bacterial overgrowth 4. **Digestion of connective tissue**: Dissolves collagen and connective tissue components in food 5. **Calcium and iron absorption**: Converts insoluble Fe3+ to soluble Fe2+ (ferrous); dissolves Ca2+ compounds for absorption in duodenum 6. **Activation of gastric lipase**: Optimal activity of gastric lipase is in acidic environment 7. **Regulation of gastric emptying**: Acid in duodenum triggers secretin release → inhibits gastric emptying → allows proper neutralization by pancreatic bicarbonate 8. **Chymosin activation**: In infants, HCl activates rennin (chymosin) which curdles milk --- ### Q11. Pancreatic juice: composition, properties. Regulation of pancreatic secretion. #### Composition and Properties - **Volume**: 1200-1500 mL/day - **pH**: 7.1-8.3 (alkaline due to high HCO3-) - **Color**: Clear, colorless - **Specific gravity**: ~1.005-1.010 **Components:** **1. Electrolytes (from centroacinar and ductal cells)**: - **HCO3-**: 20-150 mEq/L; KEY component; neutralizes gastric acid in duodenum; maintains optimal pH for pancreatic enzymes (~7-8) - Na+, K+: similar to plasma - Cl-: inversely proportional to HCO3- (sum remains constant ~150 mEq/L) - Ca2+, Mg2+, Zn2+ **2. Digestive Enzymes (from acinar cells)**: *Proteolytic enzymes (secreted as inactive zymogens):* - **Trypsinogen** → **trypsin** (activated by enterokinase/enteropeptidase in duodenum, then by trypsin itself - autocatalytic) - Trypsin activates all other zymogens - Endopeptidase: cleaves after Lys, Arg - **Chymotrypsinogen** → **chymotrypsin**: cleaves after aromatic AAs (Phe, Tyr, Trp) - **Proelastase** → **elastase**: cleaves after small neutral AAs (Ala, Gly, Ser) - **Procarboxypeptidases A and B** → **carboxypeptidases**: exopeptidases; remove C-terminal AAs *Lipolytic enzymes:* - **Pancreatic lipase**: most important fat-digesting enzyme; requires colipase and bile salts; cleaves sn-1,3 bonds of triglycerides → 2-monoglyceride + 2 fatty acids - **Colipase**: co-enzyme secreted as procolipase; anchors lipase to fat droplet surface; activated by trypsin - **Phospholipase A2**: cleaves fatty acid from sn-2 position of phospholipids; secreted as prophospholipase; activated by trypsin - **Cholesterol esterase (sterol ester hydrolase)**: hydrolyzes cholesterol esters *Amylolytic enzyme:* - **Pancreatic amylase**: hydrolyzes starch, glycogen → maltose, maltotriose, limit dextrins (cleaves internal alpha-1,4-glycosidic bonds); secreted in active form *Nucleolytic enzymes:* - **DNase and RNase**: digest nucleic acids **Trypsin inhibitor**: small protein secreted with pancreatic juice; inhibits trypsin within pancreatic duct (self-protection against autodigestion) #### Regulation of Pancreatic Secretion (Three Phases) **1. Cephalic Phase (~20% of response)**: - Sight, smell, taste, thought of food → vagal stimulation (ACh) → acinar cells secrete enzyme-rich juice (small volume) - Vagal stimulation of G-cells → gastrin → stimulates pancreatic enzymes **2. Gastric Phase (~10%)**: - Distension of stomach → vagal-vagal and ENS reflexes → pancreatic enzyme secretion - Gastrin (from antrum) → stimulates acinar cells **3. Intestinal Phase (~70% - most important)**: - **Secretin** (S-cells, duodenum): - Stimulus: acid (H+) in duodenum (pH <4.5) - Effect: ductal cells → large volume, HCO3--rich juice (watery secretion) - Primary purpose: neutralize gastric acid - **Cholecystokinin (CCK)** (I-cells, duodenum and jejunum): - Stimulus: fat and protein (amino acids) in duodenum - Effect: acinar cells → enzyme-rich juice - Also: contracts gallbladder, relaxes sphincter of Oddi → bile flow - Potentiates secretin effect on HCO3- secretion - **VIP (Vasoactive Intestinal Peptide)**: stimulates HCO3- and water secretion - **ACh** (vagus): augments both enzyme and HCO3- secretion **Inhibition**: - **Somatostatin**: inhibits pancreatic secretion - **Pancreatic polypeptide**: inhibits enzyme secretion - High fat, acid-suppressing drugs --- ### Q12. The role of pancreatic juice for digestion in the duodenum. The duodenum is the primary site of digestion, and pancreatic juice is essential to this process: #### 1. Neutralization of Gastric Acid - Chyme entering duodenum has pH 1.5-2.0 - **HCO3-** in pancreatic juice (+ biliary HCO3-) neutralizes acid → duodenal pH ~6-7 - Critical because: - Pancreatic and intestinal digestive enzymes are inactivated by acid - Optimal pH for pancreatic enzymes: 6.5-8.0 - Prevents duodenal ulcers - Enables bile salt micelle formation (bile precipitates at low pH) #### 2. Protein Digestion - **Trypsin** + **chymotrypsin** + **elastase**: cleave peptide bonds → large peptides - **Carboxypeptidases**: remove single AAs