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MBBS 1st Year Physiology Viva - Gastric & Pancreatic Physiology

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1. Daily Volume of Gastric Secretion

• Ganong's Review of Medical Physiology, 26th Edition

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2. pH of Gastric Juice

• Resting/fasting state: pH ~3.0 (Table 25-1, Ganong's)
• During maximal stimulation: pH can fall to 0.8–1.0 (virtually pure HCl)
• After buffering by a meal: pH rises transiently to 4–6

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3. Why Doesn't the Stomach Digest Itself?

• Mucus + bicarbonate create a protective gel layer that maintains a pH gradient (luminal pH 1–2 vs. epithelial surface pH ~7)
• Tight junctions between epithelial cells prevent back-diffusion of acid
• Rapid cell renewal replaces damaged cells every 2–3 days
• Rich blood supply washes away any acid that penetrates

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4. Protective Mechanisms of Gastric Mucosa

• Ganong's, p.461

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5. What is Alkaline Tide?

CO2 + H2O → H2CO3 → H+ + HCO3-

• H+ is secreted into the gastric lumen via the H+/K+-ATPase
• HCO3- is exported into the bloodstream via a Cl-/HCO3- exchanger at the basolateral membrane

• Ganong's, Figure 25-10; Yamada's Gastroenterology

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6. Role of Carbonic Anhydrase

H2O + CO2 ⇌ H2CO3 ⇌ H+ + HCO3-

• Provides a continuous supply of H+ ions that are pumped into the gastric lumen by H+/K+-ATPase
• Provides HCO3- ions that are exchanged for Cl- at the basolateral membrane (Cl- is then secreted into the lumen alongside H+ to form HCl)
• Without CA, the rate of H+ generation would be too slow to sustain rapid acid secretion

• Yamada's Gastroenterology; Ganong's, p.462

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7. Why Are Parietal Cells Rich in Mitochondria?

• The H+/K+-ATPase (proton pump) pumps H+ against an enormous concentration gradient - over 1,000,000-fold (plasma H+ ~40 nEq/L vs. gastric H+ ~150 mEq/L)
• This is a highly energy-demanding process requiring massive amounts of ATP
• Mitochondria supply ATP via oxidative phosphorylation to power this continuous active transport
• Parietal cells also have extensive tubulovesicular membranes and canaliculi that require energy for trafficking

• Ganong's, p.461 - "The cells are packed with mitochondria that supply energy to drive the apical H+K+-ATPase"

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8. Cephalic Phase Mechanism

1. Higher centres (cerebral cortex, hypothalamus) → dorsal vagal complex in the medulla
2. Vagal efferents release GRP (gastrin-releasing peptide) → stimulates antral G cells → gastrin release
3. Vagal efferents also release acetylcholine (ACh) directly → stimulates parietal cells and ECL cells
4. ACh on ECL cells → histamine release → acts on parietal cells via H2 receptors

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9. What Inhibits Gastrin Release?

• Ganong's, p.462 - Figure 25-7

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10. Why is Histamine Essential for Maximal Acid Secretion?

• Gastrin and ACh stimulate ECL cells to release histamine in addition to acting directly on parietal cells
• Histamine acts via H2 receptors → activates adenylyl cyclase → ↑cAMP → activates protein kinase A → stimulates H+/K+-ATPase
• Gastrin and ACh use the Ca2+/DAG pathway

• Ganong's, p.461–462

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11. Potentiation Between Gastrin, Histamine and Acetylcholine

• When the cAMP pathway (histamine) and Ca2+ pathway (gastrin/ACh) are activated simultaneously, they converge on the proton pump with supra-additive activation
• Cross-talk between cAMP and Ca2+ pathways amplifies the final activation of H+/K+-ATPase
• This explains why blocking any single pathway (especially histamine/H2) disproportionately reduces the overall response

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12. Optimum pH for Pepsin

• Optimum pH: 1.8–2.0 (some sources say 1.6–3.2)
• Pepsinogen is secreted by chief cells and is auto-activated at pH < 5.0 by cleavage of the inhibitory propeptide
• At pH < 2, pepsin is most active in cleaving peptide bonds (especially adjacent to aromatic/large aliphatic amino acids)
• Above pH 4, pepsin activity drops sharply
• Above pH 7, pepsin is irreversibly denatured - this is why pepsin causes no harm in the small intestine, where pancreatic HCO3- rapidly raises pH above 7

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13. Why Does Gastrectomy Cause Megaloblastic Anemia?