from C-terminus - Combined action: proteins → oligopeptides and free amino acids (final digestion by brush border peptidases) #### 3. Fat (Lipid) Digestion - **Pancreatic lipase + colipase**: most important step - Bile salts emulsify fat droplets → increase surface area - Pancreatic lipase (with colipase as anchor) cleaves TG → 2-monoglyceride + 2 FAs - **Phospholipase A2**: digests phospholipids → lysophospholipids + fatty acids - **Cholesterol esterase**: digests cholesterol esters → cholesterol + fatty acid - Products form **mixed micelles** with bile salts for absorption #### 4. Carbohydrate Digestion - **Pancreatic amylase**: hydrolyzes starch and glycogen → maltose, maltotriose, alpha-limit dextrins - Final digestion by brush border enzymes (maltase, sucrase, lactase) #### 5. Nucleic Acid Digestion - **DNase and RNase**: hydrolyze DNA and RNA → nucleotides - Further digested by nucleotidases and nucleosidases #### Role of Pancreatic Enzymes in Summary | Substrate | Enzyme | Products | |-----------|--------|---------| | Proteins | Trypsin, chymotrypsin, elastase | Oligopeptides | | Proteins (C-term) | Carboxypeptidases A, B | Amino acids | | TG (fats) | Pancreatic lipase + colipase | 2-MG + 2 FA | | Phospholipids | Phospholipase A2 | Lyso-PL + FA | | Cholesterol esters | Cholesterol esterase | Cholesterol + FA | | Starch | Pancreatic amylase | Maltose, dextrins | | Nucleic acids | DNase, RNase | Nucleotides | --- ### Q13. Bile: composition and participation in digestion. Functions of bile. #### Production and Flow - Produced by **hepatocytes**: 600-1000 mL/day - Stored and concentrated in gallbladder (up to 5-fold) - Released into duodenum (ampulla of Vater) in response to CCK #### Composition of Bile **Hepatic bile vs. Gallbladder bile:** | Component | Hepatic Bile | Gallbladder Bile | |-----------|-------------|-----------------| | Water | 97% | 85-90% | | Total solids | 3% | 10-15% | | Bile salts | 1.5 g/dL | 6-10 g/dL | | Phospholipids | 0.3 g/dL | 3 g/dL | | Cholesterol | 0.1 g/dL | 0.5 g/dL | | Bilirubin | 0.05 g/dL | 0.4 g/dL | | Bile color | Yellow-gold | Dark green-brown | **Major components:** 1. **Bile salts (bile acids conjugated with glycine or taurine)**: - Primary bile acids: cholic acid, chenodeoxycholic acid (synthesized in liver from cholesterol) - Secondary bile acids: deoxycholic acid, lithocholic acid (from bacterial action in colon) - Conjugated with glycine (glycocholic acid) or taurine (taurocholic acid) - Bile salt pool: 3-5 g; recycled 6-10x/day via enterohepatic circulation 2. **Bilirubin** (bile pigment): - Breakdown product of heme from aged RBCs - Conjugated in liver with glucuronic acid → water-soluble - Excreted in bile → intestine → urobilinogen → stercobilin (feces color) or absorbed → urobilin (urine) 3. **Cholesterol**: excreted via bile as free cholesterol 4. **Phospholipids**: primarily lecithin (phosphatidylcholine); helps keep cholesterol in solution 5. **Electrolytes**: Na+, K+, Cl-, HCO3- (similar to plasma) 6. **IgA**: secretory 7. **Cholesterol, fatty acids, bilirubin, alkaline phosphatase** #### Role of Bile in Digestion (Participation in Digestion) 1. **Emulsification of fats**: - Bile salts are amphipathic (hydrophilic and hydrophobic parts) - Reduce surface tension of fat droplets → emulsification → break large fat globules into smaller droplets - Increases surface area for pancreatic lipase action 2. **Micelle formation**: - Bile salts + digested fat products (2-monoglycerides, fatty acids) + phospholipids → **mixed micelles** - Micelles carry fat-soluble products to enterocyte brush border for absorption - Essential for absorption of fat-soluble vitamins A, D, E, K 3. **Activation of pancreatic lipase**: - Bile salts displace inhibitory proteins from fat droplet surface → allows lipase-colipase access 4. **Absorption of fat-soluble vitamins**: bile salts necessary for micellar solubilization of vitamins A, D, E, K 5. **Neutralization**: bile HCO3- helps neutralize duodenal acid #### Other Functions of Bile (Non-Digestive) 6. **Excretion**: bilirubin, cholesterol, drug metabolites, heavy metals, xenobiotics excreted via bile 7. **Enterohepatic circulation**: - ~95% of bile salts reabsorbed in terminal ileum → portal vein → liver → re-secreted - Only ~5% lost in feces (replaced by new synthesis from cholesterol) - Conserves bile salt pool 8. **Gut motility**: bile salts stimulate colonic motility 9. **Antimicrobial**: detergent effect kills some bacteria 10. **Stimulates bile secretion (choleretic effect)**: recycled bile salts stimulate further secretion --- ### Q14. Digestion in the small intestine. The small intestine (duodenum, jejunum, ileum; total ~6-7 m) is the primary site of nutrient digestion and absorption. #### Anatomical Adaptations for Digestion/Absorption - **Circular folds (Kerckring's valves)**: permanent folds increase surface area 3x - **Villi**: finger-like projections; increase area 10x; contain enterocytes, goblet cells, enteroendocrine cells - **Microvilli (brush border)**: on apical surface of enterocytes; increase area 20x; contain digestive enzymes - Total surface area: ~250-400 m² #### Brush Border Enzymes (Final Digestion) - **Aminopeptidases**: cleave N-terminal AAs from peptides - **Dipeptidases**: cleave dipeptides → AAs - **Maltase**: maltose → 2 glucose - **Sucrase (isomaltase)**: sucrose → glucose + fructose; also cleaves alpha-1,6 branch points - **Lactase**: lactose → glucose + galactose - **Trehalase**: trehalose → 2 glucose - **Nucleotidases and nucleosidases**: degrade nucleotides #### Chemical Digestion **Proteins**: 1. Pancreatic proteases (trypsin, chymotrypsin, elastase, carboxypeptidases) → oligopeptides 2. Brush border aminopeptidases and dipeptidases → amino acids and di/tripeptides 3. Intracellular peptidases in enterocytes **Carbohydrates**: 1. Pancreatic amylase → maltose, maltotriose, alpha-limit dextrins 2. Brush border maltase, sucrase, lactase, trehalase → monosaccharides (glucose, galactose, fructose) **Lipids**: 1. Emulsification by bile salts 2. Pancreatic lipase + colipase → 2-monoglycerides + fatty acids 3. Phospholipase A2 → lysophospholipids 4. Mixed micelle formation → absorption **Nucleic acids**: 1. Pancreatic DNase/RNase → nucleotides 2. Brush border nucleotidases → nucleosides 3. Nucleosidases → bases + pentoses #### Mechanical Processes - **Segmentation contractions**: mixing movements; do NOT propel chyme; mix chyme with digestive juices; 12-16/min in duodenum - **Peristalsis**: propulsive waves; move chyme distally; MMC (migrating motor complex) in fasting state sweeps residue distally ("intestinal housekeeper") - **Villi motility**: villus pumping enhances contact of chyme with brush border #### Intestinal Juice (Succus Entericus) - Produced by Brunner's glands (duodenum), Lieberkuhn crypts - Volume: 1800-3000 mL/day - pH: ~7.5-8.0 - Contains: mucus, water, electrolytes, IgA - **Brunner's glands** (duodenum): secrete alkaline mucus; protects duodenum from acid #### Absorption in Small Intestine - ~90% of nutrients absorbed in jejunum and upper ileum - Terminal ileum: absorption of bile salts and vitamin B12 (IF-B12 complex) - Water and electrolytes absorbed throughout --- ### Q15. Digestion, Absorption and Metabolism of Proteins. #### Dietary Protein Intake - Daily requirement: 0.8 g/kg/day (~50-60 g/day) - Also endogenous proteins: ~70 g/day (digestive enzymes, shed cells) #### Digestion of Proteins **Stomach**: - **HCl**: denatures proteins, activates pepsinogen - **Pepsin**: endopeptidase; cleaves proteins → large peptides; active pH 1.5-3.5 **Small Intestine (Duodenum/Jejunum)** - main site: - **Pancreatic endopeptidases**: trypsin (Lys, Arg), chymotrypsin (Phe, Tyr, Trp), elastase (Ala, Gly) → polypeptides - **Exopeptidases**: carboxypeptidase A (neutral AAs), carboxypeptidase B (basic AAs) → removes terminal AAs - **Brush border enzymes**: aminopeptidases, dipeptidases → amino acids, di/tripeptides #### Absorption of Proteins **As amino acids**: - Specific Na+-dependent amino acid co-transporters on brush border (luminal side) - Several families: neutral AAs (SNAT), basic AAs, acidic AAs, aromatic AAs - Exit via facilitated diffusion on basolateral side → portal blood **As di/tripeptides**: - **PepT1 (SLC15A1)**: H+-dependent co-transporter; very efficient; transports di- and tripeptides - Hydrolyzed by cytosolic peptidases inside enterocyte → amino acids → portal blood **Transcytosis**: minimal; some intact proteins in neonates (maternal IgG) or small amounts of food antigens (allergens) **Portal circulation**: amino acids travel to liver → hepatic processing #### Metabolism of Proteins **In the liver**: 1. **Transamination**: amino group transferred to alpha-ketoglutarate → glutamate + alpha-keto acid (carbon skeleton) - ALT: Ala + alpha-KG ⇌ pyruvate + glutamate - AST: Asp + alpha-KG ⇌ OAA + glutamate 2. **Oxidative deamination**: glutamate → alpha-KG + NH4+ (by glutamate dehydrogenase) 3. **Urea cycle**: NH4+ converted to urea (less toxic) → excreted by kidneys - Carbamoyl phosphate synthetase I (mitochondria) → citrulline → argininosuccinate → arginine → urea + ornithine (recycled) 4. **Protein synthesis**: albumin, clotting factors, transport proteins synthesized 5. **Gluconeogenesis**: glucogenic AAs (Ala, Gly, Ser, etc.) → pyruvate/OAA → glucose 6. **Ketogenesis**: ketogenic