1. IF is produced exclusively by parietal cells of the gastric fundus
2. Gastrectomy removes the parietal cell mass → no IF production
3. IF is essential for vitamin B12 (cobalamin) absorption in the terminal ileum (IF-B12 complex binds to cubulin receptors)
4. Without IF → B12 is not absorbed → B12 deficiency
5. B12 is needed for DNA synthesis (specifically for conversion of methylmalonyl-CoA and homocysteine); deficiency impairs nuclear maturation of RBC precursors
6. Result: megaloblastic anemia (large, immature, hypersegmented neutrophils)

• Sabiston Textbook of Surgery; Guyton & Hall; Washington Manual

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14. Difference Between Pernicious Anemia and Nutritional B12 Deficiency

• Robbins Pathologic Basis of Disease; Cellular and Molecular Immunology

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15. Types of Gastric Movements

Receptive Relaxation

• When food is swallowed, the fundus and upper body relax even before food arrives
• Mediated by vagovagal reflex (triggered by pharyngeal/esophageal distension) and VIP/NO as neurotransmitters
• Allows stomach to accommodate a meal (~1.5 L) with minimal rise in intragastric pressure
• Also called adaptive relaxation

Gastric Accommodation (Tonic Relaxation)

• After food enters, the stomach wall continues to relax as volume increases (vago-vagal reflex + intrinsic stretch reflexes)
• Mediated by vagovagal reflex with VIP/NO as the inhibitory neurotransmitter
• Allows the stomach to store 1.0–1.5 L at nearly constant pressure
• Distinguished from receptive relaxation in that it responds to actual distension of the stomach wall

Mixing Waves (Churning Movements)

• Small contractions begin in the corpus, pass toward the antrum
• Mix solid food with gastric juice → forms chyme
• Not strong enough to expel contents through pylorus initially
• 3–4 waves per minute, controlled by the gastric BER (basic electrical rhythm) set by pacemaker cells in the corpus

Peristaltic Waves

• Stronger waves originating in the mid-body (controlled by BER pacemaker cells)
• Progress toward the pylorus at 3–4 per minute (the "antral systole")
• Each wave lasts up to 10 seconds
• Most of the antral content is retropelled (squirted back) because the pylorus closes as the wave arrives

Retropulsion

• As a peristaltic wave arrives at the antrum, the pylorus contracts before the wave reaches it
• Solid food cannot exit and is squirted back into the stomach body
• This to-and-fro action is the primary mechanism of mechanical grinding of solid food into particles < 1–2 mm (necessary for pyloric passage)

Peristaltic Waves vs Mixing Waves

• Mixing waves: weaker, earlier in digestion
• Peristaltic waves (antral systole): stronger, responsible for grinding and emptying

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16. Gastric Emptying

• Liquids empty faster (within 20–30 min for pure liquids)
• Solids are first ground to particles < 1–2 mm; emptying begins 20–30 min after a meal
• Rate is regulated by the antro-pyloro-duodenal complex acting as a functional unit
• The antrum contracts → pylorus contracts sequentially → duodenum contracts → only semi-liquid passes

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17. Factors Affecting Gastric Emptying

• Large meal volume (distension → stretch receptors → ↑peristalsis)
• Gastrin (mild stimulatory effect)
• Motilin (in between meals, drives MMC - migrating motor complex)

• Fat in duodenum (strongest inhibitor - see Q18)
• Acid (pH < 3.5 in duodenum) → secretin release → inhibits gastric motility
• Hyperosmolar solutions in duodenum
• Protein breakdown products in duodenum → CCK release
• Emotional stress/pain → sympathetic activation
• Lying down (vs. upright position accelerates)
• Diabetes mellitus (autonomic neuropathy → gastroparesis)

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18. Why Do Fats Delay Gastric Emptying?