AAs (Leu, Lys, Ile, Phe, Trp, Tyr) → acetyl-CoA → ketone bodies **In peripheral tissues**: - **Protein synthesis**: structural proteins, enzymes, hormones - **Energy production**: AAs used for energy (catabolized to TCA cycle intermediates) - **Transamination**: especially muscle (alanine cycle) **Nitrogen balance**: - Positive: synthesis > breakdown (growth, pregnancy, healing) - Negative: breakdown > synthesis (starvation, illness, burns) - Neutral: normal adult state --- ### Q16. Digestion, Absorption and Metabolism of Lipids. #### Dietary Lipids - ~80-100 g/day; mainly triglycerides (TGs); also phospholipids, cholesterol, fat-soluble vitamins #### Digestion of Lipids **Mouth/Esophagus**: - **Lingual lipase** (von Ebner's glands): active pH 3-6; cleaves short/medium chain TGs; 10% of fat digestion **Stomach**: - **Gastric lipase**: active pH 2-7; cleaves sn-3 position → fatty acid + diglyceride; 10-30% of fat digestion - Mechanical churning helps emulsify fat **Small Intestine (main site)**: 1. **Bile salts**: emulsify fat → small droplets (~1 µm); increase surface area; displace surface inhibitors; reduce surface tension 2. **Pancreatic lipase + colipase**: cleaves sn-1 and sn-3 bonds of TG → **2-monoglyceride + 2 free fatty acids** 3. **Colipase**: anchors lipase to bile salt-covered fat droplet; activated by trypsin 4. **Phospholipase A2**: cleaves sn-2 bond → lyso-phospholipid + fatty acid 5. **Cholesterol esterase**: hydrolyzes cholesterol esters → cholesterol + fatty acid 6. **Mixed micelle formation**: products (2-MG, FA, lyso-PL, cholesterol) + bile salts + phospholipids → mixed micelles (~4-7 nm) #### Absorption of Lipids 1. **Micelles** diffuse to unstirred water layer at enterocyte brush border 2. **Fatty acids and 2-monoglycerides** diffuse into enterocytes (passive; fat-soluble) 3. Short and medium chain fatty acids (C<12): directly absorbed into portal blood without re-esterification 4. Long chain fatty acids (C>12) and 2-MG: - Inside enterocyte: re-esterified to **triglycerides** (by SER enzymes) - Combined with cholesterol, phospholipids, and **apolipoproteins (ApoB-48)** → **chylomicrons** - Chylomicrons exocytosed into **lacteals** (lymphatic capillaries) → thoracic duct → subclavian vein **Fat-soluble vitamins (A, D, E, K)**: - Incorporated into mixed micelles - Absorbed with fat; packaged into chylomicrons **Bile salts**: NOT absorbed in jejunum; reabsorbed in terminal ileum → enterohepatic circulation #### Metabolism of Lipids **Exogenous pathway (dietary fats)**: - Chylomicrons in blood → LPL (lipoprotein lipase) on capillary endothelium (activated by ApoC-II) → TG hydrolyzed → FAs taken up by muscle/adipose - Chylomicron remnants → liver **Endogenous pathway (hepatic)**: - Liver synthesizes VLDL (TG + cholesterol + ApoB-100) - VLDL → IDL → LDL (LDL receptor-mediated uptake by cells) **Beta-oxidation** (primary energy production from fat): - FA activated → fatty acyl-CoA (cytoplasm) - Transported into mitochondria via **carnitine shuttle** (carnitine palmitoyl transferase I - rate limiting) - Repeated cycles: fatty acyl-CoA → acetyl-CoA + FADH2 + NADH - Acetyl-CoA → TCA cycle → ATP **Lipogenesis** (fat synthesis): - Excess glucose/AA → acetyl-CoA → malonyl-CoA → palmitate (by FAS, fatty acid synthase) - Occurs in liver and adipose tissue; insulin promotes, glucagon inhibits **Cholesterol metabolism**: - Synthesis: HMG-CoA reductase (rate-limiting; inhibited by statins) - Used for: cell membranes, steroid hormone synthesis, bile acid synthesis, vitamin D --- ### Q17. Digestion, Absorption and Metabolism of Carbohydrates. #### Dietary Carbohydrates - ~300-400 g/day; mainly starch (polysaccharide), also sucrose and lactose (disaccharides) - Fiber (cellulose): non-digestible polysaccharide; no alpha-amylase effect #### Digestion of Carbohydrates **Oral cavity**: - **Salivary amylase (ptyalin)**: cleaves internal alpha-1,4-glycosidic bonds - Starch → dextrins, maltotriose, maltose - Active pH 6.7-7.0; continues briefly in stomach until HCl inactivates **Stomach**: - No carbohydrate-digesting enzymes - Salivary amylase inactivated by HCl (pH <4) **Small intestine** (main site): - **Pancreatic amylase**: most important; cleaves alpha-1,4 bonds; starch/glycogen → maltose, maltotriose, alpha-limit dextrins (has alpha-1,6 branch points) **Brush border (final digestion)**: - **Maltase**: maltose → 2 glucose - **Sucrase-isomaltase complex**: sucrose → glucose + fructose; alpha-limit dextrins → glucose (cleaves alpha-1,6) - **Lactase (beta-galactosidase)**: lactose → glucose + galactose - **Trehalase**: trehalose (mushrooms) → 2 glucose - **Glucoamylase**: cleaves one glucose at a time from