1. Fat enters the duodenum → stimulates I cells in the duodenal/jejunal mucosa → releases CCK (cholecystokinin)
2. CCK acts on the pyloric sphincter (causes contraction) and inhibits gastric peristalsis
3. CCK also stimulates pancreatic enzyme secretion and gallbladder contraction to prepare for fat digestion
4. Peptide YY (released by ileal L cells in response to fat) also inhibits gastric emptying - the "ileal brake"
5. Neural mechanism: Fatty acids in duodenum activate local nerve plexuses → enterogastric inhibitory reflex → ↓antral contractions
6. GIP (glucose-dependent insulinotropic peptide) also plays a minor inhibitory role

• Ganong's, p.503 - "Fats, carbohydrates, and acid in the duodenum inhibit gastric acid and pepsin secretion and gastric motility"

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19. Zollinger-Ellison Syndrome

1. Fulminating peptic ulcers (often multiple, atypical sites - 2nd/3rd part of duodenum, jejunum)
2. Extreme gastric acid hypersecretion
3. Non-beta islet cell tumor of pancreas (or duodenum)

• Gastrinoma secretes gastrin autonomously (not suppressed by acid)
• ↑Gastrin → ↑parietal cell mass (hypertrophy) + ↑maximal acid output
• Acid overwhelms duodenal and jejunal buffering → ulcers even in jejunum
• Acid also inactivates pancreatic lipase in the duodenum → steatorrhea
• ↑Gastrin also inhibits IF absorption → can cause B12 deficiency

• Bailey and Love's Surgery; Goldman-Cecil Medicine

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20. Dumping Syndrome

• Rapid entry of hyperosmolar food into the small intestine
• Osmotic shift of water from plasma into gut lumen → hypovolemia + hypotension
• Rapid distension activates autonomic reflexes → tachycardia, flushing, diarrhea, nausea
• GI hormones (serotonin, VIP) released in bulk

• Rapid glucose absorption → hyperinsulinemia (reactive) → hypoglycemia ~2 hours post-meal
• Weakness, sweating, confusion (hypoglycemic symptoms)

• Ganong's Clinical Box 27-2, p.503

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21. Why Does Stress Increase Ulcer Risk?

1. Sympathetic activation → splanchnic vasoconstriction → reduced mucosal blood flow → ischemia of gastric mucosa → impaired removal of back-diffused H+ + reduced HCO3- delivery
2. Glucocorticoids released during stress → suppress prostaglandin synthesis → ↓mucus and HCO3- secretion → breaks mucosal barrier
3. Adrenal medullary catecholamines → also reduce mucosal perfusion
4. Increased vagal tone in some stress states → increased acid secretion
5. In critically ill patients (burns, surgery, head injury): "stress ulcers" develop rapidly; head injury specifically causes Cushing's ulcers (vagal hyperstimulation → massive acid secretion)

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22. Why is Pancreatic Juice Isotonic?

• The ductal cells secrete a HCO3--rich fluid where the sum of HCO3- + Cl- remains constant (reciprocal exchange via CFTR and Cl-/HCO3- exchanger) - as flow rate increases, HCO3- rises and Cl- falls, but total anion concentration stays near isotonic
• Na+ and K+ concentrations mirror plasma
• Water follows osmotically through aquaporins to maintain isotonicity
• This protects the duodenum - hypertonic secretion would draw water osmotically; isotonic fluid maintains mucosal integrity

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23. Which Enzymes Digest Nucleic Acids?

• DNase cleaves DNA strands
• RNase cleaves RNA strands
• Both are secreted as active enzymes (not zymogens)
• Final digestion to nucleosides/nucleotides by intestinal brush border nucleotidases and nucleosidases

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24. Which Enzyme is Absent in Pancreatic Juice?