polysaccharide chain #### Absorption of Carbohydrates Only **monosaccharides** are absorbed: - **Glucose and galactose**: Na+-dependent SGLT1 transporter (secondary active transport); enter portal blood - **Fructose**: GLUT5 (facilitated diffusion; Na+-independent) - Exit basolateral via GLUT2 → portal vein → liver #### Metabolism of Carbohydrates **Glycolysis** (cytoplasm; all cells): - Glucose → pyruvate (anaerobic: pyruvate → lactate; aerobic: pyruvate → acetyl-CoA) - Net yield: 2 ATP, 2 NADH per glucose (anaerobic) - Regulated by: hexokinase/glucokinase, PFK-1 (key), pyruvate kinase **Pyruvate dehydrogenase** (mitochondria): - Pyruvate → Acetyl-CoA + CO2 + NADH - Requires: TPP (B1), lipoic acid, FAD (B2), NAD+ (B3), CoA (pantothenic acid) **Krebs/TCA cycle** (mitochondrial matrix): - Acetyl-CoA (2C) + OAA → citrate → ... → OAA - Yields: 3 NADH, 1 FADH2, 1 GTP per acetyl-CoA - Total yield from 1 glucose: ~30-32 ATP (aerobic) **Glycogenesis** (insulin-stimulated): - Glucose → UDP-glucose → glycogen (liver: up to 100g; muscle: ~400g) - Rate-limiting enzyme: glycogen synthase **Glycogenolysis** (glucagon/epinephrine-stimulated): - Glycogen → glucose-1-phosphate (phosphorylase) → glucose-6-phosphate → glucose (liver; not muscle) **Gluconeogenesis** (liver and kidney; fasting state): - Lactate, pyruvate, glycerol, glucogenic AAs → glucose - Bypasses irreversible glycolytic steps (3 bypass enzymes: pyruvate carboxylase, PEPCK, fructose-1,6-bisphosphatase, glucose-6-phosphatase) **Pentose phosphate pathway (HMP shunt)**: - Glucose-6-phosphate → ribose-5-phosphate (nucleotide synthesis) + NADPH (antioxidant, lipid synthesis) **Blood glucose regulation**: - Normal: 70-100 mg/dL (fasting); <140 mg/dL 2h postprandial - Insulin: lowers BG (promotes glycolysis, glycogenesis, lipogenesis) - Glucagon, cortisol, epinephrine, GH: raise BG --- ### Q18. Digestion in duodenum. Role of pancreas for digestion. Composition and properties of succus entericus. #### Digestion in the Duodenum The duodenum (~25 cm long) is the most active digestive segment: **Events in the duodenum**: 1. Receives acidic chyme from stomach (pH ~2) 2. Receives pancreatic juice (alkaline, enzyme-rich) via pancreatic duct 3. Receives bile via common bile duct 4. Together these neutralize acid and begin full chemical digestion **Brunner's glands** (submucosa of duodenum): - Secrete thick alkaline mucus (pH 8.2-9.3) - Protect duodenal mucosa from acidic chyme - Stimulated by: vagal stimulation, secretin, acid in duodenum **Digestion in duodenum**: - Protein: pancreatic trypsin, chymotrypsin, elastase, carboxypeptidases → polypeptides - Fat: bile salt emulsification + pancreatic lipase → 2-MG + FA; micelle formation - Carbohydrate: pancreatic amylase → maltose, dextrins - Final brush border digestion begins here #### Role of Pancreas in Digestion (see Q11, Q12 for full detail) Summary: 1. **HCO3-** neutralizes acid → optimal pH for enzyme activity 2. **Proteases**: complete protein digestion 3. **Lipase + colipase**: essential for fat digestion (~90%) 4. **Amylase**: starch → sugars 5. Without pancreas: fat malabsorption (steatorrhea), protein malabsorption, weight loss #### Succus Entericus (Intestinal Juice) **Production**: secreted by **Lieberkuhn crypts** (intestinal glands) throughout small intestine; Brunner's glands (duodenum) **Volume**: 1800-3000 mL/day **Properties**: - pH: 6.5-7.5 (slightly alkaline) - Color: clear to slightly turbid - Specific gravity: 1.007-1.011 - Isotonic to plasma **Composition**: - **Water**: ~99% - **Mucus**: from goblet cells; protects mucosa - **Electrolytes**: Na+, K+, Cl-, HCO3- (similar to plasma; slightly higher HCO3-) - **IgA (secretory)**: immunological protection - **Shed epithelial cells**: source of brush border enzymes (released when cells are shed) - **Brush border enzymes** (technically on cell surface, not secreted): - Maltase, sucrase-isomaltase, lactase, trehalase - Aminopeptidases, dipeptidases - Enterokinase (enteropeptidase): activates trypsinogen → trypsin (most important activator) - Alkaline phosphatase, 5'-nucleotidase - **Enterogastrones**: GIP, secretin, CCK secreted here **Regulation**: - Vagal stimulation → increases secretion - Distension of intestinal wall → local ENS reflexes → increases secretion - Cholecystokinin, secretin, VIP: increase secretion --- ### Q19. Basal metabolism. Factors determining basal metabolism. Values of basal metabolic rate. #### Definition **Basal Metabolic Rate (BMR)** is the rate of energy expenditure by the body at complete rest, in a **thermally neutral environment**, in the **post-absorptive state (12-14 hours after eating)**, under **awake but fully rested** conditions. It