• A brush border enzyme secreted by duodenal mucosa (not the pancreas)
• Its sole function is to activate trypsinogen → trypsin by cleaving the N-terminal hexapeptide
• This is the essential initiating step of the entire pancreatic zymogen cascade

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25. Why Doesn't the Pancreas Digest Itself (Normally)?

1. Zymogens: Proteases are synthesised and stored as inactive precursors (trypsinogen, chymotrypsinogen, proelastase, etc.)
2. Trypsin inhibitor (PSTI/SPINK1): Pancreatic secretory trypsin inhibitor is co-secreted in the juice and immediately inactivates any trypsin that forms prematurely
3. Enterokinase activation only in duodenum: Trypsinogen is activated only after reaching the duodenum by brush-border enterokinase - not in the pancreatic duct
4. Sequestration: Zymogen granules are membrane-bound and segregated from lysosomal enzymes (which could theoretically activate them)
5. Alkaline pH of pancreatic juice (pH ~8) does not favor enzyme auto-activation

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26. Role of CFTR

• Cl- exits the cell via CFTR into the duct lumen
• This Cl- is then exchanged for HCO3- via an apical Cl-/HCO3- exchanger (SLC26A6)
• Result: HCO3- secretion into the pancreatic duct lumen (essential for neutralising gastric acid in duodenum)

• Regulates other ion channels (K+ channels, ENaC)
• Maintains hydration of secretions in the pancreas, lung, sweat glands, intestine

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27. Why Does Cystic Fibrosis Affect the Pancreas?

1. Defective Cl- secretion → defective HCO3- secretion (since Cl-/HCO3- exchange requires luminal Cl-)
2. Pancreatic juice becomes viscous and acidic (unable to alkalinise) → protein plugging of small pancreatic ducts
3. Plugs obstruct the ducts → back-pressure → acinar cell destruction → fibrosis and cysts ("cystic fibrosis of the pancreas")
4. Loss of acinar cells → exocrine pancreatic insufficiency → malabsorption, steatorrhea
5. Eventually, islet cells are also destroyed → CF-related diabetes mellitus

• Yamada's Gastroenterology; Robbins Pathologic Basis of Disease

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28. Role of Colipase

• Bile salts are excellent emulsifiers but they also coat the surface of fat droplets, physically displacing pancreatic lipase from the lipid-water interface
• Colipase acts as an anchor - it binds simultaneously to the bile salt-coated lipid surface AND to pancreatic lipase
• This restores lipase activity at the lipid surface, allowing it to hydrolyse triglycerides to 2-monoglycerides + free fatty acids

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29. Steatorrhea

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30. Why Can the Pancreas Digest Itself (in Pancreatitis) But the Stomach Doesn't Digest Itself?

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31. Why is Bicarbonate Secretion Defective in Cystic Fibrosis?

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32. Enterohepatic Coordination During Digestion

1. Liver synthesises primary bile acids (cholic, chenodeoxycholic) → conjugated to glycine/taurine → secreted in bile (~500 mL/day)
2. Bile stored in gallbladder; CCK (released by fat/protein in duodenum) contracts the gallbladder → bile enters duodenum
3. Bile acids emulsify fat → micelle formation → fat absorption
4. ~95% of bile acids are actively reabsorbed in the terminal ileum (sodium-dependent bile acid transporter, IBAT)
5. Portal blood returns bile acids to liver → re-conjugated and re-secreted (5–6 cycles per day)
6. Only ~5% lost in feces (replaced by new hepatic synthesis)

• Secretin (from S cells when acid enters duodenum) → stimulates liver + pancreas to secrete HCO3--rich fluid (neutralises gastric acid)
• CCK (from I cells when fat/protein enters) → contracts gallbladder + stimulates pancreatic enzyme secretion (coordinates bile + enzyme delivery)
• Gastric phase acid output is coordinated with delayed pancreatic and biliary secretion to arrive simultaneously in the duodenum

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33. Why is Trypsin the "Master Enzyme" of the Pancreas?