represents the minimum energy needed to maintain vital functions. #### What BMR Represents - **60-70%** of total daily energy expenditure - Maintains: breathing, circulation, cell function, body temperature, organ function #### Values of BMR - **Average adult male**: ~1600-1800 kcal/day (~1 kcal/min) - **Average adult female**: ~1200-1400 kcal/day (~0.9 kcal/min) - Per unit body weight: ~24-25 kcal/kg/day - Per body surface area: ~35-40 kcal/m²/hour - **Respiratory quotient (RQ) at rest**: 0.82 (mixed diet) - RQ = CO2 produced / O2 consumed - Carbohydrate only: RQ = 1.0 - Fat only: RQ = 0.71 - Protein only: RQ = 0.82 #### Measurement - **Indirect calorimetry**: measure O2 consumption and CO2 production - 1 L O2 consumed ≈ 4.82-5.0 kcal (depending on RQ) - **Direct calorimetry**: measure heat production (less practical) #### Factors Affecting BMR **1. Age**: - BMR highest in infancy/childhood (rapid growth) - Declines ~2% per decade after age 30 (loss of lean mass) - Children >10 kcal/kg/day above adult values **2. Sex**: - Males have ~5-10% higher BMR than females - Due to greater lean body mass (muscle has higher metabolic activity) **3. Body composition / Lean body mass (LBM)**: - Muscle tissue has high metabolic rate; fat tissue is relatively inactive - BMR correlates best with lean body mass - Athletes have higher BMR **4. Thyroid hormones (T3 and T4)**: - Most important hormonal regulator of BMR - T3 increases Na+/K+-ATPase activity → more ATP consumption → more heat - **Hyperthyroidism**: BMR increased 30-60% - **Hypothyroidism**: BMR decreased 20-40% **5. Body temperature**: - Fever raises BMR: each 1°C rise → ~13% increase in BMR - Hypothermia decreases BMR **6. Sympathetic nervous system / Catecholamines**: - Adrenaline, noradrenaline → increase metabolic rate (especially with stress, cold, exercise) - Thermogenesis in brown adipose tissue (via UCP1, uncoupling protein) **7. Nutritional status**: - Starvation/malnutrition → decreased BMR (metabolic adaptation) - Overfeeding → increased BMR (diet-induced thermogenesis) **8. Pregnancy**: - BMR increases ~15-20% in 3rd trimester (fetal metabolic needs) **9. Cortisol and growth hormone**: - Generally increase metabolic rate and catabolism **10. Climate/Temperature**: - Cold climate → higher BMR (thermogenesis to maintain body temperature) - Tropical climates → ~10% lower BMR **11. Menstrual cycle**: - BMR slightly higher in luteal phase **12. Sleep**: - BMR decreases ~10-15% during sleep **13. Drugs**: - Caffeine, nicotine → slightly increase BMR --- ### Q20. Absorption in different parts of GIT. Types and mechanisms of absorption through biological membranes. #### Sites of Absorption Along the GIT | Segment | Substances Absorbed | |---------|-------------------| | Oral cavity | Some drugs (sublingual: nitroglycerin, some steroids) | | Esophagus | Minimal | | Stomach | Alcohol (~20%), some lipid-soluble drugs (aspirin), water (minimal) | | Duodenum | Iron (Fe2+), calcium, glucose, amino acids, fats, fat-soluble vitamins, folate, B1, B2, zinc, some drugs | | Jejunum | Main site: glucose, amino acids, fatty acids, cholesterol, most vitamins (except B12), water, electrolytes (major absorption) | | Ileum | Bile salts (terminal ileum, active), vitamin B12-IF complex (terminal ileum), water, electrolytes | | Large intestine | Water (1-2 L/day), Na+, Cl-, K+ secreted, some drugs (rectal), vitamin K (from bacteria), short-chain fatty acids (from bacterial fermentation) | | Rectum | Some drugs (suppositories), water | #### Types and Mechanisms of Absorption **1. Passive Diffusion (Simple Diffusion)**: - Movement down concentration/electrochemical gradient - No energy required, no carrier - Follows Fick's law: rate ∝ (concentration gradient × area × membrane permeability) - Examples: water, short-chain fatty acids, some drugs (aspirin), alcohol, O2, CO2 - More effective for: lipid-soluble, small, uncharged molecules **2. Facilitated Diffusion (Carrier-mediated, Passive)**: - Down concentration gradient; no energy; requires specific carrier protein (transporter/channel) - Shows saturation kinetics - Examples: - Fructose: GLUT5 transporter - Exit of glucose/galactose from enterocyte: GLUT2 - Amino acid transporters (some) **3. Active Transport (Primary Active Transport)**: - Against concentration/electrochemical gradient; requires ATP directly - Specific carrier proteins (ATPases) - Examples: - Na+/K+-ATPase: pumps Na+ out, K+ in; creates Na+ gradient used for secondary active transport - H+/K+-ATPase: parietal cells (HCl secretion) - Ca2+-ATPase: calcium absorption **4. Secondary Active Transport (Co-transport)**: - Uses energy indirectly (Na+ gradient created by Na+/K+-ATPase) - Symport: substance + Na+ transported in same direction - Examples: - **SGLT1**: Na+-glucose/galactose co-transporter (small intestine) - Na+-amino acid co-transporters (several types) - Na+-bile acid co-transporter (ileum) - NKCC2 (thick ascending limb of Henle) - Counter-transport (Antiport): substance transported against Na+ gradient - Na+/H+ exchanger (NHE3): Na+ in, H+ out (in PCT) **5. Osmosis**: - Water movement across semipermeable membrane from low to high solute concentration - Paracellular and transcellular routes - Through **aquaporins** (AQP3, AQP4, AQP7, AQP8 in gut) - Drives large water absorption following solute absorption **6. Endocytosis / Pinocytosis**: - Membrane engulfs substances in vesicles - **Receptor-mediated endocytosis**: IF-B12 complex (cubam receptor in ileum) - Neonates: maternal IgG transcytosis - Some intact proteins, antigens **7. Paracellular transport**: - Between cells through tight junctions - For ions, small molecules, water - Varies with tight junction permeability ("leaky" vs. "tight" epithelium) - Small intestine has relatively leaky junctions; colon has tight junctions --- ### Q21. Role of the liver in digestion. The liver is the largest internal organ and plays multiple roles in digestion and metabolism. #### 1. Bile Production and Secretion - Produces 600-1000 mL of bile/day - Bile salts: essential for fat emulsification and micelle formation - Bilirubin conjugation and excretion - Detergent action for lipid digestion and fat-soluble vitamin absorption - (see Q13 for full detail) #### 2. Processing of Absorbed Nutrients (Portal Blood) All products of digestion (except fats) enter portal blood and reach the liver first: - **Carbohydrates**: glucose → glycogen (glycogenesis) or FA (lipogenesis); regulates blood glucose - **Amino acids**: deamination, transamination, urea synthesis, plasma protein synthesis - **Short-chain fatty acids**: absorbed into portal blood, processed in liver - **Alcohol**: metabolized (alcohol dehydrogenase → acetaldehyde) #### 3. Protein Metabolism - Synthesis of plasma proteins: albumin (oncotic pressure), clotting factors (I, II, V, VII, IX, X), transport proteins (transferrin, ceruloplasmin, haptoglobin), complement - Deamination and transamination of amino acids - **Urea synthesis**: detoxifies NH3 from amino acid catabolism - Gluconeogenesis from amino acids #### 4. Lipid Metabolism - Synthesizes and exports **VLDL** (endogenous lipid transport) - Synthesizes cholesterol (HMG-CoA reductase) - Converts cholesterol → bile acids - Fatty acid oxidation (beta-oxidation) and ketone body synthesis - Lipid storage (steatosis if overwhelmed) - Synthesis of lipoprotein enzymes (LCAT, hepatic lipase) #### 5. Carbohydrate Metabolism - **Glycogenesis** (fed state): stores 100g glycogen - **Glycogenolysis** (fasting): releases glucose - **Gluconeogenesis**: maintains blood glucose during fasting - **Galactose and fructose**: converted to glucose - **Blood glucose regulation**: key organ maintaining euglycemia #### 6. Detoxification and Drug Metabolism - Cytochrome P450 enzymes (CYP system): oxidize drugs, toxins → water-soluble metabolites - Phase I (oxidation, reduction, hydrolysis) and Phase II (conjugation: glucuronidation, sulfation) - Ammonia → urea - Inactivation of hormones (steroids, insulin, glucagon) - Kupffer cells (resident macrophages): phagocytose bacteria from portal blood #### 7. Storage Functions - Glycogen: 100g - Fat-soluble vitamins: A (1-2 year supply), D, E, K - Vitamin B12: 3-5 year supply - Iron: stored as ferritin and hemosiderin - Copper: excess stored and excreted in bile #### 8. Immunological Function - Kupffer cells: phagocytosis of bacteria, endotoxins, antigens from portal blood - IgA secretion into bile - Complement synthesis --- ### Q22. Describe functions of GIT hormones. | Hormone | Source | Main Stimuli | Key Functions | |---------|--------|-------------|--------------| | **Gastrin** | G-cells (antrum, duodenum) | Protein/AA in stomach, vagal (ACh), stomach distension | Stimulates gastric HCl and pepsinogen secretion; trophic to GI mucosa; stimulates gastric motility | | **Secretin** | S-cells (duodenum) | Acid (H+) in duodenum (pH <4.5); fat, protein (weak) | Stimulates pancreatic HCO3- and water secretion; stimulates biliary HCO3-; inhibits gastric acid secretion and gastric emptying; "physiological antacid" | | **Cholecystokinin (CCK)** | I-cells (duodenum, jejunum) | Fat and protein (AA) in duodenum | Stimulates pancreatic enzyme secretion; gallbladder contraction; relaxes sphincter of Oddi; inhibits gastric emptying; satiety signal | | **GIP (Gastric Inhibitory Peptide / Glucose-dependent Insulinotropic Peptide)** | K-cells (duodenum, jejunum) | Glucose, fat, protein in duodenum | Inhibits gastric acid secretion; stimulates insulin release from beta-cells (incretin effect); inhibits gastric motility | | **Motilin** | M-cells (duodenum, jejunum) | Alkaline duodenal pH; fasting state | Initiates Migrating Motor Complex (MMC) in small intestine (housekeeping function); prokinetic | | **VIP (Vasoactive Intestinal Peptide)** | Neurons throughout GIT | Neural stimulation | Relaxes smooth muscle (lower esophageal sphincter, stomach); stimulates intestinal secretion; vasodilation; inhibits gastric acid | | **Somatostatin** | D-cells (stomach, duodenum, pancreatic islets) | Acid, fat, protein, CCK, secretin | Inhibits: gastric acid, gastrin, insulin, glucagon, pancreatic enzymes; reduces splanchnic blood flow | | **Ghrelin** | P/D1 cells (fundus, body of stomach) | Fasting, hypoglycemia | Potent hunger/appetite stimulator; stimulates GH secretion; stimulates gastric motility; opposite of satiety hormones | | **Glucagon-like peptide-1 (GLP-1)** | L-cells (ileum, colon) | Fat, carbohydrate, protein | Incretin: stimulates insulin, inhibits glucagon; slows gastric emptying; suppresses appetite (satiety) | | **Peptide YY (PYY)** | L-cells (ileum, colon) | Fat, protein | "Ileal brake": inhibits gastric emptying and acid secretion; reduces appetite | | **Neurotensin** | N-cells (ileum) | Fat | Inhibits gastric acid and motility; stimulates pancreatic secretion | --- ### Q23. Describe the walls of the gastrointestinal tract and their functions. The GIT wall has a consistent 4-layer structure (from lumen outward): #### Layer 1: Mucosa Three sub-layers: - **Epithelium** (innermost): varies by region: - Esophagus: stratified squamous (abrasion resistance) - Stomach: simple columnar (secretion); gastric pits with glands - Small intestine: simple columnar with villi and microvilli; absorptive cells (enterocytes), goblet cells, enteroendocrine cells, Paneth cells - Large intestine: simple columnar without villi; many goblet cells; absorption of water/electrolytes - **Lamina propria**: loose CT; lymphocytes (MALT/GALT), capillaries, lacteals, nerve fibers; IgA secretion - **Muscularis mucosae**: thin smooth muscle layer; creates folds; maintains contact between epithelium and contents **Functions of mucosa**: secretion of digestive juices and hormones; absorption of nutrients; immunological barrier; protection against pathogens #### Layer 2: Submucosa - Dense irregular connective tissue - Large blood vessels (submucous plexus of Meissner) - **Meissner's (submucosal) plexus**: ENS ganglia; controls glandular secretion and local blood flow - Peyer's patches (in ileum submucosa): aggregated lymphoid follicles; immune surveillance - Brunner's glands (duodenum only): in submucosa; secrete alkaline mucus **Functions**: structural support; blood/lymph supply; secretomotor control via Meissner's plexus; immune surveillance #### Layer 3: Muscularis Externa Two smooth muscle sub-layers: - **Circular muscle layer** (inner): fibers run circumferentially; when contracts → narrows lumen; responsible for segmentation contractions - **Myenteric (Auerbach's) plexus**: between the two muscle layers; ENS ganglia; controls motility - **Longitudinal muscle layer** (outer): fibers run along length; when contracts → shortens gut; propulsive peristalsis - **Exception**: stomach has 3 layers (+ oblique inner layer); rectum has modifications (tenia coli in colon) **Functions of muscularis externa**: - **Peristalsis**: propels contents distally; wave of relaxation then contraction - **Segmentation**: mixing contractions; non-propulsive; in small intestine - **Tonic contractions**: sphincter maintenance (LES, pyloric, ileocecal, internal anal sphincter) - **Haustrations**: in colon; slow movement #### Layer 4: Serosa (or Adventitia) - **Serosa**: thin layer of visceral peritoneum (simple squamous epithelium + thin CT); covers intraperitoneal organs (stomach, small intestine, transverse colon) - **Adventitia**: fibrous CT without peritoneum; covers retroperitoneal organs (duodenum, ascending/descending colon, esophagus) - Contains blood vessels, lymphatics, nerve fibers (sympathetic from celiac/mesenteric ganglia) **Functions**: reduces friction, anchors organs, conduit for vessels and nerves #### Enteric Nervous System (ENS) - "Mini Brain" - **Meissner's plexus** (submucosa): controls secretion, blood flow - **Auerbach's (myenteric) plexus** (between muscle layers): controls motility - Contains ~100 million neurons; functions independently of CNS - Intrinsic reflexes: peristaltic reflex (ascending excitation + descending inhibition)