Enterokinase (duodenal brush border)
         ↓
Trypsinogen → TRYPSIN
         ↓ (auto-catalytic)
Trypsin activates:
  - Chymotrypsinogen → Chymotrypsin
  - Proelastase → Elastase
  - Procarboxypeptidases → Carboxypeptidases A & B
  - Pro-phospholipase A2 → Phospholipase A2
  - Pro-colipase → Colipase

• Enterokinase deficiency → complete failure of protein + fat digestion
• In pancreatitis, premature trypsin activation initiates the entire autodigestive cascade

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34. Why is Gastric Emptying Delayed in Diabetes?

1. Autonomic neuropathy (most common mechanism): Chronic hyperglycaemia damages the vagus nerve → reduced cholinergic drive to the gastric smooth muscle and enteric neurons → decreased peristalsis and impaired receptive relaxation
2. Loss of interstitial cells of Cajal (ICC): The pacemaker cells of the gut are damaged by hyperglycaemia → disrupted gastric BER → impaired coordination of mixing and peristaltic waves
3. Acute hyperglycaemia (independent of neuropathy): Blood glucose > 10 mmol/L directly impairs gastric motor function even in non-diabetics
4. Reduced motilin sensitivity and impaired MMC (migrating motor complex) between meals

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35. Receptive Relaxation (detailed)

• Definition: Active relaxation of the fundus and proximal body of the stomach in anticipation of and upon swallowing
• Mediator: Vagovagal reflex; efferent limb releases VIP (vasoactive intestinal peptide) and NO (nitric oxide) which are inhibitory neurotransmitters causing smooth muscle relaxation
• Trigger: Pharyngeal/esophageal distension activates afferents → NTS (nucleus tractus solitarius) in medulla → vagal efferents
• Effect: Stomach volume can increase from ~50 mL (empty) to 1.0–1.5 L with only a small rise in intragastric pressure
• Clinical relevance: Loss of receptive relaxation (after proximal gastrectomy or vagotomy) → rapid rise in intragastric pressure with small meals → early satiety and dumping

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36. Why Does Milk Stay Longer in the Stomach?

1. Fat content: Milk contains ~3.5% fat → fat in the duodenum triggers CCK release → inhibits gastric emptying (strongest inhibitor of all dietary components)
2. Protein content: Casein (main milk protein) is coagulated by acid into a semi-solid curd → solid particles require longer grinding/liquefaction before passing pylorus (must be reduced to < 1–2 mm)
3. Buffering effect: Milk buffers gastric acid initially → raises pH → reduces acid feedback inhibition → initially more gastrin release, but the fat/protein in duodenum compensates with strong inhibition
4. High calcium content: Calcium stimulates gastrin release slightly, but more importantly slows gastric motility via duodenal mechanisms

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37. Why Does Fear Reduce Gastric Motility?

1. Sympathetic activation → splanchnic vasoconstriction → reduced gastric mucosal blood flow → reduced parietal cell activity
2. Norepinephrine acts on α2 and β2 adrenergic receptors on enteric neurons and smooth muscle → inhibits gastric peristalsis and reduces motility
3. Sympathetic activation inhibits the enteric nervous system by pre-synaptic inhibition of acetylcholine release
4. CRH (corticotropin-releasing hormone) released during stress/fear directly inhibits gastric motility via CRH receptors in the enteric nervous system
5. Blood flow is redirected to skeletal muscle, heart, and brain - digestive functions are suppressed as "non-essential" during an emergency

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38. Why Are Gastric Epithelial Cells Replaced Every 2–3 Days?

1. Continuous acid and pepsin damage: Despite the mucus layer, some cells are inevitably damaged and must be replaced constantly
2. High turnover protects mucosal integrity: Stem cells in the gastric pit base continuously divide → daughter cells migrate up the gland and onto the surface → old cells are shed into the lumen
3. Rapid repair after focal injury: If the mucus layer is breached (by NSAIDs, H. pylori, alcohol), rapid cell restitution (surface cells migrate to cover the defect within hours) and renewal (new cells arrive in days) restores integrity
4. Prostaglandins and EGF (epidermal growth factor) drive this rapid proliferation

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